CJMC Volume 2, Issue 1

CJ MC

Volume 2, Issue 1

Vol. 2•1 Summer 2020

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Controversies in cannabis

Has legalized cannabis impacted fertility in Canada?

Real World Data

Real-world data: A natural approach to gathering cannabis data; Collecting RWD on cannabis use with a smart phone app

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Oral Health

Is the use of cannabis associated with periodontitis in adults? Oral health implications of increased cannabis use among older adults

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Crohn’s Disease

New study evaluates cannabidiol dosages in clinical populations; The therapeutic role of medical cannabis in Crohn’s disease

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Anorexia

Cannabidiol effectiveness in cancer-induced anorexia; “The munchies” New survey explores users’ experience of cannabis effects on appetite

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Research Supplement

Contribution of cannabis use to variation in the incidence of psychotic disorder across Europe (EU-GEI): A multicentre case-controlled study

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Cannabis Q

Dr. Shafiq Qaadri interviews Dr. M-J Milloy

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Research scientist and assistant professor at the University of British Columbia

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Opinion: Cannabis edibles pose serious risks to our kids Edibles offer lucrative opportunity for business, but delayed onset can lead to over-consumption IN OCTOBER 2019, Health Canada approved the sale of

During the early phase of cannabis legalization in Oregon and Alaska, 253 overdoses—some requiring stays in the intensive-care unit and including one death—were reported to poison centres over a 16-month period: 71 individuals were under the age of 12, and 42 were between the ages of 12 and 17. The median age was only 20 years old. Beyond the risks of acute toxicity, cannabis use that starts in adolescence has been linked to a variety of harms including depression, suicidality, psychosis and schizophrenia. Considering that Canadian youth are the highest adolescent users in the world and that they believe, despite strong scientific evidence to the contrary, that cannabis will improve their mood, anxiety and sleep, there are significant challenges in protecting them from potential cannabis-related harms. Intoxicants aren’t candy Unfortunately, Health Canada has allowed troublingly high THC concentrations (up to 30% in some cases) in dried cannabis products. While many edibles will be purchased directly from retailers, edibles made at home may have higher THC concentrations. Health Canada has also done little to rein in misleading advertising by the cannabis industry: it has allowed licensed producers to make unsubstantiated claims about

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cannabis edibles, topicals and extracts for early 2020. Let us hope that one of Health Canada’s New Year’s resolutions will be to do a better job of regulating cannabis and protecting the public, and in particular youth, from harm. Cannabis edibles offer a lucrative opportunity for licensed cannabis producers and retailers in both the medical and recreational market. However, while governments and businesses move to meet public demand and their bottom lines, there is a need to acknowledge the inherent risks cannabis, and in particular Dr. Anita edibles, can pose. Srivastava While edibles may provide a delivery system that provides the intoxicating effects of cannabis while avoiding the risks of smoking, the delayed and variable absorption of cannabis edibles can result in over-consumption and unpredictable results. As both an addiction medicine and family physician, I have seen many adolescents whose cannabis use has negatively affected their mood, motivation, sleep and ability to simply function.

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Substantial harm to youth The intoxicating effects of cannabis when taken orally can be delayed up to 90 minutes, peaking a few hours later, and may last for several hours. Aside from the expected diminished concentration, decreased executive functioning and impaired memory, acute cannabis toxicity can present as severe anxiety, panic attacks, nausea, delirium or psychosis. In Colorado, where cannabis sales were legalized for people 21 and older in 2012, edible products are the major cause of cannabis intoxication. Emergency room visits and hospitalizations due to adverse reactions from cannabis edibles have increased in Colorado since legalization, and adolescent visits rose to 4.9 per 1,000 visits in 2015 from 1.8 per 1,000 visits in 2009. It’s true that often these symptoms are temporary and that a cannabis overdose likely won’t kill someone, but it can cause significant mental and physical disability. ABOUT THE AUTHOR Dr. Anita Srivastava is an associate professor at the University of Toronto in the department of family and community medicine. She practices both family and addiction medicine. In addition, she is a physician at St. Joseph’s Healh Centre. Dr. Srivastava has also co-authored provincial and national clinical guidelines on chronic pain, opioid addiction, alcohol and cannabis.

the medicinal value of cannabis, which only further contributes to positive adolescent social attitudes towardcannabis. While Health Canada does not permit direct advertising of cannabis and requires plain packaging and warnings on all cannabis products, the cannabis industry is able to market through media stories and their websites. The Ontario Cannabis Store, a Crown corporation, has a picture of chocolate squares to advertise edibles on their website and is set to roll out more than 50 new edible and vape products. Canopy Growth is reportedly rolling out cannabis-infused flavoured sparkling waters and gourmet chocolate bars in three different flavours. Health Canada needs to do better —please turn to page 28 Public consumption of edibles is CANADIAN JOURNAL OF MEDICAL CANNABIS • 3

Call for papers Canadian Journal of Medical Cannabis The Canadian Journal of Medical Cannabis (CJMC) is pleased to announce a call for papers for potential inclusion in upcoming editions of the Journal. With the rapidly changing use of medical cannabis in Canada, CJMC is intended as the first scholarly clinical publication devoted to curating and disseminating discoveries concerning the therapeutic use of cannabis in patient care to Canadian physicians. CJMC is accepting the submission of original research reports, briefs, case studies, reviews and expert commentary. If you have a paper you would like to submit, commentary you would like to provide on current cannabis research or an anecdote you would like to share from your practice, we invite you to contact the Journal. Specific topics of interest include: n Pain management n Multiple sclerosis n Movement disorders n HIV/AIDS n Autoimmune and inflammatory disorders n Ophthalmology n Dermatology n Other: specialties where cannabis therapy may demonstrate efficacy or patient benefit. CJMC is also accepting nominations for the Journal’s Medical Advisory Board, for twoyear appointments. Descriptions of the duties of Medical Advisory Board members will be posted to www.cjmc.ca. Nominations should be offered in writing and be in compliance with selection criteria.

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Authorship For authors submitting to the Canadian Journal of Medical Cannabis (CJMC), papers should only be submitted for consideration if all contributing authors have given consent. Corresponding Author One individual author will be the primary contact for communication with CJMC during the submission process and publication process. The corresponding author will be responsible for signing the publication agreement between all contributing authors and CJMC. Please be sure to include the name and contact information of the individual, including e-mail address, two phone numbers and the address of the corresponding author(s). Formatting Articles should be submitted in a PDF or Word document and must be written in English, 12-point font. There should be no promotional logos. Name(s) of authors and credentials must be included. Headings, subheadings and sections must be clearly defined. Artwork Any artwork submitted must be in TIFF or JPEG format with a minimum resolution of 300 dpi. Artwork can be either black and white or colour. If your paper includes figures, charts or tables created in Microsoft Word, please include them in the main text as opposed to the end of the document. Electronic publication All original research reports, briefs, case studies, reviews, and expert commentary published by CJMC will be published in print and online at www.cjmc.ca Submission Process Papers can be submitted by e-mail at cjmc_edit@gmx.ca, by mail at 555 Burnhamthorpe Rd., Ste 306, Toronto Ont. M9C 2Y3, or online at www.cjmc.ca on the “Paper Submission” page. If submitting by e-mail please, make the subject line “Paper Submission” followed by your name. CJMC reserves the right not to publish any research reports, briefs, case studies, reviews and expert commentary that do not meet the criteria of the Journal’s mission or editorial content. CJMC Readers Council: Interested in shaping the future of the Canadian Journal of Medical Cannabis, and contributing toward explorations of cannabinoids in patient health? We invite you to join the C J M C Readers Council, an “insiders” online forum and poll series designed to exchange knowledge and expertise among medical specialists and family physicians in communities across Canada and around the world, through polls and discussion groups. Learn more at www.cjmc.ca

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Published four times annually by the proprietor, CJMC Publications and Media Group, a unit of Chronicle Information Resources Ltd. from offices at 555 Burnhamthorpe Rd., Suite 306, Toronto, Ont. M9C 2Y3, Canada. Telephone: 416.916.2476; Fax 416.352.6199. E-mail: cjmc_questions@gmx.ca. Contents © CJMC Publications and Media Group, A Chronicle Company, 2020, except where noted. All rights reserved worldwide. The Publisher prohibits reproduction in any form, including print, broadcast and electronic, without written permission. Printed in Canada. Subscriptions: $59.95 per year in Canada, $79.95 per year in all other countries, in Canadian or US funds. Single copies: $7.95 per issue. Subscriptions and single copies are subject to 13% HST. Canada Post Canadian Publications Mail Sales Product Agreement Number 40016917. Please forward all correspondence on circulation matters to: Circulation Manager, 555 Burnhamthorpe Rd., Suite 306, Toronto, Ont. M9C 2Y3 Canada. E-mail: cjmc_subs@gmx.ca.

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currents

Pandemic shortage fears spur cannabis stockpiling AFTER AN INITIAL SURGE in March, spurred by pandemic-related concerns about availability, cannabis consumer purchasing habits returned to pre-crisis levels by April, reports Global News (May 15, 2020). “There was a kind of pantryloading in late March, when there was a concern that maybe the supply chain would be closing down and whether cannabis as an industry would be deemed essential,” Michael Singer, interim chief executive at Aurora Cannabis Inc, told the news out-

let. Singer noted that the stockpiling seemed to stop after the cannabis industry was deemed an essential service in several provinces. “The behaviours were very similar to before that pantryloading process at the end of March.” Global News reported that cannabis distributors in several provinces, including Ontario and Alberta, warned of delivery delays arising from the increase in orders. The Ontario Cannabis Store (OCS) increased its staffing and expanded its courier offerings to accommodate the interest in cannabis. The OCS had received between 2,500 and 3,500 orders prior to March 9, 2020. After wide-scale adoption of social dis-

tancing, orders peaked at 13,000 during one week, before decreasing to a still-elevated rate of 5,000 orders per week.

New clinical syndrome emerging in e-cigarette users ACCORDING TO A NEW STUDY,

e-cigarette smokers—the majority of whom used products containing THC—with respiratory illnesses presented with similar clinical characteristics, although the substance that caused the injury is still unknown. The researchers looked at 98 case patients in Wisconsin and

Rates of cannabis consumption and interest in the Dark Web found to be correlated INTEREST IN THE DARK WEB correlated with rates of cannabis consumption in the United States over a

four-year period when cannabis was commonly sold on the Dark Web, according to a new study. The researchers of the study, published in the International Journal of Drug Policy (Feb. 2020), tracked Google Trends to measure the level of interest that was being taken in the United States in the anonymous portion of the Internet where cannabis was commonly sold between 2011 and 2015. The end of the study period coincided with Silk Road and similar websites being shut down. Using regression analysis, the researchers cross-compared data from the Bureau of Justice Statistics’ Justice Expenditure, the National Survey on Drug Use and Health and a number of other databases to come to their conclusions. They found that cannabis consumption rates among adults over the age of 26 correlated with an interest in the Dark Web, where cannabis can be illegally and anonymously purchased in online marketplaces such as Silk Road. Interest in the Dark Web was also associated with an increase in cannabis consumption, according to the authors. However, the effect was more significant in states with higher rates of cannabis users and in states where recreational cannabis is legal. 6 • CANADIAN JOURNAL OF MEDICAL CANNABIS

Illinois with similar respiratory illness thought to be caused by ecigarette smoking. Eighty-nine per cent said they had used products containing THC, although not all used the same brand product. According to the authors of the study, published in the New England Journal of Medicine (Mar. 5, 2020), respiratory, gastrointestinal and constitutional symptoms were reported. All patients tested had bilateral infiltrates, which were observed under X-ray. These symptoms could not be attributed to other causes, said the researchers, although they did not pinpoint which ingredient or substance was responsible.

Secondary metabolites in cannabis plant parts profiled RESEARCHERS HAVE PROFILED

secondary metabolites of cannabis by plant part, with the aim of forming a baseline of reference values useful for research and clinical studies to understand the “entourage effect” of cannabis as a whole. The investigators, who published their findings in Scientific Reports (Feb 24, 2020), also hope that the profiles will allow other researchers to rediscover the therapeutic potential of each part of the cannabis plant from their traditional use by applying

Volume 2, Issue Number 1, 2020 The editors invite your comments on articles appearing in the current literature. Connect with us at www.cjmc.ca Share occurences in your community or institution at cjmc_news@gmx.ca modern scientific methodologies. The researchers profiled 14 cannabinoids, 47 terpenoids—including 29 monoterpenoids, 15 sesquiterpenoids and three triterpenoids—three sterols and seven flavonoids in cannabis flowers, leaves, stem barks and roots in three chemovars that they had available for study. Cannabis inflorescence was characterized by cannabinoids (15.77–20.37%), terpenoids (1.28–2.14%) and flavonoids (0.07–0.14%); the leaves by cannabinoids (1.10– 2.10%), terpenoids (0.13–0.28%) and flavonoids (0.34–0.44%); stem barks by sterols (0.07– 0.08%) and triterpenoids (0.05– 0.15%); and roots by sterols (0.06–0.09%) and triterpenoids (0.13–0.24%).

Cannabis use while pregnant poses risk to fetus: Study CANNABIS EXPOSURE DURING

pregnancy may have negative effects on the development of the fetus, according to a new study. The research was conducted on both rat models and human placental cells by investigators at Western University and Queen’s University in Ontario. Published in Scientific Reports (Jan. 17, 2020), the study found that in rats, exposure to daily doses of THC during pregnancy led to reduced birth weights and stunted growth of or-

gans such as the brain and liver. THC also affected gene expression that allows the placenta to function properly, according to the authors of the study. The researchers said that the active chemicals in cannabis may disrupt the normal flow of oxygen and nutrients between the mother and the fetus, specifically affecting the glucose transporter, GLUT-1. This can result in underdeveloped fetuses. According to the authors, as many as one in five women use

cannabis during pregnancy. In a press release, the investigators said they pursued the study because of a need for more understanding about the effects of cannabis use on pregnancy.

Few consumers understand THC levels in edibles MANY CANNABIS USERS DO NOT

Cannabis and drug-drug interaction list created A COMPREHENSIVE LIST of 57 medications that may not function as

intended when used alongside cannabinoids, CBD oil and marijuana has been compiled, according to an article published in the journal Medical Cannabis and Cannabinoids (Aug. 3, 2020). The medications analyzed had a narrow therapeutic index, which are taken at measured doses to avoid causing harm. Dr. Kent Vrana, professor and chair of pharmacology at the Penn State College of Medicine, created the list with Paul Kocis, a pharmacist at Penn State Health Milton S. Hershey Medical Center, using a list of enzymes from prescription cannabinoid medication that process ingredients like THC and CBD. They compared this to prescribing information from medications to determine any drug-drug interactions. Dr. Vrana recommended patients be honest with their healthcare providers about their cannabis use to avoid overlap with prescribed medications. “The drug-drug interaction information from medical cannabinoids may be useful as medical professionals consider the impact of over-the-counter or illicit cannabinoid products,” said Dr. Vrana in a recent press release. A list of an additional 139 medications with potential for drug-drug interactions has been published online. The authors plan to keep the list regularly updated when evaluations of medications and new information is released.

understand what the THC numbers on packages of cannabis edibles mean, according to a study conducted at the University of Waterloo in Ontario and published online ahead of print in Drug and Alcohol Dependence (Feb. 2020). The researchers surveyed nearly 1,000 Canadians between the ages of 16 and 30 and found that most consumers could not identify whether a cannabis edible contained “low” or “high” levels of THC based on the label. Additionally, the study found that descriptive information such as symbols and words is more effective in helping consumers understand THC potency and approximate serving sizes for cannabis products. The researchers conducted two experiments: the first investigated whether consumers understood how many servings were in a package, and the second looked at whether consumers could identify the product’s potency. The authors concluded that approximately 6% of respondents could identify the serving size on products that had no label or only listed the weight, whereas 77% were able to identify the serving size when the dosage was listed. n Please turn to page 18 for a listing of clinical trials investigating the effects of cannabinoids on conditions such as Tourette’s syndrome and chronic pain.

