Towards evidence-based medical cannabis

Introduction

Medical cannabis (MC) is at a crossroads just like alcohol during prohibition from 1919 in the United States after the 18th Amendment which banned access to alcohol. Indeed, alcohol was a prescription item, which could be prescribed by doctors for specific indications (Figure 1).¹

Figure 1

Prohibition era medicinal alcohol prescription

Medical Cannabis

Cannabis is a complex set of compounds (circa 400–500) which include cannabinoids, terpenes and flavonoids. These interact and produce the so-called ͚entourage effect͛ whereby non-psychoactive compounds(mostly cannabidiol - CBD) modulate the psychoactive effects of (mostly) THC (tetrahydrocannabinol).

The MC industry needs evidence-based medicine to sell MC as there is still some residual stigma among themedical profession and evidence is need in order to persuade doctors to prescribe after interacting with medical representative and after exposure to studies in conferences.

The requisite papers must be high quality research: double-blind, randomized control trials (RCT), systematic reviews and meta-analyses. For example, in the UK, the study hierarchy for evidence based medicine is as per Table 1.

The medical profession expects level 1 evidence. Such evidence would further promote MC with the inevitable inclusionin guidelines. For example, the European Society͛s guidelines for the treatment of hypertension are based on, and literally riddled by levels of evidence (Figure 2).²

Figure 2

European Society’s guidelines for the treatment of hypertension – see levels of evidence and class thereof on the right²

Another example from the American Pain Society is equally salutary, stating that when considering initiation of methadone, recommends that clinicians perform an individualized medical and behavioral risk evaluation to assess risks and benefits of methadone, given methadone's specific pharmacologic properties and adverse effect profile (strong recommendation, low-quality evidence).³

A strong recommendation, low-quality evidence͟ is the least that will be accepted by any doctor as the basis for prescribing a drug. This article will not dwell on the importance of evidence-based medicine as the readers of this journal are fully cognizant of such matters. However, the MC industry is not traditional pharma and may not be aware of the ramifications and requirements for marketing a drug to doctors. The demonstration of non-inferiority of MC to extant treatment, or better still, superiority, is mandatory.

How can this be done? If a suitable product exists, creating the requisite research for a particular indication requires a plethora of disparate skills:

• Create a convincing proposal for a double-blind
  • Based on exhaustive literature
  • Including clear consent
• Apply for ethical approval and data protection
• Find a grant/funding.
• Register the study -
• Purchase insurance
• Enroll subjects: recruitment, informed
• Run the
• Collect the
• Analyse
• Write a paper
• Present at conferences:
  • A compelling abstract
  • An attractive poster
  • A captivating presentation
• Professionally lay out a paper
• Know which journals to target
• Understand journal editors
• Negotiate the peer-review
• Consider open-access publication

Once several studies are in hand, a systematic review may be carried out e.g. using the PICO framework (patient,problem or population; intervention; comparison, control or comparator and outcome).⁴

MC currently incorporate relatively few commercial products, and those that are developed and marketed with standardized ingredients and with the requisite quality control (e.g. nabilone) have been welcomed by the medical community as they permit proper RCTs. Thus far however, MC has not been shown to be terribly effective and has been associated with significant side effects.⁵

Clearly, new products and more clinical trials are required, since currently, patients preference for cannabinoids exceeds cannabinoids effectiveness.⁶ These will take time and will cost money. For example, for a modelled, pharmaceutical industry-sponsored trial with 20 subjects required:

• Circa 4,012 man hours.
• 17 office visits/patient.
• Circa 200 hours/patient.
• 32% of total hours devoted to nonclinical activities related to
  • Institutional review board submission.
  • Completion of clinical reporting forms.

Thus, excluding overheads, this was estimated to cost circa $6,000 per enrolled subject, including $2,000 devotedto nonclinical costs, and this was back in 2003 with 20 subjects.⁷ The reality is that studies are usually far larger. Forexample, the 2017 CANTOS trial of the anti-inflammatory drug canakinumab (Ilaris, Novartis) enrolled 10,000cardiovascular high-risk patients.⁸

Current evidence

At the time of writing, evidence for the usefulness of MC is limited. For example, a recent (2017) reviewregarding MC effectiveness for the treatment of pain concluded that evidence for inhaled marijuana for pain is too sparse and poor to provide good evidence-based guidance.Synthetic MC-derived products may modestly improve neuropathic pain for one in 11- 14 users but perhaps not for other pain types. Additionally, longer and larger studies (better evidence) show no effect. Adverse events areplentiful.⁶

