- Email: [email protected]
Marijuana Use by Adolescents and Young Adults with Inflammatory Bowel Disease
ARTICLE IN PRESS THE JOURNAL OF PEDIATRICS • www.jpeds.com
ORIGINAL ARTICLES
Marijuana Use by Adolescents and Young Adults with Inflammatory Bowel Disease Edward J. Hoffenberg, MD1,2, Shannon K. McWilliams, MA1, Susan K. Mikulich-Gilbertson, PhD1, Brittany V. Murphy, PhD2, Megan Lagueux, SM2, Kristen Robbins, BS2, Analice S. Hoffenberg, MD, MSPH1, Edwin de Zoeten, MD, PhD1,2, and Christian J. Hopfer, MD1 Objective To evaluate marijuana use by adolescents and young adults with inflammatory bowel disease (IBD). Study design This descriptive cross-sectional study of patients seen between December 2015 through June 2017 at Children’s Hospital Colorado for IBD enrolled patients 13-23 years of age, independent of marijuana use status. Information obtained consisted of chart review, electronic and interview self-report, and serum cannabinoid levels. Marijuana ever-users were compared with never-users for clinical characteristics and perceptions of risk with use; users provided information on routes, patterns, motivations, and perceived benefits and problems with use. Results Of 99 participants, ever-use was endorsed by 32% (32 of 99) and daily or almost daily use by 9% (9 of 99). Older age was the only characteristic related to endorsing marijuana use. Twenty-nine ever-users completed all questionnaires. After adjusting for age, users were 10.7 times more likely to perceive low risk of harm with regular use (P < .001). At least 1 medical reason for use was endorsed by 57% (17 of 30), most commonly for relief of physical pain (53%, 16 of 30) (2 did not complete all questionnaires). Problems from use were identified by 37% (11 of 30), most commonly craving/strong urge to use. Most common route of use was smoking (83%) followed by edibles (50%), dabbing (40%), and vaping (30%). Conclusions Marijuana use by adolescents and young adults with IBD is common and perceived as beneficial. Guidelines for screening, testing, and counseling of marijuana use should be developed for patients with IBD. (J Pediatr 2018;■■:■■-■■).
F
orty-six states have approved medical marijuana and 8 states have laws allowing possession and consumption for recreational use. Inflammatory bowel disease (IBD, Crohn’s disease, or ulcerative colitis) is an indication for access to medical marijuana in multiple states.1 Marijuana (cannabis) is a biotic compound that contains multiple active cannabinoids including delta-9 tetrahydrocannabinol (THC) and cannabidiol (CBD).2 The National Academy of Sciences has concluded that, in adults, marijuana is effective for chemotherapy-related nausea and vomiting, and may improve chronic pain as well as multiple sclerosis-related spasticity.2 Patients and families have advocated using marijuana for the treatment of medical conditions and ask care providers about it for treating their IBD.3,4 Emerging understanding of the endocannabinoid system provides a rationale for considering the medical benefits of marijuana.5 In addition to reducing pain, there may be effects on nausea, vomiting, gastrointestinal tract motility, and inflammation.6 These benefits, however, have not been tested empirically and must be weighed against the risks of regular marijuana use in adolescence with potential adverse effects including risk for addiction,7 lower educational performance,8 and psychiatric disorders such as schizophrenia.8 There are no studies evaluating benefit of marijuana use in pediatric IBD. Three observational studies of about 300 adult participants with IBD9-11 and 1 study of 37 young adults 18-21 years of age12 suggest that use of marijuana is associated with subjective relief of symptoms. There are 2 placebo-controlled clinical trials in adults with Crohn’s disease. THC cigarettes showed improvement of symptoms but not inflammatory markers compared with placebo,13 and low dose CBD compared with placebo showed no benefit for Crohn’s disease.14 Aside from subjective reFrom the 1Departments of Pediatrics and Psychiatry, sponses, there is no evidence supporting disease-modifying, long-term benefits University of Colorado School of Medicine, Aurora, CO; and 2Children’s Hospital Colorado, Aurora, CO of marijuana for patients with IBD. Funded by the Colorado Department of Public Health and In Colorado, medical marijuana card applications surged in 2012 after restricEnvironment, which had no role in study design, data collection, analysis or interpretation, report writing, or tions were loosened, and recreational marijuana stores opened in 2014. In 2015, decision to publish. The authors declare no conflicts of interest. 38% of Colorado high school students have tried marijuana, and 21% endorse Portions of this study were presented as an abstract at 15 use in the past month. It is widely available in many forms including edibles, the World Congress of Pediatric Gastroenterology,
CBD IBD THC
Hepatology and Nutrition, October 7, 2016 in Montreal, Canada, and the North American Society for Pediatric Gastroenterology, Hepatology and Nutrition Annual Meeting, November 3, 2017 in Las Vegas, NV.