CANADIAN JOURNAL OF MEDICAL CANNABIS • 7

controversies in c

Has legalized cannabis impacted fe No impact on fertility treatment seen in outcomes in women

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egalization of cannabis in Canada has resulted in a slight but not significant increase in the use of the substance by women seeking fertility treatment, according to research presented in Ottawa at the annual meeting of the Canadian Fertility and Andrology Society. “We looked at the impact of legalization on cannabis consumption in our patient population,” said Dr. Noga Fuchs Weizman, a physician at the CReATe Fertility Centre in Toronto, whose research focuses on the effect of assisted reproductive technologies on oocyte maturation, Dr. Noga Fuchs embryo development and Weizman developmental preimplantation genetics. “Legalization did not affect the concentrations of what our patients were consuming, but we did see a slight trend toward increased frequency of use [of cannabis].” To their knowledge, Dr. Fuchs Weizman and colleagues performed an investigational first as they measured metabolites from cannabis in human follicular fluid. “It has never been done before,” she said. “We used mass spectrometry [to measure the metabolites of cannabis].” Secondarily, they wanted to look at the level of marijuana consumption in their patient population prior to legalization of cannabis in Canada and after legalization, to explore if legalization had an impact on the level of consumption and then to correlate the levels with self-reporting of cannabis use among their patients and oocyte quality and development. They used the centre’s biobank of follicular fluid, which had been extracted from 260 patients who were treated at the centre between January 2018 and August 2019 and who had consented to the use of their follicular fluid for this study. “Legalization happened in the middle of this time period,” said Dr. Fuchs Weizman.

“We had 17 samples positive for at least one of the [cannabis] metabolites.” The researchers found that the frequency of use rose from 5.8% to 8.5%, which was not statistically significant. “Legalization did not affect the concentrations of THC and its metabolites, but we did see a trend to increased frequency of use in our patient population,” said Dr. Fuchs Weizman. In comparing the characteristics of fertility patients who had positive samples to those who did not, Dr. Fuchs Weizman and colleagues found cannabis users to be younger than non-users (p=0.02). They did not find cannabis users differed on other variables, such as body mass index or response to fertility treatment, compared to non-users. One of the observations was that cannabis use in their patient population was markedly reduced compared to use in the general population in Canada. The researchers looked at data from Statistics Canada to compare cannabis use in their patient population to the general population. “We found that consumption was much lower [among patients seeking fertility treatments] than [among] age-matched controls,” she said. “Both pre and post [rates of cannabis consumption in our patient population] are dramatically lower than what we see in the general population. We were surprised by the low consumption rate.” Effect of cannabis on embryology Because of the small quantity of positive samples, the researchers matched the positive samples with a ratio of 3 to 1 to look for any impact of cannabis on embryology outcomes, according to Dr. Fuchs Weizman. The investigators found that the use of cannabis did not influence embryology outcomes, noted Dr. Fuchs Weizman. “We wanted to look at the potential implications on follicle development,” she said. “We did not detect any difference in terms of maturation, fertilization, cleavage, blastulation rate or high-quality blastulation rate. We cannot say if this means that there is no difference. It

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may be because of the small sample [that no significant difference was observed].” Dr. Fuchs Weizman and colleagues reviewed the literature to evaluate existing evidence with respect to the effect of cannabis on fertility treatments. She pointed to a very recent study that concluded that the incubation of oocytes with THC during in vitro maturation (IVM) of oocytes was able to elevate the blastocyst rate in response to IVF (Cell Physiol Biochem 2019; 53(3):439–452). “In the rat model, it improved the blastulation rate,” she said. In a 2016 investigation with animal models, researchers concluded that cannabinoid agonists may offer benefit as IVM supplements as they up-regulate expression in blastocysts of key genes for embryo quality during oocyte maturation (Reproduction 2016; 152(6):603–612). “They managed to show that exposing bovine oocytes to THC or to a more potent analogue increases the maturation rate,” she said. A study with patients, however, was not consistent in concluding that cannabis positively influenced fertility treatment: a prospective study of 221 patients involved in in vitro fertilization and gamete intrafallopian transfer (IVF/GIFT) concluded that marijuana use negatively influenced IVF/GIFT (Am J Obstet Gynecol 2006; 194(2):369–376). “They [investigators] were able to show that consuming marijuana leads to worse results with IVF,” she said. “They were also able to show a correlation between a time lag, from last consuming to IVF, that led to worse results. The shorter the time lag, the worse the results.” Dr. Fuchs Weizman and colleagues plan to examine how exposure to THC alters the dynamics of endogenous cannabinoids in the developing follicle and explore how THC and its metabolites affect IVM in humans, as well as how THC and its metabolites affect the microenvironment of the maturing oocyte. Dr. Fuchs Weizman noted limitations of the study, including its retrospective nature and the fact that investigators did not look at blood serum samples from patients. —Louise Gagnon, CJMC Correspondent

cannabis

ertility in Canada? More study needed to pinpoint how endocannabinoids affect male fertility

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sing endocannabinoids as a biomarker in male reproduction is still at a very early stage, according to Mauro Maccarrone, PhD, MSc, chair of biochemistry and molecular biology at Campus Bio-Medico, University of Rome, Rome, Italy, speaking in Ottawa at the 65th annual meeting of the Canadian Fertility and Andrology Society about the effects of endocannabinoids on male reproduction. Giving a historical overview of the discovery of endocannabinoids, Dr. Maccarrone pointed out that tetrahydrocannabinol (THC) was isolated in Dr. Mauro 1964 and that about 30 Maccarrone years later, the endogenous counterparts of THC, referred to as endocannabinoids, were uncovered, and they include anandamide and 2-arachidonoylglycerol (2-AG). “Cannabis is a unique source of phytocannabinoids and more than 400 other compounds,” said Dr. Maccarrone. Endocannabinoids affect various systems in the body, including the cardiovascular system, the gastrointestinal tract, the immune system and the reproductive system, and recent investigations have found that they have an effect on kidney disease. Endocannabinoids and male fertility Infertility is fairly common, affecting one in six couples, with male factors influencing 50% of cases of infertility in couples, noted Dr. Maccarrone. Some of the male factors linked to infertility can be explained by anatomy, but some variables involved in the modulation of spermatogenesis and sperm function remain to be elucidated, with endocannabinoids potentially being one of those variables. Many studies have linked cannabis use to reduced sperm concentrations, signifying an adverse effect on fertility. The role of naturally occurring endocannabinoids in male infertility is

not clear. “The endocannabinoid system is complex,” said Dr. Maccarrone, noting that there is some reason to speculate that endogenous cannabinoids may influence fertility. “Cannabinoid receptors are the same targets for plant-derived and endogenous cannabinoids.” He pointed to data showing that the seminal plasma of men in infertility clinics, with either asthenozoospermia or oligoasthenozoospermia, had N-arachidonoylethanolamine (AEA)/anandamide, N-palmitoylethanolamide (PEA) and Noleoylethanolamine (OEA) levels that were significantly reduced compared to men with normozoospermia (Fertil Steril 2014; 102:1260–1267). Additionally, supraphysiological levels of methanandamide, a non-hydrolyzable analogue of AEA, reduces sperm motility and maintains viability without affecting mitochondrial activity. Moreover, PEA and OEA have been shown to enhance in vitro sperm motility and maintain viability without influencing mitochondrial activity (Fertil Steril 2014; 102:1260–1267; Hum Reprod 2013; 28:2058–2066). Findings such as these allude to a normal endocannabinoid system being needed for the preservation of healthy sperm function and overall male fertility, according to Dr. Maccarrone. PEA and OEA, when given as supplements, enhance sperm antioxidant activity in men who have infertility with an unknown cause. As a result, they enhance sperm kinematic parameters and hyperactivation in vitro. Sperm is shielded from oxidative damage because of the properties of PEA and OEA as they are anti-inflammatory, antimicrobial and antioxidant. Accumulating evidence points to manipulation of the endocannabinoid system in preserving normal, healthy sperm function and intact male fertility, noted Dr. Maccarrone. A closer examination of specific cells, such as Sertoli cells, which control spermatogenesis by releasing various proteins in tubular fluid, may help to better illuminate the role of endocannabinoids, explained Dr. Maccarrone.

The impact of endocannabinoids is not limited to the male reproductive system, said Dr. Maccarrone. Endocannabinoid signalling can affect female reproduction, he emphasized. “Pregnancy can be adversely affected,” he said. Interestingly, both silencing and amplification of endocannabinoid signalling can adversely impact female reproductive functions, with endocannabinoid signalling in female reproductive events mainly mediated by type 1 cannabinoid receptor. Specifically, type 1 cannabinoid receptor is not strongly expressed within both the fallopian tubes and the endometrium of women who have an ectopic pregnancy. This fact had led to the suggestion that irregular endocannabinoid signalling within the fallopian tubes may lead to an ectopic pregnancy, noted Dr. Maccarrone. But endocannabinoids can offer benefit and treat female sexual dysfunction, which needs to be addressed to ensure optimal sexual health in females. Endocannabinoid-based therapies that are commercially available, such as products containing PEA, have a role in the management of conditions characteristic of female sexual dysfunction, such as chronic vestibulodynia, vulvodynia and vaginismus. One of the challenges in studying the effects of cannabis, in reproductive medicine and other medical specialties, is that there is no standardized form that is used in research investigations, which makes it difficult to draw conclusions across studies, according to Dr. Maccarrone. Given that regulations on the use of cannabis are gradually being lifted in various parts of the world, consumption is likely to increase, which warrants further exploration of cannabis and its impact on fertility, said Dr. Maccarrone. One of the possible avenues of exploration is looking at the combined effect of THC and CBD (cannabidiol). “If you put them [THC and CBD] together, you get additional activities that are beneficial for certain diseases,” said Dr. Maccarrone. —Louise Gagnon, CJMC Correspondent

CANADIAN JOURNAL OF MEDICAL CANNABIS • 9

Medical cannabis and

R E A L W O R L D D ATA

Real-world data: A natural approach to gathering cannabis data?

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here is growing recognition that evaluating health-related interventions requires evidence gathered through real-world data (RWD). A recent analysis points out the risks associated with those data. According to the report by Wendy Lipworth of the University of Sydney in Australia, there are particular questions regarding the quality of RWD and the potential conflicts of interest that may exist (Lipworth W: Real-world data to generate evidence about healthcare interventions: The application of an ethics framework for big data in health and research. Asian Bioethics Review 2019; 11:289–298). RWD is especially important for evaluating interventions that cannot be readily studied in randomized controlled trials (RCTs), such as surgeries. But gathering sufficient RWD may require use of data from multiple sources, such as health records, pharmacy databases or insurance claims. This can mean that such information may have been originally collected for administrative purposes and not by people trained

in scientific methodologies. Moreover, the bigger the data sets used, the more the data may be open to differing interpretations. Lipworth cited the case of rosiglitazone, a drug approved for the treatment of type 2 diabetes, to illustrate this problem. Analysis of RCTs suggested a risk of myocardial ischemia. Subsequent evidence gathered from RWD indicated no such problem. Further analysis of RWD from health utilization databases, along with more RCTs, suggested that the connection did exist and was used to remove the drug from the market. The result has been ongoing controversy about both the RCTs and the real-world evidence taken from RWD (Rawson NSB: Review of the quality of observational studies of the association between rosiglitazone and acute myocardial infarction. Journal of Population Therapeutics and Clinical Pharmacology 2014; 21(2):e214–e232). The other major issue is that many of the sources of RWD are not governed by the same rules as scientific studies. Much of the RWD—even from medical registries—is sup-

plied voluntarily, is not reviewed by external authorities or is shaped to point to a conclusion favourable to a particular intervention, profession or commercial or political interest. Data supplied by or involving pharmaceutical companies can be an example of these possible conflicts of interest. Researchers using RWD need to be aware of their own potential conflicts of interest, be willing to follow strict scientific values, be open with RWD study participants and prioritize the public benefit above any other interests. Such research should also have ethics committees, data access committees and peer reviewers in place. Lipworth concluded that although the use of RWD is increasingly important, it requires special precautions. Particular attention must be paid to both the methods used to gather the data and any distortions that might exist as a result of commercial, political or other conflicts of interest. Transparency about the RWD and its sources is critical. —Kate Kneisel, CJMC Correspondent

Commentary Jacob Vigil, PhD, Albuquerque, N.M.,U.S.A.

AS CLINICIANS AND RESEARCH SCIENTISTS, we are taught that randomized controlled trials are the gold standard for conducting scientific investigations. It is often overlooked that the more artificial or controlled the environment, the less representative it is of the environment outside that laboratory. Because cannabis is inherently heterogeneous in nature, with different chemotypical profiles even within batches, patients are never able to truly obtain the same product twice, and researchers are essentially not able to replicate an intervention. Very few studies have measured the effects of common and commercially available cannabis products—the same types millions of people are using every day. The study I co-authored with Sarah Stith is a novel approach to addressing that research gap. In the U.S., little information is given to medical providers, leaving them largely ignorant of therapeutic use of cannabis and unable to answer a patient’s basic questions. I call it a form of secondary victimization, whereby as a society, we have different epidemics of anxiety and chronic pain and autism being treated with conventional medications—conditions that are exacerbated when treatments are ineffective or have intolerable side effects. I often describe cannabis as an existential threat to the pharmaceutical industry. So many data directly, empirically show that when people have access to cannabis, they often 10 • CANADIAN JOURNAL OF MEDICAL CANNABIS

stop using their conventional medications. Veterans in the U.S. are heavily overmedicated and suffering from medication side effects; that’s just one example of a large patient population that is quite receptive to improving what they have access to. And my data show that a lot of people are shifting from antidepressants to cannabis. So this is an opportunity to embrace a paradigmatic shift in how we think about healthcare. Cannabis forces the patient to experiment, and that is a good thing because it gives individuals the opportunity to take more control over their healthcare and monitor the effects of those decisions. I warn physicians that once people start using cannabis more widely, they won’t be seeing their patients so frequently. I know some practitioners are really embracing the utilization of cannabis within the primary healthcare system—not pitting one against the other, but using them in complementary fashion. I truly believe that is probably the most effective way to go about it from the role of a provider. As a research team, and now through our research education platform, Cannabis Connection University (https://www.cannabisconnectionuniversity.com/), we want to let people know that it is okay to experiment with alternative forms of medication. Jacob Vigil is an associate professor of psychology at the University of New Mexico in Albuquerque.