Besides pain, a recent (2017) review with regard to the effectiveness for treatment of other conditions concluded that for most conditions (example anxiety), cannabinoid evidence is sparse (at best), low quality and non-convincing. Dronabinol/nabilone improve control of nausea/vomiting post chemotherapy for 1 in 3 users overplacebo. Nabiximols likely improve multiple sclerosis spasticity ≥30% for ~1 in 10 users over placebo.⁶

With regard to epilepsy, a recent (2018) systematic review and meta-analysis on the efficacy and safety ofcannabidiol concluded that AEs significantly associated with CBD were somnolence, decreased appetite, diarrhea, and increased serum aminotransferases. Adjunctive CBD in patients with Lennox-Gastaut syndrome (LGS) and Dravet syndrome (DS) experiencing seizures uncontrolled by concomitant anti- epileptic treatment regimens is associated with a greater reduction in seizure frequency and a higher rate of AEs than placebo.⁹

A recent (2018) review of the role of cannabis in the management of inflammatory bowel disease commissioned by the Crohn's and Colitis Foundation noted that human studies have found benefit in controlling symptoms and improving quality of life, but no studies have established true disease modification given the absent improvement in biomarker profiles or endoscopic healing.¹⁰

Side effects

MC is also plagued by a significant risk of adverse effects, which are well known, and unexpected effects alsofrequently manifest. For example, cannabis use increases risk for revision after total knee arthroplasty.¹¹

Another alarming example is that marijuana was found to have induced a Type I Brugada Pattern in a patient inwhom this could not later be provoked with procamide challenge^.12 Indeed a recent (2017) review with regard to theharms associated with MC therapy concluded that compared to placebo, medical cannabinoids cause multiple different adverse events in patients, from visualdisturbance or hypotension (1 in 3-10) to hallucination or paranoia (1 in 20).

Stopping due to adverse effects occurs in 1 in every 8-20 patients. Regardless of the type of medical cannabinoidused, adverse events are common and likely underestimated. Given the extensive harms, potential benefits mustbe impressive to warrant a trial of therapy.¹³

Additionally, concern has been raised by the finding that chronic marijuana use predominantly affects brainregions that supervise critical thought processes, such as attention, memory, and social interactions. The authors concluded that disruption of these areas has been documented in schizophrenia and Alzheimer's disease, illnesses with symptoms and brain changes that parallel findings in marijuana abusers. These findings counter the claim that marijuana is a harmless drug and are a cause for alarm in persons with cannabis dependence.¹⁴

Conclusion

Extant data/product/s may not even be representative for the purposes for which MC is sought. There is clearly a knowledge gap must be bridged if MC is to ever be treated as medicine and routinely prescribed. MC must meet the same exacting standards of quality, effectiveness and safety of any other prescription drug or it risks being ignored or marginalized by the medical community. Indeed, the medical community assumes a contradictory stance toward medical marijuana (MM). Health care providers use the agent clinically…However, most professional medical associations do not offer clinical guidance on the subject, medical practice infrastructure does not always take MM into account, and some physicians who recommend MM clinically acknowledge that they do not understand it well enough to do so.¹⁵

MC is thus at a crossroads and must decide whether to continue as is, with equivocal studies and remain marginally used, largely a last ditch prescription mostly due to side effects. Or to improve and prove the value of extant and new products with RCTs that will lead to the inclusion of MC in medical society guidelines, ensuring their wider and useful use.

For all of these reasons, including the many unanswered questions, the MC industry constitutes an exciting and lucrative opportunity for Malta.

