VIEWPOINT

Medicinal : moving the debate forward Giles Newton-Howes, Sam McBride

ABSTRACT There has been increased interest in cannabis as a medicine both nationally and internationally. Internationally, cannabis is accepted as a medication for a variety of purposes in a variety of legal guises and this, associated with anecdotes of the utility of cannabis as medication has led for calls for it to be ‘medicalised’ in . This viewpoint discusses the issues associated with this approach to accessing cannabis and some of the di iculties that may be associated with it. It is important doctors are at the forefront of the debate surrounding medicalised cannabis. Recommendations as to the ongoing debate are o ered.

Recent debate on medicinal cannabis was included in the US Pharmacopoeia from has occurred with doctors, those expected 1850 through to 1937.5 Prohibition in the to prescribe, largely silent. The use of fi rst half of the twentieth century refl ected medicinal cannabis in some overseas less the harms of cannabis than the socio-po- jurisdictions has seen the introduction of litical prejudices of the day. One profound a product as a medicine outside of usual consequence of prohibition was to confound criteria and driven by legislation and research into the medical potential of popular demand rather than strong evidence cannabis, a situation that is only just being for effi cacy.1 The lines between recreational addressed in some jurisdictions today. use and that of cannabis for medicinal Levels of cannabis restriction vary from reasons are blurred. These factors have the minimal restraints as found in countries potential for prescribers to become either such as the Netherlands to a strict prohi- the gatekeepers for recreational use or to bitionist approach such as occurs at a US prescribe in situations in which diagnostic Federal level,6 New Zealand being more categories become meaningless. The medical closely aligned to the latter. Despite the profession needs to not only contribute criminal liability associated with cannabis, to but also lead any debate on medicinal its use in New Zealand is widespread. The cannabis. This viewpoint aims to encourage reported annual prevalence of use of 10.2% this debate by outlining the context of is high by international standards and medicinal cannabis, surrounding issues and cannabis remains the most widely used illicit providing a framework for consideration of drug in New Zealand.7 The high levels of medicinal cannabis in New Zealand. cannabis use suggest a degree of acceptance of use within New Zealand and imply a ready The context population of people who may wish to access Cannabis is one of the fi rst recorded cannabis should it be available medically. medications with prescriptions for its use Greater acceptance of cannabis has dating back to 1500BC.2 The introduction of contributed to the increasing advocacy for cannabis into Western medicine occurred medicinal use of cannabis. Medical regimes via physicians exposed to its use in India are more likely to be introduced where use with reported use as an analgesic, appetite in general is higher and medicinal cannabis stimulant, anti-emetic, muscle relaxant and has largely been a consumer-led initiative.8,9 anticonvulsant.3 Use was not just restricted This dynamic is refl ected in New Zealand. to the most impoverished as, potentially, Public fi gures have spoken about their use an escape from the hardship of life. Dr in New Zealand typically in the context J Reynolds, Queen Victoria’s personal of serious illness. The New Zealand Drug physician, described 30 years of use in a Foundation and the New Zealand Law range of conditions.4 In the US, cannabis Commission have argued for increased