Collecting Real World Data on cannabis use with a smart phone app As reported in Scientific Reports 2019; DOI: 10.1038/s41598-019-39462-1

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ederal barriers and logistical challenges have contributed to a true state of ignorance regarding the real-world effects of cannabis use for therapeutic reasons, according to researchers from the University of New Mexico. Toward gathering data that reflect real-time outcomes under naturalistic circumstances, lead author Sarah Stith, assistant professor of economics, and colleagues provided participants in their cannabis study with a mobile device software: a publicly available, incentivefree app that was commercially developed by three study co-authors to educate patients on the effects of various aspects of therapeutic use of cannabis. Their observational study (Stith SS, Vigil JM, Brockelman F, et al: The association between cannabis product characteristics and symptom relief Scientific Reports 2019; DOI: 10.1038/s41598-01939462-1) showed that “whole natural dried flower—found to be the most commonly used product—statistically offered greater potential for symptom relief than other types of products. The flower seems to be particularly effective at predicting greater point reductions in symptom intensity for anxiety, pain and depression,” co-author Jacob Vigil, associate professor of psychology at the University of New Mexico, told the CANADIAN JOURNAL OF MEDICAL CANNABIS in an interview. Symptom improvement linked with higher THC levels Overall, patients showed an average symptom improvement of 3.5 (SD=2.6) on an 11-point scale across the 27 measured symptom categories. “However, once we controlled for cannabinoid contents across product characteristics, only higher tetrahydrocannabinol [THC] levels were independently associated with greater symptom relief and prevalence of positive and negative side effect,” said Vigil. As well, products made from pure Cannabis indica strains were more effective than products made from Cannabis sativa, reflecting patient-reported preferences for C. indica for treating conditions such as pain and insomnia, the group noted (Cohen NL, Heinz AJ, Ilgen M, et al: Pain, cannabis species, and cannabis use disorders. Journal of Studies on Alcohol and Drugs 2016; 77(3):515–520; Pearce DD, Mitsouras K, Irizarry KJ: Discriminating the effects of Cannabis sativa. Journal of Alternative and Complementary Medicine 2014; 20(1):787–791). Variable cannabinoid profiles may partially explain inconsistent findings of cannabis studies on various outcomes, such as the conflicting findings regarding the benefits of cannabis in the treatment of chronic neuropathic pain (see Cohen et al, cited above, versus Andreae MH, Carter GM, Shaparin M, et al: Inhaled cannabis for chronic neuropathic pain: A meta-analysis of individual patient data. The Journal of Pain 2015; 16(12):1221–1232). Data collection Between 2016 and 2018, 3,341 people completed almost 20,000 selfadministered cannabis sessions using the mobile device software ReleafApp to record real-time ratings of health symptom severity levels,

prior to and immediately following administration, and side effects. The authors pointed out that patient-reported outcomes were not cross-referenced with clinical assessments. The potency levels of cannabidiol (CBD) were generally not associated with significant symptom changes or side effects of any kind across this large data set, Vigil said. “This is controversial because we hear a lot about how THC is the devil’s component and CBD is the virtuous component. We’re not always finding that. We do have other studies that indicate that CBD seems to be statistically predictive of symptom reductions, but in most cases, THC seems to be the greater player.” This could be related to inaccurate (e.g., inflated) CBD potency levels displayed on labels of the products consumed in the study, he explained. Alternatively, it is possible that compared to THC, CBD has more latent effects that expand beyond the 90-minute observation window used in this study. The team acknowledged this potential limitation, noting that the ReleafApp may be better suited to tracking more immediate versus delayed responses. Within the phytocannabinoid family, CBDs are known to differ from other cannabinoids, such as THC, in several ways. In addition to having immunosuppressant and anti-inflammatory effects (Burstein S: Cannabidiol (CBD) and its analogs: A review of their effects on inflammation. Bioorganic & Medicinal Chemistry 2015; 23(7):1377–1385; McPartland JM, Duncan M, Di Marzo V, et al: Are cannabidiol and Δ(9)-tetrahydrocannabivarin negative modulators of the endocannabinoid system? A systematic review. British Journal of Pharmacology 2015; 172(3):737–753), CBDs have no affinity to CB1 receptors, are an antagonist to GPR55 receptors and tend to result in opposite effects than does THC. As Vigil explained: “So CBD doesn’t block the effects of THC; rather, the two seem to balance each other out, reflecting the entourage effect that has been widely accepted as resulting in greater therapeutic potential than the isolated analogs alone.” Thus, it is possible that although CBD may operate inconspicuously to improve certain health outcomes, the adjunctive consumption of THC is needed to consciously experience or be aware of such effects, the group wrote. Future research Furthermore, although different routes of administration deliver variable amounts of cannabinoid contents, Stith and colleagues did not find variation in symptom relief with the use of pipes, joints or vaporization combustion devices. However, negative side effects were reported less with vaping than with smoking joints, Vigil noted. Stith and team said, “Future research will capitalize on our ever increasing sample size to analyze the pharmacodynamic interactions of major cannabinoids and other organic compounds including terpenoids, as well as the harm of cannabis production practices. For example, the use of solvents to extract cannabinoids for making concentrates used in making non-flower products (e.g., edibles, tinctures) may place patients at risk for respiratory and cardiovascular problems and be a cause of increased emergency cases of Cannabinoid Hyperemesis Syndrome.” —Kate Kneisel, CJMC Correspondent CANADIAN JOURNAL OF MEDICAL CANNABIS • 11

Medical cannabis in

O R A L H E A LT H

Is the use of cannabis associated with periodontitis in adults?

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eriodontitis is a chronic disease that causes inflammation of the gums and increasing loss of attachment and bone. Periodontitis is most common among the elderly. In this study, Chisani et al conducted a meta-analysis to investigate the potential association between cannabis use and periodontitis (Chisini LA, Cademartori MG, Francia A, et al: Is the use of cannabis associated with periodontitis? A systematic review and meta-analysis. Journal of Periodontal Research 2019; 54(4):311–317. The researchers performed electronic searches of PubMed and other medical databases using relevant keywords. They included longitudinal and cross-sectional studies investigating the association between use of cannabis and periodontitis. Periodontitis was clinically assessed using measurements of probing depth and attachment loss. Cannabis use was assessed by self-report and categorized by frequency of use. A total of 143 records were found in the initial searches. After exclusions, five

remained. These were included in the systematic review, and four of these papers were included in the meta-analysis. All studies were of high quality. In the four studies included in the meta-analysis, a positive association was seen between the use of cannabis and the presence of periodontal disease. Cannabis contains 400 compounds, including about 60 cannabinoids. Cigarettes are similar to cannabis except they contain tobacco and do not contain cannabinoids. THC, a main component of cannabis, is an agonist to the CB1 and CB2 receptors. The CB2 receptor appears to play a role in the regulation of bone metabolism and affects the function of osteoclasts. Although cannabis promotes an antiinflammatory response, its effect on bone remodelling may contribute to or help increase periodontal destruction, said the researchers. One previous study they cited, of rats, showed that it is possible that cannabis does not start the bone loss but

Commentary Aaron Burry,

IN THE META-ANALYSIS CONDUCTED BY CHISANI ET AL, published in the Journal of Periodontal Research, the researchers concluded that the use of cannabis is associated with a higher prevalence of periodontitis regardless of the use of tobacco. At this point in time, the research is starting to confirm what people have seen for years. The challenge with cannabis has been that it was illegal for a long time; thus, not much research was conducted. Any research done was based on small numbers. In Canada, patients are disclosing their use of cannabis more readily, so we can make connections more easily. In terms of comparing the effects of cannabis on periodontitis to those of tobacco, first we have to clarify that we are talking about smoking cannabis. Since cannabis and tobacco use similar mechanisms, we would expect similar results. The majority of patients I see mix cannabis and tobacco, so there is a combined effect. Smoking tobacco, smoking cannabis, and vaping all cause an inflammatory response and have an impact on periodontitis. This can lead to the destruction of bone. In the study, the researchers suggested that the CB2 re12 • CANADIAN JOURNAL OF MEDICAL CANNABIS

rather that it increases the loss when present. In the present study, the researchers found that cannabis had a higher impact on periodontitis in adults and the elderly compared to adolescents. This could be because the general prevalence of periodontitis in adolescents is low, as well as due to the shorter exposure time to cannabis in this population. Interestingly, in one study included in the meta-analysis, among people who never smoked tobacco, those who used cannabis had a significantly higher prevalence of severe periodontitis compared to those who did not use cannabis. However, this result should be interpreted with caution due to the small sample size (13 individuals). The researchers concluded that the use of cannabis is associated with a higher prevalence of periodontitis regardless of the use of tobacco. Health agencies need to recognize the role of cannabis in the development of periodontal disease. —Sherene Chen-See, CJMC Correspondent

DDS, Ottawa,Ont

ceptor has a role in bone metabolism, and since cannabis targets this receptor (in addition to CB1), this could in part explain why this drug is associated with increased periodontitis. We are just starting to understand how CB1 and CB2 work, so this is a plausible theory that requires further investigation. The study also showed that cannabis has a higher impact on periodontitis in adults and the elderly compared to teens. This was not surprising. Typically, the inflammation and bleeding in teenagers come from smoking cannabis, but there is no bone loss yet. In general, periodontitis is a complex, multifactorial condition, often with genetic and lifestyle components. Smoking cannabis can contribute to periodontitis. At the Canadian Dental Association, we advise that patients not smoke cannabis. The health impact on the mouth is clear. We now recommend that dentists ask their patients about cannabis use. This is essential because they can’t fully address their patients’ oral health if they have not been able to have that discussion. Dr. Burry is the associate director of professional affairs at the Canadian Dental Association.

Oral health implications of increased cannabis use among older adults As reported in Journal of Substance Abuse 2018; 24(1):61–65

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he population is aging quickly. Given that older individuals are typically affected by multiple medical conditions, including oral diseases, and cannabis use among older adults is rising, Le and Palamar decided to investigate correlations between oral health status and trends in cannabis use in this population (Le A, Palamar JJ: Oral health implications of increased cannabis use among older adults: Another public health concern? Journal of Substance Abuse 2018; 24(1):61–65). Cannabis is the third most used drug in older adults, after alcohol and tobacco. Findings in the United States have shown that the “most notable growth in rates of any type of cannabis (i.e., medicinal or recreational) occurred among Americans aged 65 or older,” said the researchers. Seniors are the age group showing the most growth in cannabis use in Canada as well according to Statistics Canada.1 “It is important to point out that some elderly cannabis users may have started smoking early, essentially being lifelong users; thus, smoking cannabis is more likely to have a cumulative effect,” says Dr. Aaron Burry, associate director of professional affairs at the Canadian Dental Association (CDA). “Others might not have started until age 65, and the majority of those were prescribed cannabis for medical purposes. Generally, this latter group is using smaller amounts and is considering other forms of cannabis, such as foods or oils.” Oral health conditions in older adults Older adults have a high incidence of oral conditions, including cavities, untreated tooth decay and periodontitis. Rates of oral cancer progressively increase with age, and most cases occur in people 60 years of age or older. Oral diseases can have a major impact on quality of life. Physical, sensory or cognitive impairments associated with aging can make oral hygiene difficult, reported the researchers. In addition, the elderly are more likely to be taking numerous medications at once, including those that have the side effect of dry mouth, which increases the risk of cavities and oral infections. Also, gingival recession is common with aging and makes teeth more prone to decay. Oral health implications of cannabis use Cannabis use can adversely affect the oral cavity. Cannabis users who also use tobacco tend to have more smooth surface decay than those who only use tobacco. This type of decay is a concern because it is usually easier to maintain smooth surfaces with normal oral hygiene. Cannabis also tends to cause dry mouth, which is a risk factor for cavities. “Smoking anything is associated with periodontitis and increases risk and progression,” says Dr. Burry. “This is why the CDA recommends that people avoid smoking or vaping, and that includes smoking cannabis.” The researchers also mentioned that there may be a potential relationship between cannabis use and oral and neck cancers. “There have been specific continuing medical education confer-

ences related to cannabis as there is far more information emerging now that cannabis is legally available and being researched in more places of the world,” says Dr. Burry. “These conferences often include sessions related to having conversations with patients about what we are learning about cannabis, and topics such as the differences between recreational and medical use.” “It is important to link dental professionals with this information, which they can share with patients to help them understand the recommendations related to additional care that may be required to lessen the impact of using cannabis.”

“It is important to point out that some elderly cannabis users may have started smoking early, essentially being lifelong users; thus, smoking cannabis is more likely to have a cumulative effect.” –Dr. Aaron Burry

Future research Some ideas for future research in this field might focus on the following: • causes of the association between cannabis use and cavities/periodontitis • specific mechanisms of action by which cannabis use leads to periodontitis or oral cancer • the quantity and frequency of cannabis use among older adults • the best ways to help dental professionals provide appropriate care to growing numbers of medically and behaviourally impaired patients • improving screening of older adults for cannabis use. Conclusion The population is aging, and the health burden is increasing in the elderly age group. Oral health is an important part of public health, and the incidence of oral disease is expected to increase. The use of cannabis in the elderly is increasing, and this signifies a potential concern that could affect the geriatric burden on health systems. The current study showed that cannabis use is correlated with a deterioration in oral health in the elderly. Health policies geared toward older adults need to include oral health as an important component. —Sherene Chen-See, CJMC Correspondent CANADIAN JOURNAL OF MEDICAL CANNABIS • 13

Medical cannabis in

CROHN’S DISEASE

New study evaluates cannabidiol dosages in clinical populations

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ith its favourable toxicity and side effect profile, cannabidiol (CBD) is under increasing investigation in the medical industry to treat many inflammatory diseases, including Crohn’s disease. However, its effective dose in different disease states remains unclear. At the time of writing, there were 49 clinical trials registered on clinicaltrials.gov investigating CBD alone. Surprisingly, none of these trials have explicitly included a study design to investigate the dose-ranging efficacy of CBD. Another issue is that the blurred lines between CBD as a licensed medicine and as an over-the-counter health and food supplement contribute to the overall lack of understanding of what dose of CBD may be therapeutic. This is further hindered by the lack of standardization in over-the-counter CBD products and their unregulated labelled doses. The aim of this systematic review was to

better understand the range of doses of CBD used in clinical studies (Miller SA, Stone NL, Bellman ZD, et al: A systematic review of cannabidiol dosing in clinical populations. Br J Clin Pharmacol 2019; 85(9):1888–1900). A systematic search of PubMed, EMBASE (including MEDLINE) and clinicaltrials.gov was conducted to retrieve all articles reporting CBD administration in clinical populations. A total of 1,038 articles were retrieved, 35 of which met inclusion criteria covering 13 medical symptoms, with doses ranging between <1 and 50 mg/kg/d. CBD did not significantly change the primary outcomes in Crohn’s disease (n=19) (Naftali T, Mechulam R, Mani A, et al: Low-dose cannabidiol is safe but not effective in the treatment for Crohn’s disease, a randomized controlled trial. Dig Dis Sci 2017; 62(6):1615–1620). However, an average low dose of 2.4 mg/kg/d (range 0.3–13. 3 mg/kg/d) was

used in these studies, which is very low in the clinical and clinical trial setting compared to other studies. Despite its long history of sole administration to patients, surprisingly little has been published about the pharmacokinetic properties of CBD, particularly its bioavailability, making it difficult to estimate true effective doses. In those studies that showed good rationales for CBD use in Crohn’s disease, neutral results may be secondary to subtherapeutic dosing. Therefore, the next logical step would be dose escalation trials with embedded pharmacokinetic studies. Although larger clinical trials examining dosing in more detail for each medical context are required, this review concluded that CBD appears to offer a wide range of activity between 1 and 50 mg/kg/d. Studies that used higher doses tended to have better therapeutic outcomes compared to lower doses overall. —Diane Bracuk, CJMC Correspondent

Commentary Keith A. Sharkey, PhD, Calgary, Alta.