References

1. Appel JM. " Physicians are not Bootleggers": The Short, Peculiar Life of the Medicinal Alcohol Movement. Bull Hist Med. 2008 Summer;82(2):355-86
2. Williams B, Mancia G, Spiering W, Agabiti Rosei E, Azizi M, Burnier M, Clement D, Coca A, De Simone G, Dominiczak A, Kahan T, Mahfoud F, Redon J, Ruilope L, Zanchetti A, Kerins M, Kjeldsen S, Kreutz R, Laurent S, Lip GYH, McManus R, Narkiewicz K, Ruschitzka F, Schmieder R, Shlyakhto E, Tsioufis K, Aboyans V, Desormais I; List of authors/Task Force members. 2018 Practice Guidelines for the management of arterial hypertension of the European Society of Hypertension and the European Society of Cardiology: ESH/ESC Task Force for the Management of Arterial Hypertension. J Hypertens. 2018 Dec;36(12):2284-2309.
3. Chou R, Cruciani RA, Fiellin DA, Compton P, Farrar JT, Haigney MC, Inturrisi C, Knight JR, Otis-Green S, Marcus SM, Mehta D, Meyer MC, Portenoy R, Savage S, Strain E, Walsh S, Zeltzer L1 American Pain Society; Heart Rhythm Society. Methadone safety: a clinical practice guideline from the American Pain Society and College on Problems of Drug Dependence, in collaboration with the Heart Rhythm Society. J Pain. 2014 Apr;15(4):321-37.
4. Schardt C, Adams MB, Owens T, Keitz S, Fontelo P. Utilization of the PICO framework to improve searching PubMed for clinical questions. BMC Med Inform Decis Mak. 2007 Jun 15;7:16.
5. MacCallum CA, Russo EB. Practical considerations in medical cannabis administration and dosing. Eur J Intern Med. 2018 Mar;49:12-19.
6. Alberta College of Family Physicians. Any Other ͞Doobie͟ous Effects of Medical Cannabinoids? Tools for Practice. 2017; December. https://www.acfp.ca/wp-content/uploads/tools-for- practice/1512754221_tfp201medcanotherfv.pdf . Accessed 13/11/18
7. Emanuel EJ, Schnipper LE, Kamin DY, Levinson J, Lichter AS. The costs of conducting clinical research.  J Clin Oncol. 2003 Nov 15;21(22):4145-50.
8. Ridker PM, Libby P, MacFadyen JG, Thuren T, Ballantyne C, Fonseca F, Koenig W, Shimokawa H, Everett BM, Glynn RJ. Modulation of the interleukin-6 signalling pathway and incidence rates of atherosclerotic events and all-cause mortality: analyses from the Canakinumab Anti-Inflammatory Thrombosis Outcomes Study (CANTOS). Eur Heart J. 2018 Oct 7;39(38):3499-3507.
9. Lattanzi S, Brigo F, Trinka E, Zaccara G, Cagnetti C, Del Giovane C, Silvestrini M. Efficacy and Safety of Cannabidiol in Epilepsy: A Systematic Review and Meta-Analysis. Drugs. 2018 Nov 3. doi: 10.1007/s40265-018-0992-5.
10. Swaminath A, Berlin EP, Cheifetz A, Hoffenberg E, Kinnucan J, Wingate L, Buchanan S, Zmeter N, Rubin DT. The Role of Cannabis in the Management of Inflammatory Bowel Disease: A Review of Clinical, Scientific, and Regulatory Information: Commissioned by the Crohn's and Colitis Foundation. Inflamm Bowel Dis. 2018 Oct 24. doi: 10.1093/ibd/izy319.
11. Law TY, Kurowicki J, Rosas S, Sabeh K, Summers S, Hubbard Z, Roche M. Cannabis use increases risk for revision after total knee arthroplasty. J Long Term Eff Med Implants. 2018;28(2):125-130. doi: 10.1615/JLongTermEffMedImplants.2018027401.
12. Kariyanna PT, Jayarangaiah A, Hegde S, Marmur JD, Wengrofsky P, Yacoub M, Post M, McFarlane SI. Marijuana Induced Type I Brugada Pattern: A Case Report. Am J Med Case Rep. 2018;6(7):134-136.
13. Alberta College of Family Physicians. Harms of Medical Cannabinoids: Up in Smoke! Tools for Practice. 2017; December. https://www.acfp.ca/wp-content/uploads/tools-for- practice/1511480622_tfp200harmsmmfv.pdf. Accessed 13/11/18.
14. Stoecker WV, Rapp EE, Malters JM. Marijuana Use in the Era of Changing Cannabis Laws: What Are the Risks? Who is Most at Risk? Mo Med. 2018 Sep-Oct;115(5):398-404.
15. Braun I, Tulsky J. Reconciling the Discrepancies in Medicine's Relationship to Medical Marijuana. Ann Intern Med. 2018;169(9):646-7.

Figure

Test image