Cannabidiol Inflammatory bowel disease Delta-9 tetrahydrocannabinol
0022-3476/$ - see front matter. © 2018 Elsevier Inc. All rights reserved. https://doi.org10.1016/j.jpeds.2018.03.041
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THE JOURNAL OF PEDIATRICS • www.jpeds.com oils, and smokeable products.16 Here we report on baseline information for 99 pediatric participants with IBD enrolled in an ongoing study to describe their IBD course and their use patterns. We hypothesized that marijuana use might be common in adolescents with IBD and that users might have higher rates of clinical or perceived medical benefit than nonusers. In addition, we sought to obtain detailed information on use patterns, motivations, and perceptions of benefit and harm.
Methods We designed a descriptive cross-sectional study of patients with IBD 13-23 years of age treated at Children’s Hospital Colorado. All patients with IBD were enrolled into the Improve Care Now (www.improvecarenow.org) network so that standardized clinical data were obtained.17 Participants were recruited from December 2015 through June 2017 by a research coordinator during their outpatient clinic visit, inpatient admission, or during a visit for medication infusion. Of the 174 potential participants, 19 were still undecided or were still to sign consent at next visit; of the remaining 155, 72% (111 of 155) agreed to enroll (Figure) but 12 were excluded from this analysis because of incomplete data (6 cannabinoid levels pending; 6 did not complete surveys). Consent was signed by parent or participant if 18 years and over, and assent by participants <18 years of age. Study information was provided in a private setting without the presence of a parent. Information obtained from the electronic medical record included demographic data such as age, sex, race, as well as weight, height, type of IBD, and physician global assessment of disease activity.18 The physician global assessment is a subjective measure in which the physician assigns a disease status to 1 of 4 categories: inactive, mild, moderate, or severe.
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Self-report data on appetite, pain, quality of life, depression, anxiety, and marijuana use were collected and managed using Research Electronic Data Capture (REDCAP) tools.19 Appetite and pain scores were assessed by a visual analog scale from 0 to 100.20 Validated questionnaires included IBD specific health-related quality of life as assessed by the Impact III questionnaire (validated for ages 13-17 years),21 the Generalized Anxiety Disorder-7 scale, which was used to assess anxiety,22 and questions describing marijuana use reported in other studies.23 A modified version of the Patient Health Questionnaire-9 was used to assess depression in which question 9 about thoughts of self-harm was removed because our hospital standard of addressing this issue prior to patient leaving the building exceeded our resources.24 Therefore, the total score is not comparable with other distributions of the Patient Health Questionnaire-9. Questions we developed in other studies to assess use of illicit substances including marijuana were used to describe marijuana use.23 Motivation for use was assessed using 35 exploratory questions, as binary items (yes/no). These questions were adapted from studies investigating nonmedical opiate prescription use, marijuana and alcohol drinking motives, or created for this study.25-27 Some of the questionnaire items were validated previously and others were created for this study. We report on items allocated by consensus among the authors into medical (5 questions) or nonmedical (35 questions). Questions on substance abuse and dependence were derived from the Diagnostic and Statistical Manual of Mental Disorders, 4th Edition.28 Serum levels of THC and CBD were measured at enrollment by a liquid chromatography/mass spectrometry technique.29 At the time of blood draw, participants were asked about past 6-month marijuana use including quantity, route, date, and time. Participants who endorsed use in the past 6 months and/or who self-reported ever using marijuana were designated “ever-users” in analyses.
Figure. Flow diagram of study enrollment. 2
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Statistical Analysis Data were examined for accuracy and the distributional properties of each variable. Many of the results are descriptive, consisting of self-reports of marijuana perceptions and use in adolescents with IBD. We compared the marijuana everuse and never-use groups on demographics; IBD disease characteristics; serum levels for THC, metabolites, and/or CBD; and perceptions of risk with regular marijuana smoking. Groups were compared with independent t tests and c2 tests; nonparametric equivalents (Mann-Whitney U, Fisher exact tests) were used as appropriate if normality assumptions were violated. Logistic regression adjusting for demographic characteristics that differed significantly between groups were further used to evaluate differences in perceptions of risk from using marijuana regularly between ever-users and never-users. All
analyses were conducted in SPSS v 24.0 (IBM Corporation, Armonk, New York) and were based on 2-tailed probability tests with 0.05 significance level. All participants received a substance abuse resource pamphlet at time of the consent. The study was approved by the Colorado Multiple Institution Review Board.