MY EXPERTISE IS WITH THE ENDOCANNABINOID SYSTEM, specifically in relation to gut motility and intestinal inflammation. Although I haven’t been directly involved in any studies using medical cannabis (MC) for inflammatory bowel diseases (IBDs) such as Crohn’s disease, I’ve done extensive research in this area. Most recently, I did a podcast for Crohn’s and Colitis Canada with my clinical colleague, gastroenterologist Dr. Yasmin Nasser, exploring the potential benefits and downsides of MC based on the existing literature. Given that the gut is rich in cannabinoid receptors, I was slightly surprised that the studies showed that MC had little effect on altering the course of IBD. One reason is that studies of MC in relation to gut diseases are very limited. That said, there are studies, albeit of a limited nature, that do point to the beneficial effects of MC in IBD. One being done in Canada points to improved quality of life in some patients. Although their disease is not cured, patients feel better and appear to have some relief of symptoms, which is not a small thing. Potentially, if cannabis were to be proven safe in clinical trials in the IBD population—and that’s a big if—it could possibly be used for symptom management and therefore as an adjunct therapy with an existing drug such as Humira. But it would have to be used in conjunction with the existing medication and not replace it. This is important because many people with Crohn’s disease self-medicate, which raises safety concerns. The 14 • CANADIAN JOURNAL OF MEDICAL CANNABIS

IBD and Crohn’s disease population is commonly diagnosed relatively early in life, which can make MC use problematic for some people. For example, because cannabis is known to alter brain development, it is strongly contraindicated in pregnant women or in early childhood. In addition, a lot of people under the age of 25 are being diagnosed with Crohn’s disease. Since brain development is still going on in the early 20s, it would be strongly contraindicated in these individuals. This leads to one of the biggest safety issues: the perception that cannabis is harmless because it’s a natural product. The reality is that when someone consumes drugs—whether they are natural or synthetic—they interact in the body and with one another. Natural products can significantly interfere with some of the drugs given for IBD. Physicians have always been concerned about this, and rightly so. Just because something is natural doesn’t necessarily mean that it’s safe. We need good clinical trials to see if there are true benefits of MC. The Canadian Institutes of Health Research is supporting research proposals to fund cannabis-related research for gastrointestinal disorders, and I’m delighted by that. We’ll see real data rather than the arm waving we’re doing now. Dr. Keith Sharkey is a professor of physiology and pharmacology and Crohn’s and Colitis Canada Chair in IBD Research at the University of Calgary.

Is there a therapeutic role for medical cannabis in Crohn’s disease? As reported in Therapeutic Advances in Gastroenterology 2019 Sep 3; DOI: 10.1177/1756284819870977

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rohn’s disease (CD) is a type of chronic inflammatory bowel disease (IBD) that causes inflammation of parts of the digestive tract. Although animal studies have suggested that medical cannabis (MC) may improve intestinal inflammation, the few randomized controlled trials in patients have not demonstrated efficacy in modulating inflammatory disease activity. However, it may be effective in managing symptoms. “Over the past few years, I’ve come across several patients who have self-trialled cannabis for their IBD, with many reporting significant improvement in their symptoms as well as control of disease activity,” said Dr. Sherman Picardo, a gastroenterologist at the Department of Gastroenterology and Hepatology, Royal Perth Hospital, Perth, Australia, in an online interview with the Canadian Journal of Medical Cannabis. “These positive experiences have inDr. Sherman creased my interest in research, specifically as to Picardo how cannabis may modulate inflammatory activity in IBD.” “Our paper gives an overview of the role of cannabis in inflammatory bowel disease, including our current understanding of the endocannabinoid system, mechanism of action in IBD, plus a summary of the current trials in IBD, as well as safety issues” (Picardo S, Kaplan GG, Shakey KA, et al: Insights in the role of cannabis in the management of inflammatory bowel disease. Therap Adv Gastroenterol 2019 Sep 3; DOI: 10.1177/1756284819870977). MC as a therapeutic option in IBD The human body contains a network of cannabinoid receptors and transmitters known as the endocannabinoid system (ECS). Studies have shown that the ECS is widely distributed throughout the gastrointestinal tract and is involved in the regulation of gastric secretion, gastric and intestinal motility and intestinal inflammation. Although early observational studies showed that MC had promise as a therapeutic option, the potential has not held up. A more recent pilot study investigated oral CBD in 19 patients with refractory CD, using an oral formulation. These patients were refractory to standard therapy (steroids, thiopurines or TNF antagonists) and were randomized to 10 mg of oral CBD or placebo twice daily for 8 weeks. This was a negative study with no improvement in disease activity as measured by the Crohn’s Disease Activity Index (CDAI), as well as several laboratory parameters between groups. There were, however, no significant differences in adverse effects in the treatment group compared to the placebo group (Naftali T, Mechulam R, Mani A, et al: Low-dose cannabidiol is safe but not effective in the treatment for Crohn’s disease, a randomized controlled trial. Dig Dis Sci 2017; 62(6):1615–1620). According to Dr. Picardo, there are a number of limitations with the current human studies. “The main one is that they have only involved small numbers of patients. These are insufficiently powered to detect significant differences between those treated with

“[Medical cannabis] may interact with patients’ medications or mask the symptoms of the active disease, so physicians need to be aware of its use.” —Dr. Sherman Picardo cannabis and placebo. We also still do not know the optimal routes, doses and formulations of cannabis that may be effective.” Potential long-term side effects are also an issue Although Dr. Picardo pointed out that MC can improve a number of gastrointestinal symptoms, including abdominal pain, cramping, diarrhea and nausea, long-term use may potentially make the conditions worse. “Chronic use can paradoxically lead to the development of a disorder called cannabis hyperemesis syndrome,” he explained. “This syndrome involves recurrent episodes of severe nausea [and] intractable vomiting and may also be associated with abdominal pain. The mechanism of this condition remains unknown, but patients often find symptomatic relief by bathing in hot water. Cannabis cessation leads to resolution of these symptoms.” In addition, prolonged cannabis use has been associated with a number of neurocognitive side effects, including anxiety, depression and risk of addiction. It should be avoided in pregnant women and those with a pertinent medical/family history of psychosis and mental illness,” he said. Exercising caution with edibles Dr. Picardo also expressed concerns about edibles, which are often viewed as a safer alternative to smoking or vaping MC. “The main concern with edibles is the delayed onset of action as compared to inhaled MC. Ingested cannabis takes a longer time to have its effect, and it also takes a longer time for the body to clear. This may lead to greater than intended consumption, which can lead to an overdose, resulting in serious side effects and even death.” Guidelines and clinical recommendations The Canadian Association of Gastroenterology (CAG) released a position statement in 2018 on the use of MC for several gastroenterological disorders, stating that cannabis does not appear to alter the course of the disease in IBD (for better or worse) based on the current evidence available. CAG has also recommended that MC should not replace current approved therapies for patients with IBD. Given that many patients are already using MC in managing IBD symptoms (and often don’t report it to their doctors), Dr. Picardo stressed the importance of physicians actively asking and counselling their patients about MC use. “MC may interact with patients’ medications or mask the symptoms of the active disease, so physicians need to be aware of its use,” he said. “There are potential short- and long-term effects associated with MC use that need to be monitored. Hopefully, our paper will help educate both patients and physicians about its potential use and help provide a framework for the development of formal clinical guidelines.” —Diane Bracuk, CJMC Correspondent CANADIAN JOURNAL OF MEDICAL CANNABIS • 15

Medical cannabis in

ANOREXIA

Cannabidiol in cancer-induced anorexia

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annabinoids, the chemical compounds found in cannabis, have been shown to improve appetite by acting on cell membrane receptors and altering neurotransmitter release. Nabilone, a synthetic cannabinoid, has been used to treat loss of appetite in cancer patients, along with cancer-induced nausea and vomiting (CINV). However, there is much uncertainty about its clinical effectiveness and evidence-based guidelines. This Rapid Response Report aimed to review the clinical effectiveness of nabilone in these areas. Guidelines associated with nabilone use in these areas were also examined. This was an update and upgrade of two previous Canadian Agency for Drugs and Technologies in Health (CADTH) reports examining the clinical effectiveness of and guidelines pertaining to the use of nabilone for the treatment of nausea and vomiting or anorexia in adults and adolescents (Ho C, MacDougall D: Nabilone for the Treatment of Nausea and Vomiting or Anorexia: A Re-

view of Clinical Effectiveness and Guidelines. Ottawa (ON): CADTH; 2019). This report made use of a literature search developed for a previous CADTH report. The original literature search was conducted in June 2017 on key resources, including PubMed, EMBASE, the Cochrane Library, University of York Centre for Reviews and Dissemination (CRD) databases and Canadian and major international health technology agencies, as well as a focused Internet search. Regarding the management of nausea and vomiting, the guideline recommended against the use of medical cannabis (MC) as first- or second-line treatment of CINV owing to limited comparison with first-line agents and known harms. With respect to using cannabis to improve appetite, however, their recommendations were more positive. One randomized controlled trial examined the efficacy and safety of 8 weeks of treatment with nabilone for patients with

advanced non-small cell lung cancer diagnosed with anorexia (Turcott JG, Del Rocío Guillen Núñez M, Flores-Estrada D, et al: The effect of nabilone on appetite, nutritional status, and quality of life in lung cancer patients: A randomized, double-blind clinical trial. Support Care Cancer 2018; 26(9):3029–3038). Patients who received nabilone increased their caloric intake (mean 342 kcal) compared to placebo, significantly increasing their daily intake of carbohydrates compared to placebo. However, there was no statistical difference in daily intake of proteins, fat or iron between the nabilone group or the placebo group. Despite this, the authors concluded that nabilone was an adequate and safe therapeutic option in the treatment of patients diagnosed with anorexia due to non-small lung cancer. Hallucination, drowsiness, dysphoria, depression, vertigo, dry mouth and lack of muscle coordination were also noted as possible side effects. —Diane Bracuk, CJMC Correspondent

Commentary Tamara Pryor, PhD, FAED, Denver, Colo., U.S.A.

EATING DISORDERS (EDS) are complex psychopathologies that present clinical challenges for many reasons. A major one is that EDs often co-occur with a substance use disorder (SUD). This includes cannabis abuse, which can begin before, concurrently with or after the onset of an ED. Given this, our clinic uses an integrative model in treating the SUD along with other ED symptoms, such as anxiety, obsessivecompulsive disorder and depression. Another challenge is that individuals with anorexia are empowered by resisting the temptation of eating. Therefore, the appetite-stimulating properties of cannabis can’t necessarily overcome the neurobiological issues that are also intimately involved with their ED. That being said, medical cannabis (MC) might be a helpful tool for some people in conjunction with therapies such as cognitive-behavioural therapy (CBT). There are three primary strains of cannabis: sativa, indica and hybrids. Sativa is the activating strain of cannabis that tends to energize the user and produce the “high.” It can be used to relieve the symptoms of depression, fatigue and mood disorders. Indica is a more sedating strain that produces relaxation and full-body effects and is preferred by the majority of our ED patients. Hybrids are varying functions of these two strains that are thought to balance the positive effects of both. One patient reported that MC helped slow down her mind, allowing her to observe her irrational thoughts sur16 • CANADIAN JOURNAL OF MEDICAL CANNABIS

rounding food. Food began to taste better, making her mealtimes an enjoyable experience. Addiction, of course, is a big concern. Between 7 and 9% of our ED patients who use cannabis show signs of addiction. With 364 legal dispensaries in Denver and 1,021 in Colorado, we can clearly expect that up to 50% of our ED patients are using. Moreover, testing an individual’s level of intoxication has proven to be a challenge due to the length of time THC takes to clear the body. How do we deal with this dilemma? We begin with a very extensive physical and psychological diagnostic assessment for the history of the ED and substance use/abuse. We need to determine whether the patient can participate in our program and is using edibles or tinctures or smoking. Is the patient using indica or sativa? Can we wean the patient off the higher levels of THC with a mix of CBD and a much lower percentage of THC? Finally, what withdrawal effects, such as irritability, insomnia and changes in appetite, need to be treated while still focusing on the patient’s compromised emotional and medical state due to the ED? There are many unanswered questions concerning MC use in ED. We have learned to practise “beginner’s mind” with an attitude of openness, curiosity and a lack of preconceptions or judgment when learning the adaptive function of both the ED and the cannabis use. Dr. Tamara Pryor is the executive clinical director and director of clinical research at EDCare in Denver.

New survey explores the effect of cannabis on appetite

As reported in Journal of Psychopharmacology 2019; 33(9):1149–1159

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t is widely accepted that acute cannabis intoxication produces a stimulatory effect on appetite, more commonly known as “the munchies.” Yet, because most studies in this area have been done on animals, the psychological changes that underlie the munchies are under-researched. “We conducted our study to start to formalize the anecdotal accounts of what the munchies are in humans because, amazingly enough, this has not been done to any great extent in the past,” said Dr. Carl Roberts, a neuroscientist at the University of Liverpool in an online interview with the CANADIAN JOURNAL OF MEDICAL CANNABIS “Our review is the most detailed, specific data set on subjective experiences of cannabis effects on human appetite in a very large sample that [has] been done to date.” Using an online survey, focusing specifically on appetite- and eating-related aspects of cannabis self-administration, the study aimed to create a scale that could reliably measure the psychological components of the munchies (Roberts CA, Jager G, Christiansen P, et al: Exploring the munchies: An online survey of users’ experiences of cannabis effects on appetite and the development of a Cannabinoid Eating Experience Questionnaire. J Psychopharmacol 2019; 33(9):1149–1159). Methods Frequent cannabis users—both recreational and medical users— completed a 46-item questionnaire (Cannabinoid Eating Experience Questionnaire [CEEQ]) about their eating experience under the influence of cannabis. Human appetite involves a complex interplay between motivation, reward and behavioural control. To capture as broad a range of munchies-related phenomena as possible, items were devised relating to each of the six identified themes: (a) eating for pleasure rather than need; (b) loss of control over eating; (c) increased salience of food; (d) taste; (e) increased hunger; and (f) increased sensory perception. Dispelling stereotypes about the munchies “It was noteworthy that we asked about food preferences under the influence of cannabis,” Dr. Roberts said. Indeed, the questions about food preferences yielded unexpected results. Contrary to previous reports, the survey found that it wasn’t only sweet snack foods that were reported as more rewarding with the munchies. The highest response from each sample group was“anything/everything” from each sample group. Moreover, a small group (8.1%) actually preferred healthy foods, such as fruit and salads. According to Dr. Roberts, these counterintuitive findings hold great therapeutic potential. For example, the capacity of cannabis to enhance the desire to eat a variety of foods would be invaluable in a therapeutic context, encouraging consumption of a beneficial, nutritionally optimized diet. “While the common narrative in the media is that people crave junk food, we knew that this might not be completely accurate,” he

said. “Our findings are positive because it suggests that people may be able to have improved appetites and a balanced diet when using medical cannabis [MC] for involuntary appetite loss.” Dr. Roberts was quick to point out, however, that cannabis’s appetite-stimulating benefits may not be applicable in cases of classic anorexia. “Eating disorders are chronic conditions with serious underlying mental health associations,” he explained. “It is the chronicity and rigid thought patterns associated with these disorders which differentiate it from illness- or drug-induced anorexia. Our study, on the other hand, was looking at the underlying phenomena around pleasure from eating and motivations to eat that make some people consume more food Dr. Carl when they are intoxicated with cannabis. It is Roberts this angle which may, in the future, be developed to produce therapeutics for people who have involuntary appetite loss.” Differences between medicinal and recreational users Another significant finding was that there were distinct differences between individuals who used cannabis medicinally and those who used it recreationally. “The group who reported using cannabis for medical reasons scored lower on hedonic and appetite components of our questionnaire than recreational users. It’s difficult to explain this finding in all honesty,” he said. “Perhaps these differences reflect a lower pre-cannabis intoxication baseline for appetitive and hedonic aspects of the eating experience in MC users. However, given the variation in types of medicinal user, it’s difficult to infer what underlies these differences without more detailed study of individuals with specific disorders and more insights into their pathologies/comorbidities.” The data were based on retrospective accounts of people’s experience while taking cannabis, which could be problematic given the association between cannabis use and memory function. Similarly, there was no specific information about the effective or optimal doses necessary to induce the munchies or how routes of administration (inhalation versus ingestion) affected experience. Conclusions Despite the limitations, the CEEQ provided a valid, reliable assessment of the psychological features of cannabis-induced alterations to appetite, which are so lacking in this area. Moreover, it is the most detailed, specific survey of subjective experiences of cannabis effects on human appetite to date. We now have a valid and reliable source to quantify the principle features of ‘the munchies,’” Dr. Roberts said. “However, these are only baby steps. We hope this paper will provide further impetus for further randomized controlled trials and research into the therapeutic application of cannabis for conditions involving involuntary loss of appetite and body weight in the clinical and aging populations.” —Diane Bracuk CJMC Correspondent CANADIAN JOURNAL OF MEDICAL CANNABIS • 17