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access to medicinal cannabis.10 Advocacy and neocortex in addition to peripheral groups such as Green Cross, United in nerve terminals. CB2 receptors are found Compassion and NORML campaign largely within peripheral areas, including vigorously. Industry is also calling for cells of the immune system. The endocanna- development of a legal market extolling the binoid system is believed to be involved in potential economic benefi ts. a large range of bodily functions, including This local support occurs against a analgesia, vomiting, immune system regu- backdrop of increasing international use of lation, appetite, cognitive processes and cannabis in health settings, though models motor control, providing biological plausi- of use vary widely from use of bility to the use of cannabis as a medicine 15 medications, removal of criminal sanctions and potential targets. for patients using cannabis for medical The argument for the use of purposes to access to ‘medical grade’ herbal cannabis as a medicine cannabis. Use of herbal cannabis is autho- Despite the hiatus in the investigation of rised or legislated for in some jurisdictions cannabis, largely related to prohibition, suffi - in the US, Netherlands, Canada, Israel, cient data has been accumulated to allow Finland, Denmark, Uruguay and the Czech formal review. A systematic review into the 11 republic. Australia has recently passed use of cannabis for treatment of chronic amendments into their Narcotics Drugs Act non-cancer pain concluded that there was 1967 allowing cultivation of cannabis for evidence for moderate effi cacy of cannabi- medical and scientifi c purposes, and paving noids in neurological pain with preliminary the way for trials into and the potential use evidence for fi bromyalgia and rheumatoid 12 of herbal cannabis for medical purposes. arthritis.16 A recent systematic review What is cannabis? and meta-analysis concluded that there The leaves and fl owers of cannabis was moderate-quality evidence to support contain over 400 distinct compounds and the use of for treatment of contain at least 100 different phytocanna- chronic pain and spasticity with low-quality binoid compounds (cannabinoids occurring evidence to support cannabinoids being naturally within the cannabis plant). The useful in nausea and vomiting due to chemo- two major constituents are ∆9 tetrahydro- therapy, weight gain in HIV infection, sleep (∆9THC or THC) and disorders and Tourette syndrome.17 (CBD). THC is responsible for most of Other evidence for the utility of cannabis the psychoactive properties of cannabis, as a medicine is limited. Trials of other including effects sought by recreational neurological conditions including: levodopa users. Cannabidiol has anxiolytic and induced dyskinesia in patients with Parkin- anti-psychotic properties and may moderate son’s disease, non-chorea-related symptoms some of the psychoactive effects of THC.13 of Huntington’s disease, Tourette syndrome, Emphasis has been placed upon isolating cervical dystonia and epilepsy have individual components of cannabis to use occurred.18 Despite enthusiasm for cannabi- as therapeutic compounds, such as the noids in epilepsy, a 2012 Cochrane Review use of cannabidiol for childhood epilepsy. concluded “No reliable conclusions can be However, the approach has had limited drawn at present regarding the effi cacy of success and it is postulated that the effi cacy cannabinoids as a treatment for epilepsy” of cannabis-based medications relies upon with similar results published by expert synergy between the compounds or the systematic reviews. 19,20 “entourage effect”.14 Outside of this limited range of conditions Cannabinoids interact with the endocan- there is little current evidence to suggest that nabinoid system, which is made up of the cannabis has any medical role. However, cannabinoid receptors (CB1 and CB2) and there is increased adoption of medicinal endogenous cannabinoids of which anan- cannabis internationally for conditions that damide and 2-arachidonoyl glycerol have include hepatitis C, Parkinson’s disease, been isolated.15 CB1 is the most common PTSD, glaucoma, Crohn’s disease and Alzhei- G-protein-coupled receptor in the brain. It mer’s disease. This slippage into other is widely distributed with high levels in the diagnostic categories is, unfortunately, hippocampus, cerebellum, basal ganglia not uncommon in medicine but does raise

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concerns as to who cannabis would be (Marinol®), marketed as treatment for prescribed for. The introduction of cannabis nausea/vomiting associated with chemo- by accord, rather than evidence, has led therapy and acquired immune defi ciency to the invidious situation of doctors being syndrome (AIDS) associated anorexia asked “to authorise our patients’ access to and weight loss. (Cesamet®) a product with little evidence to support is marketed for nausea and vomiting its use”.21 This creates ethical and practical associated with chemotherapy. Both problems for physician who may be asked products contain synthetic THC alone. for an intervention with little or no evidence The application criteria for access to over a treatment that is well evidenced. non-pharmaceutical grade products are more Cannabis and cannabinoids: stringent including restriction of use to a medication or flower? severe or life threatening condition, evidence Complicating any debate about medicinal that conventional products have been trialed cannabis is that it may refer to herbal without adequately controlling symptoms, cannabis or standardised cannabis extracts that the risk benefi t analysis of medications and used in regu- has been adequately considered by a qual- lated doses. ifi ed clinical specialist, application to be made by appropriate specialist or chief medical The Ministry of Health (MOH) allows offi cer of a district health board, provision potential access to pharmaceutical grade of a certifi cate of analysis and informed products that have consent for distribution consent from either parent or guardian for in New Zealand, pharmaceutical grade minors. This allows the potential to access products that do not have consent for cannabis-based products for compassionate distribution in New Zealand and non-phar- purposes in conditions such as terminal maceutical grade products. illness where conventional products have Only one pharmaceutical grade product, failed to control symptoms or forms of Naboximols (marketed as Sativex®), an childhood epilepsy such as Dravet syndrome. extract of cannabis, is licensed for use in However, guidance for use for these New Zealand. It is approved by Medsafe products is lacking with no clear pathway as for add-on treatment for symptom to how patients or practitioners may access improvement in patients with moderate to appropriate information. Given the public severe spasticity due to Multiple Sclerosis interest in medicinal cannabis it is inevitable where response to anti-spasticity medication that doctors will be asked about products has not occurred and who respond to initial and at present most are operating in a trials of therapy. Ministerial approval may vacuum. There is an urgent need for doctors also be made for non-approved authori- to take a lead in determining what products sations such as cachexia, neuropathic and may be appropriate and both monitoring and chronic pain. Unlike other drugs whose disseminating response to their use. Neurolo- access is restricted, Ministerial approval is gists, palliative care and pain specialists have required for use due to concern about risks a particular role in this regard. of diversion and dependence. The utility of this is questionable considering the expense A case for herbal cannabis? associated with Naboximols compared to Importantly, patients prefer herbal illicit cannabis, making diversion highly cannabis.22 Herbal preparations are vari- unlikely. The level of scrutiny is also ously available as standardised cigarettes, inconsistent with other drugs such as meth- loose herb, food and drinks. Unsurprisingly adone or methylphenidate, where ‘home however, the bulk of herbal cannabis use production’ is virtually impossible and the is smoked, the form in which cannabis is expense is low (as these drugs are funded), typically used recreationally.22 Compared to making diversion considerably more likely. oral use, smoking cannabis results in rapid This appears to be a confl ation of the illegal uptake and avoids fi rst pass metabolism status of recreational cannabis and the use with resulting faster onset of action, not to of cannabinoids as pharmacotherapy. mention the signifi cant health hazards asso- ciated with smoking. Preference for herbal Synthetic preparations of THC available cannabis may also refl ect the unantagonised for medicinal use, though not licensed THC in synthetic compounds. within New Zealand, include Drobinol