Results Of the 99 participants, age range 13-22 years, 63% (62 of 99) had diagnosis of Crohn’s disease, 27% (27 of 99), ulcerative colitis, and 10% (10 of 99) indeterminate/unknown colitis, 57% (56 of 99) were male, 83% (82 of 99) had quiescent/ mild disease based on physician global assessment (Table I). The 32 participants in the ever-use group were older (mean
Table I. Clinical characteristics and perception of risk data for 99 participants with IBD 13-21 years of age, by marijuana use
Age, y, mean (SD) Male n (%)
All 99
Never use 67 (68%)
16.2 (2.2)
15.9 (2.2)
Ever use 32 (32%) 17.0 (1.9)
56 (57%)
37 (55%)
19 (59%)
Race, n (%) White/Caucasian Other Disease type, n (%) Ulcerative colitis Crohn's disease Indeterminate/unknown
80 (82%) 18 (18%)
56 (84%) 11 (16%)
24 (77%) 7 (23%)
27 (27%) 62 (63%) 10 (10%)
21 (31%) 40 (60%) 6 (9%)
6 (19%) 22 (69%) 4 (13%)
Physician global assessment, n (%) Quiescent/mild Moderate/severe
82 (83%) 17 (17%)
55 (82%) 12 (18%)
27 (84%) 5 (16%)
Visual analog scale (0-100) n, mean (SD) Pain
95, 23.0 (24.6)
66, 21.9 (23.8)
29, 25.5 (26.6)
97, 64.0 (22.7)
67, 65.9 (22.3)
30, 59.7 (23.6)
Modified PHQ-9: n, median (range)
92, 3.0 (0-18)
63, 3.0 (0-13)
29, 3.0 (0-18)
GAD-7 n, median (range)
92, 2.0 (0-20)
63, 2.0 (0-13)
29, 2.0 (0-20)
(Impact III) n, mean (SD) (13-17 y)
70, 70.4 (13.9)
52, 71.9 (13.2)
18, 66.2(15.2)
(PEDSQL) n, mean (SD)(18 + y)
25, 79.0 (13.1)
13, 81.4 (13.5)
12, 76.4(12.6)
16 (16%)
0 (0%)
16 (50%)
40 (40/95 = 42%)
16 (16/65 = 25%)
24 (24/30 = 80%)
Appetite
Detected serum cannabinoids n (%) Perceived no to low risk of harm with regular smoking of marijuana n (%) Characteristics in marijuana users only Frequency of use, typical pattern past y n = 29 Use less than wkly No use Less than once a mo Once a mo Two or more times a mo Use wkly or more frequently Once a wk Two or more times a wk Once a d More than once a d Number of d used, past 30 d Medical marijuana registry holder n (%)
14 2 9 2 1 15 3 3 3 6 10.8 4
Statistic; P value t (97) = 2.6; P = .011 c2(1) = 0.15; P = .70 c2(1) = 0.54; P = .46 c2(2) = 1.81; P = .404
c2(1) = 0.08; P = .78
t(95) = 1.2; P = .22 t(93) = −.65; P = .52 U = 888.5, P = .83 U = 823.5, P = .44 t(68) = 1.4; P = .14 t(23) = 0.94; P = .36 c2(1) = 40.0; P < .001 c2(1) = 23.8; P < .001
(48%) (7%) (31%) (7%) (3%) (51%) (10%) (10%) (10%) (21%) (SD = 9.0) (13%)
GAD-7, Generalized Anxiety Disorder-7; PedsQL, Pediatric Quality of Life Inventory; PHQ-9, Patient Health Questionnaire-9.
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THE JOURNAL OF PEDIATRICS • www.jpeds.com 17.0, SD = 1.9 years) than the 67 in the never-use group (mean 15.9 SD = 2.2 years; P = .011). The ever- and never-use groups were similar for sex, race, disease type, disease activity, and measures of pain, appetite, quality of life, depression, and anxiety. Serum cannabinoids were detected in 50% (16 of 32) of the ever-use group but in none of the never-use group (0 of 67) (P < .001). For the 32 in the ever-use group, denominators for selfreported data differ because of missing responses and are reported. Thirty of 32 ever-users provided responses to questions about perceptions and motivations, and 29 of 32 provided responses to questions about use patterns. Low to no risk of harm with regular use of marijuana was endorsed by 80% (24 of 30) of ever-users and 25% (16 of 65) of never-users (P < .001; Table I). After adjusting for age, which significantly differed between groups, ever-users were 10.7 times more likely to perceive low to no risk of harm with regular use of marijuana than never-users (OR = 10.7, P < .001). A 3-group analysis (no use, use 13- <18 years of age, and use 18 years+ of age) identified no additional differences. Use at least weekly was reported by 52% (15 of 29), and use at least daily by 31% (9/29). Only 4 reported possession of a medical marijuana registry card (Table I). For questions describing marijuana use, such as source and route of use, participants could select multiple choices if applicable (Table II). Friends (60%) and dealer/black market (17%) were the most commonly reported sources. One-half or more reported smoking (83%) or consuming edibles (50%) with dabbing (40%) and vaping (30%) also being common. At least 1 medical reason for use was endorsed by 57% (17 of 30), with 53% (16 of 30) reporting use to relieve physical pain (Table III). One or more nonmedical recreational or psychological reasons for use were reported by 87% (26 of 30). Most common nonmedical motivations for use were to relax and relieve tension 60% (18 of 30), to feel good 50% (15 of 30), and to have a good time with friends 47% (14 of 30). One or more problems with use was reported by 37% (11 of 30).