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ONGOING CLINICAL TRIALS OF NOTE Neural correlates of driving and cannabis

St. Michae’s Hospital Toronto Description: This study aims to evaluate individual driving behaviour, performance on various neurocognitive tests and their correlated neural networks both while under the influence of cannabis and while sober. The investigators will use the STISIM driving simulator, which is fully MRI compatible, to study brain activation, while participants are performing various driving maneuvers. Study Type: Interventional Estimated Enrollment: 12 participants Contact: Dr. Tom Schweizer 416-864-6060 ext 77342 schweizert@smh.ca

Cannabis for opioid substitution trial

Synergy Health Services Inc. Hamilton Description: The purpose of this study is to define common strains of cannabis that adult chronic cancer and non-cancer pain syndrome patients are using as a replacement for opioids. Identified strains, if any, will then be tested via randomized controlled trials to support an application for a Health Canada Drug Identification Number. Study Type: Observational Estimated Enrollment: 1,200 participants Contact: Andrea J Afinec 647 341-4230 aafinec@gmail.com

Cannabis oil for pain effectiveness

Hamilton Health Sciences Corporation Hamilton Description: This project is a systematic, prospective, single-arm cohort study of a safe and effective dosing regimen of an orally administered cannabis oil formulation in cancer patients with poorly controlled pain. Over a one-to-two year period, cancer patients experiencing poorly controlled pain

will receive an orally administered cannabis oil formulation as an add-on therapy to current treatment regimens. Study Type: Interventional Estimated Enrollment: 40 participants Contact: Lisa Rudd-Scott 905-527-2299 ext 43793 ruddl@mcmaster.ca

Cannabis oil for chronic noncancer pain treatment

Hamilton Health Sciences Corporation Hamilton Description: The study's investigators aim to determine whether CBD or CBD+THC is associated with a reduction in pain severity, pain interference, anxiety, depression, insomnia or the use of opioids in chronic non-cancer pain patients. Additionally, the study will look at whether CBD or

CBD+THC is associated with the use of benzodiazepines, analgesics, antidepressants, anxiolytics, or hypnotics amongst chronic non-cancer pain patients. Study Type: Interventional Estimated Enrollment: 309 participants Contact: Lisa L. Patterson 905-978-7861 pattersl@hhsc.ca

Effects of cannabis abstinence on symptoms and cognition in depression Centre for Addiction and Mental Health Toronto Description: The objective of this study is to assess the changes in symptoms and cognition that occur after a 28-day abstinence period in patients with comorbid Cannabis Use Disorder (CUD) and Major Depression

MEETINGS AND CONFERENCES The Science of Cannabis 2020 Sept. 3, 20200 Online symposium https://www.analyticalcannabis.com/webinars/the-science-of-cannabis-2020-312558 Description: This Science of Cannabis online symposium brings together speakers from established testing companies, academia and vendors. The free event will highlight developments in the world of cannabis testing.

Medical cannabis and chronic pain Sept. 3, 2020 Virtual https://www.santecannabis.ca/en/events/medical-cannabis-and-mental-health-wellness-andmindfulness/ Description: The virtual event is hosted by Dr. Alain Watier who will discuss medical cannabis and chronic pain. The two-hour talk will feature an interactive presentation followed by a question and answer period.

The Cannabis Quality Conference & Expo Sept. 8-Nov. 10, 2020 Online https://cqcexpo.com/ Description: The Cannabis Quality Virtual Conference takes place every Tuesday, from Sept. 8 through Nov. 10. The virtual series will include talks on cannabinoid research and discovery, cannabis labs, licensing and more.

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(MDD). This study employs a 28-day abstinence paradigm a total of eight visits to the CAMH Russell site. Study Type: Interventional Estimated Enrollment: 40 participants Contact: Aliya Lucatch 416-535-8501 ext 36115 aliya.lucatch@camh.ca

Safety and efficacy of cannabis in Tourettes

Toronto Western Hospital Toronto Description: This study aims to gather data regarding the dosing, efficacy, and safety of the various medical cannabis products, which are authorized in Canada for the treatment of Tourette syndrome (TS). To gather data, a double-blind, randomized, crossover pilot trial will be conducted to compare the

efficacy and safety of three vaporized medical cannabis products with different THC and CBD contents. Study Type: Interventional Estimated Enrollment: 12 participants Contact: Ferdous Parveen 416-545-5484 ferdous.parveen@uhnresearch.ca

Genetic counselling in the prevention of mental health consequences of cannabis use

Nova Scotia Health Authority Halifax Description: This study will provide genetic counselling to participants from a boardcertified genetic counsellor. Participants will be counselled regarding their individualized risk of developing and of not developing se-

Cannabis Conference Sept. 15, 22 & 29 Virtual https://www.cannabisconference.com/ Description: This three-day virtual conference will explore opportunities and challenges that face the legal cannabis market. Attendees will hear from industry executives and leaders, university researchers and consultants who will share their expertise and tips during educational sessions.

Quebec Cannabis Forum Sept. 17-18, 2020 Virtual https://www.santecannabis.ca/en/events/quebec-cannabis-forum-2/ Description: The two-day virtual event will include healthcare professionals, clinical researchers, patients and government policy makers, among others, to discuss the latest in the medical cannabis industry.

Cannabis Capital Conference October 15-16, 2020 Virtual https://www.benzinga.com/events/cannabis/virtual/ Description: The two-day virtual conference will feature an interactive forum of live and on-demand presentations from industry leaders and investors. Attendees will hear from cannabis companies about advancements in the rapidly changing market.

vere mental illness based on family history, whether or not they choose to use cannabis and genotype. The study's investigators hypothesize that this intervention will reduce exposure to cannabis compared to the youth who are not offered the intervention. Study Type: Interventional Estimated Enrollment: 120 participants Contact: Dr. Rudolf Uher 902-473-7209 uher@dal.ca

Cannabinoid profile investigation of vaporized cannabis in patients with osteoarthritis of the knee

Queen Elizabeth II Health Sciences Centre Halifax Description: The objective of this study is to determine the analgesic dose-response characteristics of vaporized cannabinoids with varying degrees of delta-9-tetrahydrocannabinol (THC)/ Cannabidiol (CBD) ratios. Additionally, investigators will aim to compare functional changes and patient preferences of different THC and CBD profiles in patients with osteoarthritis (OA). Study Type: Interventional Estimated Enrollment: 40 participants Contact: Melissa Todd 902-473-7475 melissa.todd@nshealth.ca

Safety and efficacy of inhaled cannabis (synthetic THC/CBD) for improving quality of life in advanced cancer patients

Royal Victoria Regional Health Centre Barrie, Ont. Description: This phase 3 clinical trial assesses the safety and efficacy of a secondgeneration cannabinoid-based drug to improve the quality of life in advanced cancer patients with uncontrolled symptoms. This is a 4-week treatment period study followed by an open-label period of two years. Study Type: Interventional Estimated Enrollment: 334 participants Contact: Dr. Harneet Arora 514-526-0626 ext 240 harora@medqualis.com

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RESEARCH SUPPLEMENT The contribution of cannabis use to variation in the incidence of psychotic disorder across Europe (EU-GEI): A multicentre case-control study Marta Di Forti, PhD,1,2,3 Diego Quattrone, MD,1,2,3 Tom P. Freeman, PhD,4 Giada Tripoli, MSc,5 Charlotte Gayer-Anderson, PhD,6 Harriet Quigley, MD,5 Victoria Rodriguez, MD,5 Hannah E. Jongsma, PhD,7,8 Laura Ferraro, PhD,9 Caterina La Cascia, PhD,9 Daniele La Barbera, MD,9 Ilaria Tarricone, PhD,10 Domenico Berardi, MD,10 Andrei Szöke, PhD,11 Celso Arango, PhD,12 Andrea Tortelli, PhD,13 Eva Velthorst, PhD,14 Miguel Bernardo, PhD,15 Cristina Marta Del-Ben, PhD,16 Paulo Rossi Menezes, PhD,17 Jean-Paul Selten, PhD,18 Peter B. Jones, PhD,7,19 James B. Kirkbride, PhD,8 Bart P.F. Rutten, PhD,20 Lieuwe de Haan, PhD,14 Pak C. Sham, PhD,1,21 Jim van Os, PhD,1,22 Cathryn M. Lewis, PhD,1,2 Michael Lynskey, PhD,23 Craig Morgan, PhD,6 Robin M. Murray, FRS,1,3 the EU-GEI WP2 Group † 1. SOCIAL, GENETIC AND DEVELOPMENTAL PSYCHIATRY CENTRE, INSTITUTE OF PSYCHIATRY, PSYCHOLOGY AND NEUROSCIENCE, KING’S COLLEGE LONDON, LONDON, UK 2. NATIONAL INSTITUTE FOR HEALTH RESEARCH (NIHR) MENTAL HEALTH BIOMEDICAL RESEARCH CENTRE AT SOUTH LONDON AND MAUDSLEY NHS FOUNDA TION TRUST AND KING’S COLLEGE LONDON, UK3. ACADEMIC SPIN OFF COQUA LAB S.R.L, TURIN, ITALY 3. SOUTH LONDON AND MAUDSLEY NHS MENTAL HEALTH FOUNDATION TRUST, LONDON, UK 4. ADDICTION AND MENTAL HEALTH GROUP (AIM), DEPARTMENT OF PSYCHOLOGY, UNIVERSITY OF BATH, BATH, UK 5. INSTITUTE OF PSYCHIATRY, PSYCHOLOGY AND NEUROSCIENCE AND DEPARTMENT OF PSYCHOSIS STUDIES, INSTITUTE OF PSYCHIATRY, KING’S COLLEGE LONDON, LONDON, UK 6. DEPARTMENT OF HEALTH SERVICE AND POPULATION RESEARCH, INSTITUTE OF PSYCHIATRY, KING’S COLLEGE LONDON, LONDON, UK 7. DEPARTMENT OF PSYCHIATRY, UNIVERSITY OF CAMBRIDGE, CAMBRIDGE, UK; 8. PSYLIFE GROUP, DIVISION OF PSYCHIATRY, UNIVERSITY COLLEGE LONDON, LONDON, UK 9. DEPARTMENT OF EXPERIMENTAL BIOMEDICINE AND CLINICAL NEUROSCIENCE, UNIVERSITY OF PALERMO, PALERMO, ITALY 10. DEPARTMENT OF MEDICAL AND SURGICAL SCIENCE, PSYCHIATRY UNIT, ALMA MATER STUDIORUM UNIVERSITÀ DI BOLOGNA, BOLOGNA, ITALY; 11INSERM U955, EQUIPE 11. INSTITUT NATIONAL DE LA SANTÉ ET DE LA RECHERCHE MÉDICALE, CRÉTEIL, PARIS, FRANCE 12. DEPARTMENT OF CHILD AND ADOLESCENT PSYCHIATRY, HOSPITAL GENERAL UNIVERSITARIO GREGORIO MARAÑÓN, SCHOOL OF MEDICINE, UNIVERSIDAD COMPLUTENSE, IISGM (CIBERSAM), MADRID, SPAIN; 13. ETABLISSEMENT PUBLIC DE SANTÉ MAISON BLANCHE, PARIS, FRANCE 14. DEPARTMENT OF PSYCHIATRY, EARLY PSYCHOSIS SECTION, ACADEMIC MEDICAL CENTRE, UNIVERSITY OF AMSTERDAM, AMSTERDAM, NETHERLANDS; 15. BARCELONA CLINIC SCHIZOPHRENIA UNIT, NEUROSCIENCE INSTITUTE, HOSPITAL CLINIC, DEPARTMENT OF MEDICINE, UNIVERSITY OF BARCELONA, IDIBAPS, CIBERSAM, BARCELONA, SPAIN 16. DIVISION OF PSYCHIATRY, DEPARTMENT OF NEUROSCIENCE AND BEHAVIOUR, RIBEIRÃO PRETO MEDICAL SCHOOL, UNIVERSITY OF SÃO PAULO, SÃO PAULO, BRAZIL 17. DEPARTMENT OF PREVENTATIVE MEDICINE, FACULDADE DE MEDICINA FMUSP, UNIVERSITY OF SÃO PAULO, SÃO PAULO, BRAZIL; 18. RIVIERDUINEN INSTITUTE FOR MENTAL HEALTH CARE, LEIDEN, NETHERLANDS 19. CAMEO EARLY INTERVENTION SERVICE, CAMBRIDGESHIRE & PETERBOROUGH NHS FOUNDATION TRUST, CAMBRIDGE, UK 20. DEPARTMENT OF PSYCHIATRY AND NEUROPSYCHOLOGY, SCHOOL FOR MENTAL HEALTH AND NEUROSCIENCE, SOUTH LIMBURG MENTAL HEALTH RESEARCH AND TEACHING NETWORK, MAASTRICHT UNIVERSITY MEDICAL CENTRE, MAASTRICHT, NETHERLANDS 21. CENTRE FOR GENOMIC SCIENCES, LI KASHING FACULTY OF MEDICINE, THE UNIVERSITY OF HONG KONG, HONG KONG, CHINA 22. BRAIN CENTRE RUDOLF MAGNUS, UTRECHT UNIVERSITY MEDICAL CENTRE, UTRECHT, THE NETHERLANDS; 23. DEPARTMENT OF ADDICTION, INSTITUTE OF PSYCHIATRY, KING’S COLLEGE LONDON, LONDON, UK

Keywords: cannabis, daily use, high-potency, psychotic disorder, SUMMARY Background: Cannabis use is associated with increased risk of later psychotic disorder but whether it affects incidence of the disorder remains unclear. We aimed to identify patterns of cannabis use with the strongest effect on odds of psychotic disorder across Europe and explore whether differences in such patterns contribute to variations in the incidence rates of psychotic disorder. Methods: We included patients aged 18 to 64 years who presented to psychiatric services in 11 sites across Europe and Brazil with first-episode psychosis and recruited controls representative of the local populations. We applied adjusted logistic regression models to the data to estimate which patterns of cannabis use carried the highest odds for psychotic disorder. Using EuropeReprinted with permission from Lancent Psychiatr y March 2019; http://dx.doi.org/10.1016/ S2215-0366(19)30048-3. Copyright © 2019 The Author(s). Published by Elsevier Ltd. Distributed under the Creative Commons Attribution License Content has been edited to conform with the Canadian Press Publication Style Guide

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wide and national data on the expected concentration of Δ9-tetrahydrocannabinol (THC) in the different types of cannabis available across the sites, we divided the types of cannabis used by participants into two categories: low potency (THC <10%) and high potency (THC ≥10%). Assuming causality, we calculated the population attributable fractions (PAFs) for the patterns of cannabis use associated with the highest odds of psychosis and the correlation between such patterns and the incidence rates for psychotic disorder across the study sites. Findings: Between May 1, 2010, and Apr. 1, 2015, we obtained data from 901 patients with first-episode psychosis across 11 sites and 1,237 population controls from those same sites.