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Dosage is also problematic, in contrast educational outcomes in a dose-dependent to some prescribing practices in which fashion.26, 27 Recent use of cannabis is medicines are provided in regulated doses, associated with impairment of executive instructions to patients are essentially to function including memory, and heavy use smoke to effect.21 This may be because the may be associated with defi cits in decision amount of psychoactive ingredients in making and concept formation that may not botanical cannabis can vary and be further resolve with abstinence.28 While cannabis altered by mode of preparation and method has been associated with increased rates of smoking. Although ‘use to effect’ regimes of motor vehicle accidents, early evidence may exist for the short term control of pain from Colorado where cannabis is legal has (eg with nitrous oxide or methoxyfl urane), not substantiated concerns.29 Use disorders they are rare for chronic conditions and are also a signifi cant consideration. New non-existent where the ‘medication’ is Zealand surveys suggest that there is a 1.4% smoked and the dose is not known to the prevalence of abuse and dependence related prescriber. This is further complicated by to illicit use of cannabis; this is of note given the lipophilic properties of cannabinoids and that many of the indications for which second order kinetics of metabolism, leading medicinal cannabis is suggested are chronic to prolonged release from fat in chronic users. conditions for which on-going medication is 30 Prescribing considerations likely to be required. As with any medication, for cannabis to be The implications of such fi ndings for considered as a pharmacotherapy requires widespread use of medicinal cannabis are conformity with other regulated medica- complex and need to be weighed against tions. This is the process undertaken for the the side-effect profi le of other medications. licensing of Nabimixols and herbal cannabis In this regard, proponents of medicinal would need to fulfi l the same licensing cannabis note that concerns about the regulations. This requires at minimum a risks associated with medicinal cannabis consistent reproducible medication deliv- are inconsistent with those associated ering the same dose of drug, evidence with opioid analgesia, with a lower risk of of effi cacy and ideally effectiveness, dependence and toxicity.31 However, the indications as to which disorder(s) the phar- uncertainty in relation to the effectiveness macotherapy is licensed for and symptom and side-effects prevents clear conceptu- targets. All this requires strong evidence, alisation that would allow prescribers and provided for in stage II and III randomised patients to make fully informed decisions controlled trials (RCTs). A structure by about their pharmacotherapy. which herbal cannabis could be introduced The intersect between medicinal to Australia and the complexities involved is cannabinoids and recreational outlined by Martin and Bonomo and should be given consideration in New Zealand.12 cannabis What is the threshold for which cannabis Risks relating the use of medicinal might be used? While public debate often cannabis are wide ranging, though often concentrates upon the role of cannabis overstated, and need to be held in context in terminal illness, studies suggest that with commonly used medications such as cannabis is largely used for a variety of anti-convulsants. The effects of regularly conditions, not all of which might meet smoked cannabis seem to be largely asso- criteria for disorder, including: pain, ciated with symptoms of bronchitis and insomnia and anxiety.32 A study reporting infl ammation, although an association data from Te Rau Hinengaro: the New 24 with respiratory cancer remains unclear. Zealand Mental Health Survey, in contrast to These risks may be reduced by the use expectations of those with chronic disease, of vaporizers, though evidence is lacking cannabis users were predominantly young, and complicated by the range of devices with 45% under the age of 34.33 These results 25 available and variable sophistication. suggest that the across Prescription of cannabis in adolescence a range of disorders may be a non-specifi c or early adulthood is associated with an anxiolytic effect reinforcing the confl uence increased risk of psychosis and reduced between recreational and medicinal use.