Table II. Sources and products/routes of marijuana use (multiple choices allowed) in patients with IBD who report ever using marijuana (N = 30) Sources of marijuana Friends Dealer/black market Parents Siblings Someone else with Medical Registry Card Medical marijuana dispensary Recreational marijuana dispensary Other (“grower/caregiver,” “grandparent”) Products/routes of use Smoking Ingested as edible Dab Vape Oil Other
18 (60%) 5 (17%) 4 (13%) 3 (10%) 3 (10%) 3 (10%) 2 (7%) 2 (7%) 25 (83%) 15 (50%) 12 (40%) 9 (30%) 5 (17%) 1 (3%)
Volume ■■ These 11 reported on average 3.2 (SD = 2.0) problems (range 1-6). Overall, the most common problem was craving or strong desire to use 20% (6 of 30), followed by needing to use more for same effect 17% (5 of 30) and using larger amount for longer than intended 17% (5 of 30).
Discussion This study of marijuana use by adolescents and young adults with IBD is from a state with legalized recreational marijuana use for adults and medical marijuana use for all. The principal finding in our study of participants 13-22 years of age with IBD is that 32% had ever used marijuana and 9% used daily or almost daily. Furthermore, a substantial proportion reported use for medicinal purpose, use by methods besides smoking, and perceived low risk with regular use. The detection of serum cannabinoids only in the ever-users is consistent with truthful reporting. Our study confirms that marijuana is easily accessible and is consistent with estimates that rates of use among Colorado high school students have had no statistical change from 2005 to present.15 Although a medical reason for use was reported frequently, only 4 had a medical marijuana card and friends and family were the most common source. An increasingly larger percentage of adolescents in Colorado30 and nationally16 perceives safety with regular marijuana use. In our study, 80% of users perceived low risk of harm with regular marijuana use. The National Academy of Sciences has concluded that there is an association between marijuana use frequency during adolescence and progression to developing problem marijuana use.2 Risks of high frequency use include motor vehicle collision6 and fatality24 if driving while intoxicated; drug dependence with higher rates of anxiety, depression, and psychotic disorders31; use of other drugs32; and psychosocial decline (worsening performance on neuropsychological tests).33 There is a need for further understanding of the potential medical benefits of marijuana use in IBD. We found that the most common reasons for using marijuana were to relax and relieve tension, relieve pain, and feel good. Our study did not identify differences between everusers and never-users for clinical measures of IBD severity, quality of life, anxiety, or depression. Theoretically, a different study design such as a randomized controlled trial of marijuana use or placebo could better evaluate the safety and benefit of frequent marijuana use for induction or maintenance of remission, for severe cases, and for those who discontinue established therapies in favor of marijuana alone or marijuana in combination with complementary therapies.34 However, human subject research involving cannabis remains uniquely challenging because cannabis is a schedule 1 drug under federal law.3 Route of use of marijuana by participants with IBD may also be a factor in efficacy and safety. The majority in our study smoke marijuana, like most surveys. However, other routes of use were quite common, with 50% of users reporting ingesting marijuana as an edible. Edible marijuana products have
4
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Table III. Motivations for use and problems with use reported by 30 participants with IBD who reported ever using marijuana
Table III. Continued Problems with use Having problems at school, work, or other obligations (eg, drug-related absences) Spending a great deal of time planning on getting marijuana or getting/using/ recovering from it Being high on marijuana where it increased your chances of getting hurt (eg, driving) Continuing to use marijuana despite reoccurring personal problems (eg, fights with friends, parents, and significant other) Continuing to use marijuana despite physical health problems that could get worse with it Wanting to cut down or quit using marijuana but couldn't Having problems with the law related to marijuana (eg, underage possession)
Motivations for use Medical n = 17 (57%)
Nonmedical: recreational and psychological n = 26 (87%)
Survey question: Do you think you use marijuana . . . (check all that apply) To relieve physical pain To relieve abdominal cramping To relieve nausea To improve appetite To help lose weight To relax and relieve tension To feel good To have a good time with my friends To get high Insomnia: To help me get to sleep To experiment, to see what it is like Because it's fun It helps when I feel depressed or anxious To help when I get sick Life is short. I'll live it to the fullest while I can Attention: So that I can function: study, work, concentrate To feel normal To get away from my problems or troubles Helps me not to get sick Because it helps me to enjoy a party or celebration Because of boredom, nothing else to do Because of anger and frustration To get more energy To cheer me up when I am in a bad mood To get through the day To seek deeper insights and understanding Because it tastes/smells good To help me stay awake To decrease the effects of other drugs To increase the effects of other drugs To fit in with the group I like So I won't feel left out So I'm liked Craving: I am hooked; I feel I must have it To make sex more fun
16 11 8 7 1 18 15 14 13 13 9 9 9 9 7
(53%) (37%) (27%) (23%) (3%) (60%) (50%) (47%) (43%) (43%) (30%) (30%) (30%) (30%) (23%)
Craving or strong desire or urge to use marijuana Needing to use more marijuana than you used to in order to get the same effect Over-doing it: using a larger amount of marijuana or using marijuana for more time than intended Neglecting responsibilities at home, school, or work because of marijuana use Continuing to use marijuana despite psychological problems that could get worse with it Having withdrawal symptoms (eg, craving, feeling irritable, anxious, worried, or depressed, having a low appetite, having trouble sleeping) Giving up or reducing activities (eg, sports) to use marijuana
1 (3%)
1 (3%)
1 (3%)
1 (3%)
0 (0%) 0 (0%)
© 2018 Analice S. Hoffenberg. Data as n, (%).