Daily cannabis use was associated with increased odds of psychotic disorder compared with never users (adjusted odds ratio [OR] 3.2, 95% CI 2.2–4·1), increasing to nearly fivetimes increased odds for daily use of high-potency types of cannabis (4.8, 2.5–6.3). The PAFs calculated indicated that if high-potency cannabis were no longer available, 12.2% (95% CI 3.0–16.1) of cases of first-episode psychosis could be prevented across the 11 sites, rising to 30.3% (15.2–40.0) in London and 50.3% (27.4–66.0) in Amsterdam. The adjusted incident rates for psychotic disorder were positively correlated with the prevalence in controls across the 11 sites of use of high-potency cannabis (r=0.7; p=0.0286) and daily use (r=0.8; p=0.0109). Interpretation: Differences in frequency of daily cannabis use and in use of high-potency cannabis contributed to the striking variation in the incidence of psychotic disorder across the 11 studied sites. Given the increasing availability of high-potency cannabis, this has important implications for public health. Funding source: Medical Research Council, the European Community’s Seventh Framework Program grant, São Paulo Research Foundation, National Institute for Health Research (NIHR) Biomedical Research Centre (BRC) at South London and Maudsley NHS Foundation Trust and King’s College London and the NIHR BRC at University College London, Wellcome Trust. INTRODUCTION any countries have legalized or decriminalized cannabis use, leading to concerns that this might result in an increase in cannabis use and associated

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harm,1,2 even if the latter only affects a minority of the population.3 Cross-sectional and prospective epidemiological studies4,5 as well as biological evidence6 support a causal link between cannabis use and psychotic disorder. Meta-analysis shows a dose–response association with the highest odds of psychotic disorder in those with the heaviest cannabis use.7 Nevertheless, it is not clear whether, at a population level, patterns of cannabis use influence rates of psychotic disorder.8,9,10 A systematic review11 has described a fivetimes variation in the incidence of schizophrenia worldwide. A transnational case-control study (EU-GEI) has reported an eight-times difference in the incidence of psychotic disorder across 16 European sites plus one in Brazi1.12

Differences in the distribution of risk factors for psychosis, such as cannabis use, among the populations studied might contribute to these variations. Therefore, using data from the EU-GEI case-control study of first-episode psychosis and the previously published data on incidence,12 we sought to describe differences in patterns of cannabis use across sites, identify the measure of cannabis use with the strongest impact on odds of psychotic disorder across sites, calculate the population attributable fraction (PAF) for the patterns of cannabis use associated with the highest odds for psychosis, and test whether differences in patterns of cannabis use contribute to variations in the incidence of psychotic disorder across sites.

Figure 1: Crude and fully adjusted ORs of psychotic disorders for the combined measure of frequency plus type of cannabis use in the whole sample Crude ORs are adjusted only for age, gender and ethnicity and fully adjusted ORs are additionally adjusted for level of education, employment status, and use of tobacco, stimulants, ketamine, legal highs, and hallucinogenics. Error bars represent 95% CIs. OR=odds ratio. CANADIAN JOURNAL OF MEDICAL CANNABIS • 21

Research Supplement: The contribution of cannabis use to variation in the incidence of psychotic disorder

Figure 2: Fully adjusted ORs of psychotic disorders for the combined measure of frequency plus type of cannabis use in three sites. Data are shown for the three sites with the greatest consumption of cannabis: London (201 cases, 230 controls), Amsterdam (96 cases, 101 controls), and Paris (54 cases, 100 controls). Error bars represent 95% CIs. OR=odds ratio. METHODS Study Design The EU-GEI project set out to estimate the incidence of psychosis and recruit first-episode psychosis cases and controls to investigate risk factors for psychotic disorder. First, incidence rates were estimated12 by identifying all individuals with a first episode of psychosis who presented to mental health services between May 1, 2010, and Apr. 1, 2015, in 17 areas in England, France, the Netherlands, Italy, Spain, and Brazil (appendix). Second, to investigate risk factors, we attempted to assess 1,000 firstepisode cases and 1,000 population-based controls during the same period. Participants Patients presenting with their first episode of psychosis were identified by trained researchers who carried out regular checks across the mental health services within the 17 catchment areas (one site per catchment area). Patients were eligible if they were aged 18 to 64 years and resident within the study areas at the time of their first presentation with a diagnosis of psychosis by ICD-10 criteria (F20–33); details are provided in the supplementary methods and in previous publications.12 Cases were approached via their clinical team and invited to participate. Using the Operational Criteria Checklist algorithm, all cases interviewed re-

ceived a research-based diagnosis.13 Patients were excluded if they had been previously treated for psychosis or if they met criteria for organic psychosis (F09) or for psychotic symptoms resulting from acute intoxication (F1X.5). We adopted quota sampling strategies to guide the recruitment of controls. Accurate local demographic data were used to set quotas for controls to ensure the samples’ representativeness of each catchment area’s population at risk in terms of age, gender, and ethnicity. Potential controls were initially identified on the basis of locally available sampling strategies, most commonly random sampling from lists of all postal addresses and from general practitioner lists from randomly selected surgeries. To achieve representation of hard-to-reach groups (e.g., young men), we then tried to oversample them using more ad-hoc approaches such as internet and newspaper advertisements, and leaflets at local stations, shops, and job centres. Controls were excluded if they had received a diagnosis of, or treatment for, psychotic disorder. All participants provided informed, written consent. Ethical approval was provided by research ethics committees in each site.

Medical Research Council Sociodemographic Schedule, as described previously.14 An updated version of the modified Cannabis Experience Questionnaire15 (CEQEU-GEI) was used to gather detailed history of use of cannabis and other recreational drugs (appendix). To minimize recall bias, none of the recruitment materials for cases or controls mentioned cannabis or referred to its potential role as risk factor for psychotic disorder. Participants were asked if they had ever used cannabis in their lifetime; if the answer was yes, they were then asked to give details on their pattern of use. Questions on the type of cannabis used made no reference to its potency and allowed participants to report the colloquial name, in any language, of the cannabis they used. We included six measures of cannabis use in the initial analyses, including lifetime cannabis use (i.e., whether or not the individual had ever used cannabis), currently using cannabis, age at first use of cannabis,16 lifetime frequency of use (i.e., the frequency that characterised the individual’s most consistent pattern of use), and money spent weekly on cannabis during their most consistent pattern of use. Using data published in the European Monitoring Centre for Drugs and Drug Addiction 2016 report17 that reported the concentration of Δ9-tetrahydrocannabinol (THC) in the types of cannabis available across Europe, supplemented by national data for each included country,18,19,20,21,22,23,24,25,26 we created the final measure of cannabis potency (appendix).

Statistical analysis We used complete case analyses for all analyses using Stata version 14. We used inverse probability weights to account for any oversampling of controls relative to the populations at risk (appendix); we gave each control’s data a weight inversely proportional to their probability of selection given their key demographics (age, gender and ethnicity) using census data on relevant populations. These weights were applied in all analyses. To identify potential confounders, we used χ2 and t tests to test for an association between Measures sociodemographic data and the data on drug We obtained sociodemographic data using the use with case-control status in the whole sam-

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Table 1: Sociodemographics and lifetime history of substance misuse across all included cases and controls

ple. On the basis of the χ2 and t tests, data on the use of other recreational drugs were included as confounders in the main analyses, with low or no use scored as 0 and use scored as 1 in categorical variables: tobacco (never used or smoked <10 cigarettes per day vs smoked ≥10 cigarettes or more per day); stimulants, hallucinogens, ketamine, and novel psychoactive substances (socalled legal highs; never tried vs. ever tried); and mean number of alcoholic drinks consumed daily on an average week. All sociodemographic and druguse variables associated with case-control status were controlled for in all analyses (appendix). We applied adjusted logistic regression models to estimate the effect of each of the six measures of cannabis use on the odds of a psychotic disorder (i.e., case status). The data have

a multilevel structure because cases and controls are nested within sites. To take account of this clustering in the logistic regression analysis, we used the cluster option in STATA. We fitted interaction terms to logistic models. These interaction models, using likelihood ratio tests, were run to investigate whether individual measures of cannabis use interacted with each other to significantly increase the odds ratios (ORs) for psychotic disorder and whether the ORs for psychotic disorder of the individual measures of cannabis use varied significantly by site. The STATA punafcc command was used to calculate the population attributable fraction (PAF) with 95% CIs for the two cannabis use measures that carried the largest adjusted OR for psychosis. The PAF measures the population effect of an exposure by providing an estimate of the proportion of disorder that would be prevented if the exposure were removed, assuming causality. To account for potential selection bias, we did a probabilistic sensitivity analysis using the STATA episensi command.27 This analysis assumes that we can assign prior probability distributions for the bias parameters, which capture the uncertainty about those parameters, and use these distributions in a probabilistic sensitivity analysis (appendix). Finally, we used Pearson’s correlation to test for an association between the incidence rates for psychotic disorder adjusted for ethnic minority status in each site and the prevalence of daily cannabis use and use of high-potency cannabis in the controls as representing the general population for each site. Role of the funding source Study funders contributed to the salaries of the research workers employed but did not participate in the study design, data analyses, data interpretation or writing of the manuscript. All authors had full access to the study data and had final responsibility for the decision to submit for publication.

Table 2: Measure of cannabis use and ORs for psychotic disorders for case-control sample across 11 sites

Results Between May 1, 2010, and Apr. 1, 2015, we approached 1,519 patients with first-episode psychosis; 356 (23%) refused to participate, 19 (1%)

CANADIAN JOURNAL OF MEDICAL CANNABIS • 23

Research Supplement: The contribution of cannabis use to variation in the incidence of psychotic disorder

Figure 3: Adjusted incidence rates for all psychosis for the 11 sites plotted against the prevalence of daily use in the population controls (A) and prevalence of use of highpotency cannabis in the population controls (B) Incidence rates are adjusted for age, gender, and ethnicity. Puy-de-Dôme is not included because data on ethnicity were missing for 27 (66%) of 42 incidence cases, therefore the adjusted incidence rate for this site was not calculated. could not consent because of language barriers, and 14 (0.9%) were excluded because they did not meet the age inclusion criteria. Patients who refused to participate were older (p=0.0015), more likely to be women (p=0.0063) and of white European origin (p<0.0001; appendix). Thus, 1,130 cases took part. These cases were broadly representative for gender and ethnicity of the incidence sample, although

younger (mean age 31.2 years [SD 10.6], median 29 years [IQR 23–37] for cases vs. mean 34.5 years [12.0], median 31 years [23.0–41·0] for the total incidence; p<0.0001; details by site are available in the appendix). All 17 sites contributed to the recruitment of 1,499 population controls except for Maison Blanche, which was consequently excluded from the analysis (appendix). Most sites had minimal missing sociodemographic (≤3%) or CEQEU-GEI data (<5%). However, Verona, Santiago, Oviedo, Valencia, and Cuenca had at least 10% of data missing on the measures of cannabis use or on one or more of the main confounding variables; therefore, given their small sample sizes there was insufficient data to include these sites in the analysis. This resulted in 901 cases and 1,237 controls for analysis. Compared with controls, cases were younger, more often men, and from ethnic minorities, than the controls (Table 1). Controls were more likely to have pursued higher education (p<0.0001) and to have been employed a year before assessment than cases (p<0.0001; Table 1); the differences in gender, ethnicity, education, and employment are those expected when comparing patients with psychosis with general population samples. More cases than controls reported having ever used cannabis, having smoked 10 tobacco cigarettes or more a day, or having tried other recreational drugs (Table 1). We found no difference between cases and controls in the mean number of alcoholic drinks consumed every day on an average week (5.2 drinks [SD 0.4] among controls vs. 4.8 drinks [0.4] among cases; median 2.0 drinks [IQR 0.0–6.0] for controls vs. 1.0 drink [0.0–4.0]; p=0.45). An adjusted logistic regression model showed that those who had ever used cannabis had a modest increase in odds of psychotic disorder compared with those who had never used it (Table 2); the odds were slightly greater in those who started to use cannabis at age 15 years or younger. Daily cannabis use was associated with increased odds of psychotic disorder compared with never having used it (Table 2); this re-