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The similarity between recreational and 2. In fact however, current legislation medicinal users of cannabis is also shown in allows for the use of cannabis in some other ways. Often smoked preparations are medical circumstances. Doctors need preferred and medicinal users of cannabis to be engaged in this debate and the typically have a history of recreational use of cannabis for the management use.22 A recent study examining recreation of disease. This is akin to medical and reported medicinal users of cannabis professional providing advice about found a signifi cant crossover with 86% of non-pharmaceutical products for the those reporting medicinal use also using treatment of medical disorders such cannabis recreationally.34 The availability of as fi sh oil for mood disorders. medicinal cannabis does not preclude either 3. The use of medicinal cannabinoids continuing to grow supplies or purchase needs a dialogue that clearly differen- 22 outside pharmaceutical supplies. The use tiates it from the dialogue about the of cannabis and use disorders is higher in legal status of cannabis. To this end settings where medical use is approved, we would suggest, if discussion about and it is speculated that this refl ects more cannabinoids as a medicine occurs, it 35 positive attitudes to cannabis use. It is is referred to as medicinal cannabi- possible that this relationship is bi-direc- noids, not cannabis. tional where the introduction of medical 4. The use of cannabinoids as therapies cannabis leads to normalisation of use. may be beset with possible risks, both Advocacy for may in part individual and societal, however these refl ect a desire for change of the prohib- need to be considered in a similar itive approach to cannabis in general. That light to other medications rather cannabis is certain to have a greater safety than used carte blanche to suggest profi le than alcohol despite the latter drugs’ there is no place for cannabinoids in highly commercial status and the similar medicine. aims of users is likely to add to the level of perceived injustice among advocates and 5. It is hard to justify a place for a confound informed debate.36 However, smoked medication, in light of the the authors argue that medicinal use of serious public health harms related cannabis and re-consideration of prohibition to smoking and availability of other must be considered separately, on their own methods of delivery. For this reason merits and within appropriate frameworks. the authors would not recommend continuing a debate about the use of A pathway forward for medicinal smoked medicinal cannabinoids. cannabinoid? 6. As with any medication, there needs There is the possibility that medicinal to be suffi cient evidence for effec- cannabinoids will prove of value to New tiveness to warrant prescription. Zealanders as pharmacotherapy. This may This is a central component of the be of particular value as the likely condi- medicinal cannabinoid debate and tions treated are vulnerable populations currently lacking. with chronic conditions. It will be important, 7. There is recognition of the use of regu- however, to have a framework moving latory systems already in place in New forward that allows for rational discussion. Zealand, such as the special authority We propose the following as a general forms for funded medication, that framework for this discussion: could be put to good effect should 1. The discussion between the legal medicinal cannabinoids be licensed framework of cannabis and the and publically funded. This avoids medicinal framework of cannabi- the confl ation of a medicine with a noids be kept separate. As much as prohibited substance. possible the licensing of medicinal It is important that all areas of society cannabinoids needs to conform to the engage in the medicinal cannabis debate, framework for all medications. This and the authors of this paper encourage is to prevent the ‘decriminalisation’ of ongoing robust discussion. cannabis via a medical route.

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Competing interests: Dr Newton-Howes reports that he sits on PTAC. Author information: Giles Newton-Howes, Department of Psychological Medicine, University of Otago, ; Sam McBride, Community Alcohol and Drug Service, Te-Upoko-me-te-Whatu-o- Te-Ika Mental Health, Addictions & Intellectual Disability Sector 3DHB, New Zealand. Corresponding author: Giles Newton-Howes, Department of Psychological Medicine, University of Otago, Mein Street, Wellington 6324. [email protected] URL: http://www.nzma.org.nz/journal/read-the-journal/all-issues/2010-2019/2016/vol-129-no-1445- 18-november-2016/7069

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