6 (20%) 6 (20%) 6 (20%) 6 (20%) 5 (17%) 5 5 5 5 4 3
(17%) (17%) (17%) (17%) (13%) (10%)
3 1 1 0 0 0 0 0 0
(10%) (3%) (3%) (0%) (0%) (0%) (0%) (0%) (0%)
Problems with use n = 11 (37%)
2 (7%)
6 (20%) 5 (17%) 5 (17%)
4 (13%)
4 (13%)
3 (10%)
2 (7%) (continued)
been marketed broadly35 and are popular36 in Colorado. In addition, there is a perception in the community that high CBD content edibles or oils are beneficial for the treatment of chronic diseases such as IBD37 and pediatric epilepsy.38,39 Dabbing and vaping were reported by 40% and 30% of users in our study. Dabbing is a newly popularized form of self-administering high concentrations of THC with a rapid onset of psychoactive effect. Of concern is that users may have higher rates of tolerance and withdrawal, which are symptoms of addiction and dependence.40 Understanding use of dab, oil, vape, and other new forms of marijuana products requires ongoing study. A limitation of this study is that a large proportion of participants (80%) had inactive or mild disease, making it difficult to ascertain a difference in disease activity between groups. Another limitation is the relatively small total number of participants with IBD who endorse use of marijuana. For this reason, we grouped patients with Crohn’s disease and patients with ulcerative colitis together. The only other study of marijuana use by a pediatric gastroenterology group enrolled about one-half as many and included only young adults 18-22 years old receiving infliximab infusions.12 This study found that 70% had used marijuana and one-half did so for medicinal purposes. Additional limitations include that our study did not distinguish between primarily CBD or primarily THC, forms that may have very different biologic effects,41 and we did not assess adherence rates to prescribed IBD therapies. There is no appropriate comparison group for our study. The age distribution of our patients (13-22 years old with mean age of users being 17.0 years) overlaps, but is not the same as the population- based studies that categorize by being in high school in Colorado15 or being in the 12th grade in the US.16 Each of these surveys used different methods for defining frequency of use. Furthermore, none of these studies assessed motivation for medicinal use of marijuana and no standardized tool exists, so we developed our own tool.