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mained largely unchanged when taking into account age at first use (OR 3.1, 95% CI 2.1– 5.2), money spent (2.9, 1.9–4.4), and type of cannabis used (2.6, 2.0–3.9). Those who spent €20 or more a week showed more than a doubling in the odds of a psychotic disorder (2.5, 1.6–3.8), which dropped to 1.3 (95% CI 1.0– 2.1) after controlling for daily use and type of cannabis used; we observed no interaction between daily use and money spent (p=0.67). Use of high-potency cannabis (THC≥10%) modestly increased the odds of a psychotic disorder compared with never use (Table 2); this remained largely unchanged after controlling for daily use (OR 1.5, 95% CI 1.1–2.6). Those who had started using high-potency cannabis by age 15 years showed a doubling of risk (2.3, 1.4–3.1), without evidence of interaction (p=0.63). Frequency of use and type of cannabis used were combined to generate a single-measure of frequency plus type of use because these two measures had the highest ORs. Adjusted logistic regression indicated that daily use of high-potency cannabis carried more than a four-times increase in the risk of psychotic disorder (OR 4.8, 95% CI 2.5–6.3) compared with never having used cannabis; the odds were lower for those who used low-potency cannabis daily (2.2, 1.4–3.6; Figure 1). Nevertheless, there was no evidence of interaction between frequency of use and type of cannabis used (p=0.25). When considering variation by site, neither the ORs for daily use (p=0.25) nor those for high-potency cannabis (p=0.45), compared with never use, varied significantly across sites (Table 3). The observed differences in ORs for daily use ranged from 7.1 (95% CI 3.4–11.8) in Amsterdam to 1.1 (0.4–12.2) in Puy de Dôme. Similarly, the differences in the ORs for use of high-potency cannabis, ranging from 3.6 (1.5– 7.7) in Amsterdam to 0.6 (0.1–2.5) in Palermo, are consistent with the geographical differences in its availability.17 In the three sites with the greatest consumption of high-potency cannabis, daily use of high-potency cannabis was associated with the greatest increase in the odds for psychotic disorder compared with never having used:

fect of use of high-potency cannabis on the odds for psychotic disorder. The probabilistic sensitivity analyses we ran suggest that selection bias is unlikely to explain our findings (appendix). After correction for selection bias, the OR for daily cannabis use (5.7, 95% CI 3.5–9.4) was similar to the original OR (5.7, 4.4–7.5). However, the CI for the corrected OR was wider than that for the original OR, suggesting a wider range of possible values for the true OR with 95% certainty. The results of the probabilistic sensitivity analysis to estimate the potential effects of selection Table 3: PAFs for daily use of cannabis and use of high-potency bias on high potency cannabis in the whole sample and by site cannabis use were similar (appendix). The EU-GEI incifour times greater in Paris, five times greater in dence study reported an eight-times variation London, and more than nine times greater in in the incidence rates of psychotic disorder adAmsterdam (Figure 2). Based on the prevalence of daily cannabis justed for age, gender, and ethnic minority stause, and use of high potency cannabis, in cases tus across the study sites.12 We found a and controls and the corresponding adjusted correlation between the adjusted incidence ORs, we estimated the PAFs for the whole sam- rates for psychotic disorder in our 11 sites and ple and for each of the sites (Table 3). Assum- the prevalence of daily cannabis use in controls ing causality, the proportion of new cases of (r=0.8; p=0.0109). Sites where daily use was psychotic disorder in the whole sample attrib- common such as London (26 [11.7%] of 223 utable to daily use was 20.4% (95% CI 17.6– controls) and Amsterdam (13 [13.0%] of 100 22.0) and 12.2% (3.0–6.1) for use of controls) had among the highest adjusted incidence rates (45.7 cases per 100,000 personhigh-potency cannabis (Table 3). The PAF analysis revealed variations by years in London and 37.9 per 100,000 sites, ranging from 43.8% (95% CI 34.0–69.1) person-years in Amsterdam). This differed of new cases of psychotic disorder in Amster- from sites such as Bologna where daily use was dam being attributable to daily use to just less frequent (three [4.6%] of 65 controls) and 1.2% (0.8–15.4) of cases in Puy de Dôme. Fur- the adjusted incidence rate was half that of thermore, the PAF for use of high-potency London (21.0 cases per 100,000 per person cannabis ranged from 50.3% (27.4–66.0) of years; Figure 3). Similarly, we found a correlation between cases in Amsterdam to 1.9% (0.6–16.3) estiadjusted incidence rates for psychotic disorder mated in Bologna. We did not calculate the PAF for Palermo because there was no main ef- and the prevalence of use of high-potency cannabis in controls across the 11 sites (r=0.7;

p=0.0286). Amsterdam (54 [54.0%] of 100 controls), London (58 [26.0%] of 223 controls), and Paris (21 [21.0%] of 100 controls) had the highest prevalence of use of high-potency cannabis in controls and the highest adjusted incidence rates for all psychosis (45.7 per 100,000 person-years in London, 37.9 in Amsterdam, and 46.1 in Paris; Figure 3). The prevalence of daily use and the prevalence of use of high-potency cannabis in controls were only modestly correlated (r=0.2; p=0.0413), therefore we report data for both (Figure 3). DISCUSSION Our main findings show that among the measures of cannabis use tested, the strongest independent predictors of whether any given individual would have a psychotic disorder or not were daily use of cannabis and use of highpotency cannabis. The odds of psychotic disorder among daily cannabis users were 3.2 times higher than for never users, whereas the odds among users of high-potency cannabis were 1.6 times higher than for never users. Starting to use cannabis by 15 years of age modestly increased the odds for psychotic disorder but not independently of frequency of use or of the potency of the cannabis used. These measures of extent of exposure did not interact with each other, nor did they interact with the sites. This lack of interaction between degree of cannabis use (ie, daily use of cannabis or use of high-potency cannabis) and site might reflect insufficient power in our study; however, it could also indicate that although the magnitude of the effect might vary depending on the degree of cannabis use, there is a consistent effect of daily use and use of high-potency cannabis on the ORs for psychotic disorders across all study sites. We replicated our previous finding28 that daily use of high-potency cannabis is most strongly associated with case-control status. Compared with never users, participants who used high-potency cannabis daily had four-times higher odds of psychosis in the whole sample, with a five-times increase in London and a ninetimes increase in Amsterdam. We also saw that, in the whole sample, daily use of high-potency cannabis was associated with a doubling in the

CANADIAN JOURNAL OF MEDICAL CANNABIS • 25

Research Supplement: The contribution of cannabis use to variation in the incidence of psychotic disorder

OR for psychotic disorder. The large sample size and the different types of cannabis available across Europe have allowed us to report that the doseâ&#x20AC;&#x201C;response relationship characterising the association between cannabis use and psychosis7 reflects not only the use of high-potency cannabis but also the daily use of types with an amount of THC consistent with more traditional varieties. Use of high-potency cannabis was a strong predictor of psychotic disorder in Amsterdam, London, and Paris where high-potency cannabis was widely available, by contrast with sites such as Palermo where this type was not yet available. In the Netherlands, the THC content reaches up to 67% in Nederhasj and 22% in Nederwiet; in London, skunk-like cannabis (average THC of 14%) represents 94% of the street market29 whereas in countries like Italy, France, and Spain, herbal types of cannabis with THC content of less than 10% were still commonly used.17,18 Thus our findings are consistent with previous epidemiological and experimental evidence suggesting that the use of cannabis with a high concentration of THC has more harmful effects on mental health than does use of weaker forms.28,30,31 The novelty of this study is its multicentre structure and the availability of incidence rates for psychotic disorder for all the sites. This has allowed us, for the first time, to show how the association between cannabis use and risk of psychosis varies geographically depending on prevailing patterns of use, and how the latter contributes to variation in incidence rates for psychotic disorder. Variations in patterns of cannabis use across the sites translated into differences in the proportion of new cases of psychotic disorder attributable to cannabis use. We estimated, assuming causality, that 20% of new cases of psychotic disorder across all our sites could have been prevented if daily use of cannabis had been abolished; the PAF for daily use was 21% for London, similar to that previously reported,3 but ranged from 44% in Amsterdam to 6% in Palermo. The local availability of high-potency types of cannabis resulted in a PAF of 50% for Amsterdam and 30% for Lon-

don. Therefore, assuming causality, if high-potency cannabis were no longer accessible, the adjusted incidence rates for all psychotic disorder in Amsterdam would drop from 37.9 to 18.8 cases per 100,000 person-years and in London from 45.7 to 31.9 cases per 100,000 person-years. Finally, we report what, to our knowledge, is the first evidence that differences in the prevalence of daily use and use of high-potency cannabis in the controls correlate with the variation in the adjusted incidence rates for psychotic disorder across the study sites. Our results show that in areas where daily use and use of high-potency cannabis are more prevalent in the general population, there is an excess of cases of psychotic disorder. Our findings need to be appraised in the context of limitations. Data on cannabis use are not validated by biological measures, such as urine, blood, or hair samples. However, such measures do not allow testing for use over previous years.26 Moreover, studies with laboratory data and self-reported information have shown that cannabis users reliably report frequency of use and the type of cannabis used.32,33 Our potency variable does not include the proportion of another important cannabinoid, cannabidiol (CBD),34 because reliable data on this were available for only England and Holland.17,19,24,25,34 We categorized the reported types of cannabis used as low and high potency on the basis of the available estimates of mean percentage of THC from official sources. Although this approach does not account for variations in the THC content in individual samples, we used a conservative cutoff of 10%. Given the much higher mean percentage of THC expected in types of cannabis commonly used in UK24,29 and in Holland,19 our dichotomous categorization might have led to underestimation of the effect of potency on the ORs for psychotic disorder. Furthermore, a direct measure of the THC content of the cannabis samples used by our participants would have only provided data on THC value for a single timepoint rather than an estimate covering lifetime use. When setting quotas based on the main sociodemographics of the populations at risk

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for the recruitment of controls, we applied weights to account for undersampling or oversampling of some groups. For instance, most of the sites oversampled the age group 16 to 24 years (appendix), which represents the part of the population most likely to consume cannabis17 and the most likely to suffer associated harm.6,16,35 Moreover, none of the sites mentioned either cannabis, or other, drug use in the materials used for participant recruitment, thus avoiding selection and recall bias. First-episode studies minimise the effect of recall bias, which can be a source of error when history of exposure to environmental factors is collected retrospectively in patients with well established psychosis. This study design also reduces the chances of results being biased by illness course; therefore, it is preferred to investigate aetiology.36 In conclusion, our findings confirm previous evidence of the harmful effect on mental health of daily use of cannabis, especially of high-potency types. Importantly, they indicate for the first time how cannabis use affects the incidence of psychotic disorder. Therefore, it is of public health importance to acknowledge alongside the potential medicinal properties of some cannabis constituents the potential adverse effects that are associated with daily cannabis use, especially of high-potency varieties. CONTRIBUTORS CG-A, GT, CLC, DLB, LF, EV, IT, HEJ, CMD-B, LdH, JvO, BPFR, CM, MB, CMdB, J-PS, JBK, AT, AS, CA, PRM, MDF, and all the authors in the EU-GEI group collected or supervised the data collection. MDF, DQ, GT, IT, HEJ, CLC, and LF cleaned and prepared the data for this paper analysis. MDF did the data analysis and wrote the findings in the initial manuscript. TPF, HEJ, DQ, and GT contributed to creation of the figures and tables. CM, CML, RMM, PCS, JvO, BPFR, LdH, JPS, DB, IT, ML, TPF, JBK, CA, and PBJ provided a careful statistical and methodological revision of the manuscript and contributed to the final draft. RMM, ML, and CM contributed to the interpretation of the results. All

authors had full access to all data (including statistical reports and tables) in the study and take responsibility for the integrity of the data and the accuracy of the data analysis. DECLARATION OF INTERESTS RMM reports personal fees from Janssen, Lundbeck, Sunovion and Otsuka, outside of the submitted work. MDF reports personal fees from Janssen, outside the submitted work. MB reports grants and personal fees from Adamed, Janssen-Cilag, Otsuka and Abbiotics; personal fees from Angelini and Casen Recordati; and grants from Lundbeck and Takeda, outside of the submitted work. PBJ reports personal fees from being a member of the scientific advisory boards for Janssen and Ricordati, outside of the submitted work. CA reports personal fees from Acadia, Ambrosseti, Gedeon Richter, Janssen Cilag, Lundbeck, Merck, Otsuka, Roche, Servier, Shire, Schering Plough, Sumitomo Dainippon Pharma, Sunovion and Takeda; and grants from CIBERSAM, Familia Alonso, Fundación Alicia Koplowitz, the European Commission, the Spanish Ministry of Science and Universities and the Comunidad de Madrid, during the conduct of the study. All other authors declare no competing interests. ACKNOWLEDGMENTS This study was funded by the Medical Research Council, the European Community’s Seventh Framework Program grant (agreement HEALTH-F2-2009-241909 [Project EU-GEI]), São Paulo Research Foundation (grant 2012/0417-0), the National Institute for Health Research (NIHR) Biomedical Research Centre (BRC) at South London and Maudsley NHS Foundation Trust and King’s College London, the NIHR BRC at University College London, and the Wellcome Trust (grant 101272/Z/12/Z). REFERENCES 1. Grucza RA, Agrawal A, Krauss MJ, Cavazos-Rehg PA, et al: Recent trends in the prevalence of marijuana use and associated disorders in the United States. JAMA Psychiatry 2016; 73:300301. 2. Hall W, Lynskey M: Evaluating the public health impacts of legalizing recreational cannabis use in the United States. Addiction 2016; 111:1764-1773. 3. Wilkinson ST, Yarnell S, Radhakrishnan R, Ball SA, et al: Marijuana legalization: impact on physicians and public health. Annu Rev Med

2016; 67:453-466. 4. Gage SH, Hickman M, Zammit S: Association between cannabis and psychosis: epidemiologic evidence. Biol Psychiatry 2016; 79:549-556. 5. Mustonen A, Niemelä S, Nordström T, et al: Adolescent cannabis use, baseline prodromal symptoms and the risk of psychosis. Br J Psychiatry 2018; 212:227-233. 6. Murray RM, Englund A, Abi-Dargham A, et al: Cannabis-associated psychosis: neural substrate and clinical impact. Neuropharmacology 2017; 124:89-104. 7. Marconi A, Di Forti M, Lewis CM, Murray RM, Vassos E: Meta-analysis of the association between the level of cannabis use and risk of psychosis. Schizophr Bull 2016; 42:1262-1269. 8. Ksir C, Hart CL: Cannabis and psychosis: a critical overview of the relationship. Curr Psychiatry Rep 2016; 18:12. 9. Hill M: Perspective: be clear about the real risks. Nature 2015; 525:S14. 10. Boydell J, van Os J, Caspi A, et al: Trends in cannabis use prior to first presentation with schizophrenia, in South-East London between 1965 and 1999. Psychol Med 2006; 36:1441-1446. 11. McGrath J, Saha S, Welham J, El Saadi O, MacCauley C, et al: A systematic review of the incidence of schizophrenia: the distribution of rates and the influence of sex, urbanicity, migrant status and methodology. BMC Med 2004; 2:13. 12. Jongsma HE, Gayer-Anderson C, Lasalvia A, et al: Treated incidence of psychotic disorders in the multinational EU-GEI study. JAMA Psychiatry 2018; 75:36-46. 13.McGuffin P, Farmer A, Harvey I: A polydiagnostic application of operational criteria in studies of psychotic illness: development and reliability of the opcrit system. Arch Gen Psychiatry 1991; 48:764-770. 14. Mallett R, Leff J, Bhugra D, Pang D, Zhao JH: Social environment, ethnicity and schizophrenia: a case-control study. Soc Psychiatry Psychiatr Epidemiol 2002; 37:329-335. 15. Di Forti M, Morgan C, Dazzan P, et al: High-potency cannabis and the risk of psychosis. Br J Psychiatry 2009; 195:488-491. 16. Casadio P, Fernandes C, Murray RM, Di Forti M: Cannabis use in young people: the risk for schizophrenia. Neurosci Biobehav Rev 2011; 35:17791787. 17. European Monitoring Centre for Drugs and Drug Addiction: European drug report 2016: trends and development. Publications Office of the European Union, Luxembourg, 2016. 18. European Monitoring Centre for Drugs and Drug AddictionSpanish Ministry of Health and Consumer Affairs: Spain national report (2011 data) to the EMCDDA 2012. Government Delegation for National Plan on Drugs, Madrid, 2012. 19. Niesink R, Rigter S: THC-concentraties in wiet, nederwiet en hasj in Nederlandse coffeeshops (2012–2013). AF1221. Trimbos-instituut, Utrecht, 2013. 20. Brisacier A-C, Cadet-Taïrou A, Díaz Gómez C, et al.: Drogues, chiffres clés. Observatoire Français des Drogues et des Toxicomanies, Paris, 2015. 21. Zamengo L, Frison G, Bettin C, Sciarrone R: Cannabis potency in the Venice area (Italy): update 2013. Drug Test Anal 2015; 7:255-258.