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THE JOURNAL OF PEDIATRICS • www.jpeds.com Very little is known about the potential interaction of marijuana with medications used to treat IBD. Cannabinoid metabolism primarily involves the human liver microsomes CYP2C and CYP3A.42 Tacrolimus, sometimes used to treat severe IBD,43 also shares this pathway. The use of marijuana may potentially increase the risk of tacrolimus toxicity, possibly because of altered gut absorption as well as inhibition of CYP2C44 and CYP3A45 clearance of tacrolimus. In conclusion, our study describes the use of marijuana by adolescents and young adults with IBD. Notably 32% have ever used and 9% are using daily or almost daily. The 9% daily or near daily use is clinically important to recognize and to screen for problems with use. Use for medicinal purposes was frequent, and a substantial proportion reported medicinal benefit; they perceived use as safe and beneficial. An additional phenomena that we observed is that in a state with legal pathways to medical and recreational marijuana, users were self-administering marijuana through multiple modalities including vaping, edibles, and oils besides the more traditional route of smoking. These different routes of administration potentially have different effects on the gastrointestinal system. We believe that marijuana use in adolescents and young adults with IBD is prevalent enough to warrant developing guidelines for periodic screening, testing, and counseling. ■
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Submitted for publication Jan 6, 2018; last revision received Feb 15, 2018; accepted Mar 15, 2018
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Reprint requests: Edward J. Hoffenberg, MD, B290 Digestive Health Institute, Children’s Hospital Colorado, 13123 E 16th Ave, Aurora, CO 80045. E-mail: [email protected]
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References
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31. Moore TH, Zammit S, Lingford-Hughes A, Barnes TR, Jones PB, Burke M, et al. Cannabis use and risk of psychotic or affective mental health outcomes: a systematic review. Lancet 2007;370:319-28. 32. Hall W, Weier M. Has marijuana legalization increased marijuana use among US youth? JAMA Pediatr 2017;671:116-8. 33. Meier MH, Caspi A, Ambler A, Harrington H, Houts R, Keefe RS, et al. Persistent cannabis users show neuropsychological decline from childhood to midlife. Proc Natl Acad Sci USA 2012;109:E2657-64. 34. Wong AP, Clark AL, Garnett EA, Acree M, Cohen SA, Ferry GD, et al. Use of complementary medicine in pediatric patients with inflammatory bowel disease: results from a multicenter survey. J Pediatr Gastroenterol Nutr 2009;48:55-60. 35. Ghosh TS, Van Dyke M, Maffey A, Whitley E, Erpelding D, Wolk L. Medical marijuana’s public health lessons–implications for retail marijuana in Colorado. N Engl J Med 2015;372:991-3. 36. Steffen J. Pot Edibles Were Big Surprise in First Year of Recreational Sales. Denver Post. 2014 December 19, 2014, updated October 2, 2016;Sect. News-Marijuana. 37. Walia A. 15 year old treats Crohn’s disease with cannabis and gets his life back: Collective Evolution; 2015. http://www.collective-evolution.com/2015/ 08/11/15-year-old-treats-chrohns-disease-with-cannabis-gets-his-life -back/. Accessed February 12, 2018. 38. Young S. Medical Marijuana Refugees: ‘This was our only hope’: Cable News Network; 2014 [updated March 10, 2014. U.S. Edition].
39.
40. 41. 42.
43.
44.
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http://www.cnn.com/2014/03/10/health/medical-marijuana-refugees/. Accessed February 12, 2018. Press CA, Knupp KG, Chapman KE. Parental reporting of response to oral cannabis extracts for treatment of refractory epilepsy. Epilepsy Behav 2015;45:49-52. Loflin M, Earleywine M. A new method of cannabis ingestion: the dangers of dabs? Addict Behav 2014;39:1430-3. Izzo AA, Camilleri M. Emerging role of cannabinoids in gastrointestinal and liver diseases: basic and clinical aspects. Gut 2008;57:1140-55. Stout SM, Cimino NM. Exogenous cannabinoids as substrates, inhibitors, and inducers of human drug metabolizing enzymes: a systematic review. Drug Metab Rev 2014;46:86-95. Watson S, Pensabene L, Mitchell P, Bousvaros A. Outcomes and adverse events in children and young adults undergoing tacrolimus therapy for steroid-refractory colitis. Inflamm Bowel Dis 2011;17:229. Yamaori S, Koeda K, Kushihara M, Hada Y, Yamamoto I, Watanabe K. Comparison in the in vitro inhibitory effects of major phytocannabinoids and polycyclic aromatic hydrocarbons contained in marijuana smoke on cytochrome P450 2C9 activity. Drug Metab Pharmacokinet 2012;27:294300. Hauser N, Sahai T, Richards R, Roberts T. High on cannabis and calcineurin inhibitors: a word of warning in an era of legalized marijuana. Case Rep Transplant 2016;2016:4028492.
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Marijuana Use by Adolescents and Young Adults with Inflammatory Bowel Disease Edward J. Hoffenberg, MD1,2, Shannon K. McWilliams, MA1, Susan K. Mikulich-Gilbertson, PhD1, Brittany V. Murphy, PhD2, Megan Lagueux, SM2, Kristen Robbins, BS2, Analice S. Hoffenberg, MD, MSPH1, Edwin de Zoeten, MD, PhD1,2, and Christian J. Hopfer, MD1 Objective To evaluate marijuana use by adolescents and young adults with inflammatory bowel disease (IBD). Study design This descriptive cross-sectional study of patients seen between December 2015 through June 2017 at Children’s Hospital Colorado for IBD enrolled patients 13-23 years of age, independent of marijuana use status. Information obtained consisted of chart review, electronic and interview self-report, and serum cannabinoid levels. Marijuana ever-users were compared with never-users for clinical characteristics and perceptions of risk with use; users provided information on routes, patterns, motivations, and perceived benefits and problems with use. Results Of 99 participants, ever-use was endorsed by 32% (32 of 99) and daily or almost daily use by 9% (9 of 99). Older age was the only characteristic related to endorsing marijuana use. Twenty-nine ever-users completed all questionnaires. After adjusting for age, users were 10.7 times more likely to perceive low risk of harm with regular use (P < .001). At least 1 medical reason for use was endorsed by 57% (17 of 30), most commonly for relief of physical pain (53%, 16 of 30) (2 did not complete all questionnaires). Problems from use were identified by 37% (11 of 30), most commonly craving/strong urge to use. Most common route of use was smoking (83%) followed by edibles (50%), dabbing (40%), and vaping (30%). Conclusions Marijuana use by adolescents and young adults with IBD is common and perceived as beneficial. Guidelines for screening, testing, and counseling of marijuana use should be developed for patients with IBD. (J Pediatr 2018;■■:■■-■■).
F
orty-six states have approved medical marijuana and 8 states have laws allowing possession and consumption for recreational use. Inflammatory bowel disease (IBD, Crohn’s disease, or ulcerative colitis) is an indication for access to medical marijuana in multiple states.1 Marijuana (cannabis) is a biotic compound that contains multiple active cannabinoids including delta-9 tetrahydrocannabinol (THC) and cannabidiol (CBD).2 The National Academy of Sciences has concluded that, in adults, marijuana is effective for chemotherapy-related nausea and vomiting, and may improve chronic pain as well as multiple sclerosis-related spasticity.2 Patients and families have advocated using marijuana for the treatment of medical conditions and ask care providers about it for treating their IBD.3,4 Emerging understanding of the endocannabinoid system provides a rationale for considering the medical benefits of marijuana.5 In addition to reducing pain, there may be effects on nausea, vomiting, gastrointestinal tract motility, and inflammation.6 These benefits, however, have not been tested empirically and must be weighed against the risks of regular marijuana use in adolescence with potential adverse effects including risk for addiction,7 lower educational performance,8 and psychiatric disorders such as schizophrenia.8 There are no studies evaluating benefit of marijuana use in pediatric IBD. Three observational studies of about 300 adult participants with IBD9-11 and 1 study of 37 young adults 18-21 years of age12 suggest that use of marijuana is associated with subjective relief of symptoms. There are 2 placebo-controlled clinical trials in adults with Crohn’s disease. THC cigarettes showed improvement of symptoms but not inflammatory markers compared with placebo,13 and low dose CBD compared with placebo showed no benefit for Crohn’s disease.14 Aside from subjective reFrom the 1Departments of Pediatrics and Psychiatry, sponses, there is no evidence supporting disease-modifying, long-term benefits University of Colorado School of Medicine, Aurora, CO; and 2Children’s Hospital Colorado, Aurora, CO of marijuana for patients with IBD. Funded by the Colorado Department of Public Health and In Colorado, medical marijuana card applications surged in 2012 after restricEnvironment, which had no role in study design, data collection, analysis or interpretation, report writing, or tions were loosened, and recreational marijuana stores opened in 2014. In 2015, decision to publish. The authors declare no conflicts of interest. 38% of Colorado high school students have tried marijuana, and 21% endorse Portions of this study were presented as an abstract at 15 use in the past month. It is widely available in many forms including edibles, the World Congress of Pediatric Gastroenterology,
CBD IBD THC
Hepatology and Nutrition, October 7, 2016 in Montreal, Canada, and the North American Society for Pediatric Gastroenterology, Hepatology and Nutrition Annual Meeting, November 3, 2017 in Las Vegas, NV.
Cannabidiol Inflammatory bowel disease Delta-9 tetrahydrocannabinol
0022-3476/$ - see front matter. © 2018 Elsevier Inc. All rights reserved. https://doi.org10.1016/j.jpeds.2018.03.041
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THE JOURNAL OF PEDIATRICS • www.jpeds.com oils, and smokeable products.16 Here we report on baseline information for 99 pediatric participants with IBD enrolled in an ongoing study to describe their IBD course and their use patterns. We hypothesized that marijuana use might be common in adolescents with IBD and that users might have higher rates of clinical or perceived medical benefit than nonusers. In addition, we sought to obtain detailed information on use patterns, motivations, and perceptions of benefit and harm.
Methods We designed a descriptive cross-sectional study of patients with IBD 13-23 years of age treated at Children’s Hospital Colorado. All patients with IBD were enrolled into the Improve Care Now (www.improvecarenow.org) network so that standardized clinical data were obtained.17 Participants were recruited from December 2015 through June 2017 by a research coordinator during their outpatient clinic visit, inpatient admission, or during a visit for medication infusion. Of the 174 potential participants, 19 were still undecided or were still to sign consent at next visit; of the remaining 155, 72% (111 of 155) agreed to enroll (Figure) but 12 were excluded from this analysis because of incomplete data (6 cannabinoid levels pending; 6 did not complete surveys). Consent was signed by parent or participant if 18 years and over, and assent by participants <18 years of age. Study information was provided in a private setting without the presence of a parent. Information obtained from the electronic medical record included demographic data such as age, sex, race, as well as weight, height, type of IBD, and physician global assessment of disease activity.18 The physician global assessment is a subjective measure in which the physician assigns a disease status to 1 of 4 categories: inactive, mild, moderate, or severe.