22. Niesink RJM, Rigter S, Koeter MW, Brunt TM: Potency trends of Δ9-tetrahydrocannabinol, cannabidiol and cannabinol in cannabis in the Netherlands: 2005–15. Addiction 2015; 110:19411950. 23. de Oliveira GL, Voloch MH, Sztulman GB, Neto ON, Yonamine M: Cannabinoid contents in cannabis products seized in São Paulo, Brazil, 2006–2007. Forensic Toxicol 2008; 26:31-35. 24. Potter DJ, Clark P, Brown MB: Potency of Δ9THC and other cannabinoids in cannabis in England in 2005: implications for psychoactivity and pharmacology. J Forensic Sci 2008; 53:90-94. 25. Hardwick S, King S: Home Office cannabis potency study 2008. Home Office Scientific Development Branch, London, 2008. 26. Taylor M, Sullivan J, Ring SM, Macleod J, Hickman M: Assessment of rates of recanting and hair testing as a biological measure of drug use in a general population sample of young people. Addiction 2016; 112:477-485. 27. 0rsini N, Bellocco R, Bottai M, Wolk A, Greenland S: A tool for deterministic and probabilistic sensitivity analysis of epidemiologic studies. Stata J 2008; 8:29-48. 28. Di Forti M, Marconi A, Carra E, et al: Proportion of patients in south London with first-episode psychosis attributable to use of high potency cannabis: a case-control study. Lancet Psychiatry 2015; 2:233-238. 29. Potter DJ, Hammond K, Tuffnell S, Walker C, Forti MD: Potency of Δ9-tetrahydrocannabinol and other cannabinoids in cannabis in England in 2016: implications for public health and pharmacology. Drug Test Anal 2018; 10:628-635. 30. Freeman TP, van der Pol P, Kuijpers W, et al: Changes in cannabis potency and first-time admissions to drug treatment: a 16-year study in the Netherlands. Psychol Med 2018; 48:23462352. 31. Murray RM, Quigley H, Quattrone D, Englund A, Di Forti M: Traditional marijuana, high-potency cannabis and synthetic cannabinoids: increasing risk for psychosis. World Psychiatry 2016; 15:195204. 32. Freeman TP, Morgan CJA, Hindocha C, Schafer G, Das RK, Curran HV: Just say ‘know’: how do cannabinoid concentrations influence users’ estimates of cannabis potency and the amount they roll in joints? Addiction 2014; 109:1686-1694. 33. Curran HV, Hindocha C, Morgan CJ, Shaban N, Das RK, Freeman TP: Which biological and selfreport measures of cannabis use predict cannabis dependency and acute psychotic-like effects? Psychol Med 2018. DOI:10.1017/S003329171800226X. 34. Englund A, Freeman TP, Murray RM, McGuire P: Can we make cannabis safer? Lancet Psychiatry 2017; 4:643-648. 35. Mokrysz C, Freeman TP, Korkki S, Griffiths K, Curran HV: Are adolescents more vulnerable to the harmful effects of cannabis than adults? A placebo-controlled study in human males. Transl Psychiatry 2016; 6:e961. 36. Marshall M, Lewis S, Lockwood A, Drake R, Jones P, Croudace T: Association between duration of untreated psychosis and outcome in cohorts of first-episode patients: a systematic review. Arch Gen Psychiatry 2005; 62:975-983.

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Opinion: Educating youth on cannabis is a necessary task — continued from page 3 likely to increase. In Colorado, edibles accounted for 45 per cent of all sales by 2014. Health Canada’s packaging guidelines and dose limits for edibles (10 milligrams per item) will only go so far in mitigating potential harms. Health Canada has vaguely stated that the products should not be appealing to youth but it is hard to imagine that chocolates and flavoured drinks with names like “Pineapple Orange Gummies” would not be enticing to that population.

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Canadian Journal of Medical Cannabis Relocating your practice? Taking a sabbatical? Prefer to receive the digital version of the Canadian Journal of Medical Cannabis (CJMC)? Please contact our Subscription Department via e-mail at cjmc_subs@gmx.ca Interested in promoting your upcoming educational event or activities to the readers of CJMC? Write us at cjmc_ads@gmx.ca For questions of a general nature, please write to: cjmc_questions@gmx.ca Our business offices are open weekdays from 8:30 am to 5:30 pm, excluding holidays. You may telephone toll-free at 866-63-CHRON (866-632-4766). Sending a fax? Our number is 416-352-6199. Follow CJMC on Twitter at www.twitter.com/cjmc2020 Prefer to correspond in the time-honoured manner of placing pen to paper? We do not judge. Please write to us at Canadian Journal of Medical Cannabis, 555 Burnhamthorpe Road, Suite 306 Toronto, Ont. M9C 2Y3 Canada

A more concerted public health campaign and detailed warnings on products are needed. Targeting successful cannabis education to youth is a challenging task but an imperative one. While the Supreme Court of Canada ruled to give Canadians legal access to cannabis, Health Canada now bears the regulatory and educational responsibility. In 2018, Health Canada committed a little over $100 million over six years for public cannabis education and surveillance. But $186 million tax dollars were collected in the first five months

of legalization. Health Canada could and should invest so much more into oversight and education. The collective health of our youth depends upon it. CJMC welcomes contributions for this column. If you have opinions you would like to share with CJMC readers please submit material to cjmc@gmx.ca for consideration.

Copyright 2020 TheConversation.com All rights reserved. Reprinted with permission. You can read the original article here: https://bit.ly/3bJ6Ao4

Cannabis Q: “We have a chronic pain crisis” — continued from page 30 I’m optimistic that for some people, they will be able to either wholly or in part replace opioids with cannabis. I think that replacing opioids entirely with cannabis might be too optimistic. But I’m hoping that through clinical trials we’ll figure out who might benefit from cannabis. How is it possible that, apparently, cannabinoid receptors are basically everywhere in the body—from brain to skin? Yes, that is a very good question. Most higher mammals have an endocannabinoid signalling system. Also, certain classes of plants produce molecules that fit into those receptors. This a reminder of the tremendous beauty and diversity of the natural world.

What directives might you offer to physicians who are thinking of including cannabis therapy as part of their prescribing? I would commend physicians who are openminded enough to consider adding it to their treatment arsenal. More evidence needs to be generated on dosage, on strains and on routes of administration. There is already evidence, for example, for the benefits of cannabis in pain management. We have a chronic pain crisis in this country; too many people are living with unaddressed chronic pain and uncontrolled opioid use. I’m a part of the Canadian Consortium for the Investigation of Cannabinoids (CCIC), which is a national body which aims to support clinicians, nurses, social workers and the like who are interested in cannabis therapy. We have an annual conference in which we discuss the best available evidence and hear from people working in those fields, so there are many organizations like that to support clinicians in learning about cannabis therapy and providing them [with] the best evidence.

Colorado legalized in 2014; any learnings for Canada? Colleagues in Colorado share two insights. One, this is a journey, not a destination. They impressed upon us the importance of monitoring and evaluating the impact of legalization so that the system can be adjusted. The other area of concern is around edibles. My American colleagues believe that legalizing edibles at the same Skin Spectrum Summit 2020 time was probably a mistake. In Canada’s Conference on Ethnodermatology terms of acute harm from is going VIRTUAL cannabis, almost all has to do New three-part program with with the overconsumption of live Q&A sessions. edibles. It was a smart move by the Thursday October 1, 2020, Saturday October 3, federal government to have a 2020 and Tuesday October 6, 2020 sequential legalization. Hopefully, we’ll be able to avoid Visit www.skinspectrum.ca for more information some of the harms that they saw in Colorado.

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SAVE THE DATE

Telemedicine in cannabis Telemedicine services offer guidance to cannabis patients

With some physicians hesitant about prescribing, a variety of telehealth services are attempting to fill the void

A

lthough doctors admit that there is a gap in care for clinical patients seeking cannabis as a potential therapeutic option, they are wary about telemedicine services stepping in to fill the void. Dr. Hance Clarke is the director of pain services at Toronto General Hospital and works with patients who seek cannabis as a treatment option to ensure that their needs are met. However, Dr. Clarke admits that many physicians do not feel appropriately educated on cannabis or do not believe there is Dr. Hance enough evidence to supClarke port its use. “I’m somewhat concerned regarding the purpose of telehealth based cannabis centres … other than to close this gap and get patients on to cannabis,” Dr. Clarke said in an interview with the CANADIAN JOURNAL OF MEDICAL CANNABIS “What I would hope is that these telemedicine clinics are doing a comprehensive assessment of the condition they are potentially going to treat.” Patients seeking access to MC Regardless of whether a physician prescribes it or not, patients seeking cannabis have access in Canada—that’s where services such as O Cannabis are hoping to step in and fill a need. O Cannabis whose head administration office is based in Oakville, Ont., is a decentralized medical cannabis clinic that was opened by CEO Morgan Toombs in June 2017. Toombs’ service aims to reduce time spent in the doctor’s office waiting to see a physician while taking advantage of technology to bring medical cannabis consultations to patients in their homes. O Cannabis is just one of many telehealth options for patients seeking cannabis. Ottawa-based Nurse On Board bills itself as a nurse-led healthcare navigation and pa-

tient advocacy service that offers, among other things, a registered nurse to research treatment options for patients. Canadian Cannabis Clinics has been in operation for six years, and their doctors work with patients looking for alternative treatment through cannabis. The service mainly provides patients with medical documents to send to licensed producers, allowing them to obtain medical cannabis. Having watched friends and family go through struggles to access medical cannabis through traditional channels, Toombs, a regisMorgan tered nurse, decided to Toombs open O Cannabis after nurse practitioners were authorized to prescribe cannabis in Ontario. Toombs says O Cannabis’s nurse practitioners can authorize cannabis use and offer patient support via a video link or telephone. “We are very accessible; we are in people’s homes via their smartphones, their tablets, their computers, and so instead of patients having to go to the clinics, we bring the clinic to the patient,” said Toombs. Additionally, Toombs says the service has a “robust on-boarding and health assessment with the patient” before cannabis is suggested as a treatment option. One concern for Dr. Clarke is the lines of communication between the patient’s primary care provider and the telehealth service are solid in order to ensure that proper patient care is provided and that the quarterbacks of their care are informed. “There should be solid communication between their primary care physicians, and notes should be exchanged. The telehealth interaction needs to be integrated back into the patients’ healthcare provider ecosystem,” said Dr. Clarke. “If it is happening outside of that domain, I think we may not be doing patients

right in terms of adding to their overall care.” “If you have the primary care physician at least informed, then you have closed the loop and opened a line of communication between the different practitioners; that makes sense. But if I am a patient that walks into a [telehealth clinic] and I receive a cannabis [prescription] without information from the interaction being connected to my other doctors, I am not convinced that is the best way to improve an individual’s overall health condition. ” In an effort to include the patient’s primary care provider, one of the services O Cannabis offers is a “pop-up clinic” where the nurse practitioners go to a doctor’s clinic and work alongside doctors at their practice. “We give the doctor back the treatment notes so that they are in the journey of the patient’s care as well,” Toombs explained. “We make sure the doctor is on board, knows what the patient is on, feels comfortable, etc., so that they can stay in their wheelhouse prescribing other pharmaceuticals and such, and we can stay in our wheelhouse, which is prescribing plant-based medicine.” Furthermore, O Cannabis offers patients an in-depth follow-up program via e-mail and telephone. The telemedicine service also assures patients that they will advocate on their behalf to ensure that they have access to the best quality medicine from Health Canadaapproved licensed producers. Is telemedicine needed in MC? Ultimately, Dr. Clarke felt that rather than using resources to create telehealth services aimed at filling a void, better research and products should be made available to patients seeking cannabis as a treatment option. “Instead of trying to get more patients on to cannabis because we can do this—patients can access it anyway—maybe we should help the industry bring valid, and reliable, evidence and products to the patients. That would be my starting place,” Dr. Clarke said. —Dhiren Mahiban, CJMC Correspondent

CANADIAN JOURNAL OF MEDICAL CANNABIS • 29

CJ MC

©

question & answer

Cannabis Q

The fourth in a series of CJMC interviews with thought leaders in medical cannabis In this regular column, Dr. Shafiq Qaadri, a Toronto family physician, CME lecturer, four-term member of the Ontario Provincial Parliament and CJMC contributor, interviews people of interest in the cannabis industry. In this interview, Dr. Qaadri talks with Dr.M-J Milloy, a research scientist at the British Columbia Centre on Substance Use (BCCSU) and an assistant professor in the Department of Medicine at UBC. On January 1, 2019, he was appointed to be UBC’s first Canopy Growth Professor of Cannabis Science, a position created by arms’length gifts to the university from Canopy Growth, one of the world’s largest producers of legal cannabis, and British Columbia’s Ministry of Mental Health and Addictions.

Congratulations on your appointment as Canopy Growth Professor of Cannabis Science at UBC. Thank you. It is a tremendous honour, as a young researcher, to be given such a vote of confidence. It comes at a great time—legalization is a year old, which makes it easier for researchers to finally do controlled trials in humans to figure out the risks and the benefits of cannabis therapy. Also, we are grappling with the opioid crisis across the country. It’s has taken far too many of our fellow citizens. I’m hopeful that the work we do might go some way towards determining if cannabis might be an effective intervention in that crisis. Can you share insights from the 150+ papers you have published on substance abuse and HIV? I trained in the HIV environment, as a clinical and social epidemiologist. In Vancouver, exciting work is being done on harm reduction for people who use drugs, such as heroin

I was also fortunate to play a marginal role at the BC Centre for Excellence in HIV/AIDS, where I did my training and my post-doc; through my work, I was able to see the real benefits of antiretroviral therapy on the health of people living with HIV who use drugs and cocaine. What do you anticipate with the recent legalization of cannabis edibles, potables and topicals? We are very interested in this next phase of legalization, especially edibles. My group, led by one of my PhD students, Stephanie Lake, just published a paper laying out possible public health impacts of cannabis legalDr. Shafiq Qaadri ization. There are concerns around pediatric exposure, overconsumption and vaping cannabis—especially cardiopulmonary disease caused by vaporizing THC. Tell us about the various clinical trials you are involved in. One is an industry-sponsored trial to look at cannabis use for PTSD. Recently, we published a study, also led by Stephanie Lake, using Canadian survey data showing that among Canadians with PTSD, those who were not using cannabis had a very high risk of suicidality and major depressive episodes, but [among] those using cannabis, there was no statistical association between PTSD and suffering from major depressive episodes or suicidality.

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In terms of the overdose work, we’ve got a number of clinical trials planned; one of them looks at cannabis as an adjuvant therapy for existing treatment for opioid use disorder and basically trying to answer the question, “If we pair cannabis or cannabinoids with methadone or buprenorphine, naloxone, which are really the standard firstline, second-line therapies, will there be better outcomes from treatments than just the established therapies alone?” These are part of harm reduction trials. Patients with opioid use disorder who also use cannabis have a lower risk of overdose, so we’re evaluating these interventions. Is it just a matter of research that we don’t know the appropriate doses for the massive list of indications for cannabinoids? We need evidence—not only clinical trials, but more broadly. When you plan a clinical trial, there’s no such thing as just “cannabis”—there’s a pretty large diverse class of molecules. Dosage has always been one of the most important considerations, especially in a clinical setting.

Dr. M-J Milloy

Will cannabis ever replace opioids? I’ve spoken with people who tell me that is exactly what they have done: they are currently free of opioids because they have managed to replace it with cannabis.

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Call for papers The Canadian Journal of Medical Cannabis announces a call for papers for potential inclusion in upcoming editions of the Journal.

Please see page 4 for more details

6 million Canadians live with chronic pain Isnâ&#x20AC;&#x2122;t it time you looked at alternative therapies?

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Reference: Cragg JJ, Warner FM, Shupler MS, et al. Prevalence of chronic pain among individuals with neurological conditions. Statistics Canada Health Report. Release date: March 21, 2018. Available at https://www150.statcan.gc.ca/n1/pub/82-003-x/2018003/article/54921-eng.pdf

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