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Self-report data on appetite, pain, quality of life, depression, anxiety, and marijuana use were collected and managed using Research Electronic Data Capture (REDCAP) tools.19 Appetite and pain scores were assessed by a visual analog scale from 0 to 100.20 Validated questionnaires included IBD specific health-related quality of life as assessed by the Impact III questionnaire (validated for ages 13-17 years),21 the Generalized Anxiety Disorder-7 scale, which was used to assess anxiety,22 and questions describing marijuana use reported in other studies.23 A modified version of the Patient Health Questionnaire-9 was used to assess depression in which question 9 about thoughts of self-harm was removed because our hospital standard of addressing this issue prior to patient leaving the building exceeded our resources.24 Therefore, the total score is not comparable with other distributions of the Patient Health Questionnaire-9. Questions we developed in other studies to assess use of illicit substances including marijuana were used to describe marijuana use.23 Motivation for use was assessed using 35 exploratory questions, as binary items (yes/no). These questions were adapted from studies investigating nonmedical opiate prescription use, marijuana and alcohol drinking motives, or created for this study.25-27 Some of the questionnaire items were validated previously and others were created for this study. We report on items allocated by consensus among the authors into medical (5 questions) or nonmedical (35 questions). Questions on substance abuse and dependence were derived from the Diagnostic and Statistical Manual of Mental Disorders, 4th Edition.28 Serum levels of THC and CBD were measured at enrollment by a liquid chromatography/mass spectrometry technique.29 At the time of blood draw, participants were asked about past 6-month marijuana use including quantity, route, date, and time. Participants who endorsed use in the past 6 months and/or who self-reported ever using marijuana were designated “ever-users” in analyses.
Figure. Flow diagram of study enrollment. 2
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Statistical Analysis Data were examined for accuracy and the distributional properties of each variable. Many of the results are descriptive, consisting of self-reports of marijuana perceptions and use in adolescents with IBD. We compared the marijuana everuse and never-use groups on demographics; IBD disease characteristics; serum levels for THC, metabolites, and/or CBD; and perceptions of risk with regular marijuana smoking. Groups were compared with independent t tests and c2 tests; nonparametric equivalents (Mann-Whitney U, Fisher exact tests) were used as appropriate if normality assumptions were violated. Logistic regression adjusting for demographic characteristics that differed significantly between groups were further used to evaluate differences in perceptions of risk from using marijuana regularly between ever-users and never-users. All
analyses were conducted in SPSS v 24.0 (IBM Corporation, Armonk, New York) and were based on 2-tailed probability tests with 0.05 significance level. All participants received a substance abuse resource pamphlet at time of the consent. The study was approved by the Colorado Multiple Institution Review Board.
Results Of the 99 participants, age range 13-22 years, 63% (62 of 99) had diagnosis of Crohn’s disease, 27% (27 of 99), ulcerative colitis, and 10% (10 of 99) indeterminate/unknown colitis, 57% (56 of 99) were male, 83% (82 of 99) had quiescent/ mild disease based on physician global assessment (Table I). The 32 participants in the ever-use group were older (mean
Table I. Clinical characteristics and perception of risk data for 99 participants with IBD 13-21 years of age, by marijuana use
Age, y, mean (SD) Male n (%)
All 99
Never use 67 (68%)
16.2 (2.2)
15.9 (2.2)
Ever use 32 (32%) 17.0 (1.9)
56 (57%)
37 (55%)
19 (59%)
Race, n (%) White/Caucasian Other Disease type, n (%) Ulcerative colitis Crohn's disease Indeterminate/unknown
80 (82%) 18 (18%)
56 (84%) 11 (16%)
24 (77%) 7 (23%)
27 (27%) 62 (63%) 10 (10%)
21 (31%) 40 (60%) 6 (9%)
6 (19%) 22 (69%) 4 (13%)
Physician global assessment, n (%) Quiescent/mild Moderate/severe
82 (83%) 17 (17%)
55 (82%) 12 (18%)
27 (84%) 5 (16%)
Visual analog scale (0-100) n, mean (SD) Pain
95, 23.0 (24.6)
66, 21.9 (23.8)
29, 25.5 (26.6)
97, 64.0 (22.7)
67, 65.9 (22.3)
30, 59.7 (23.6)
Modified PHQ-9: n, median (range)
92, 3.0 (0-18)
63, 3.0 (0-13)
29, 3.0 (0-18)
GAD-7 n, median (range)
92, 2.0 (0-20)
63, 2.0 (0-13)
29, 2.0 (0-20)
(Impact III) n, mean (SD) (13-17 y)
70, 70.4 (13.9)
52, 71.9 (13.2)
18, 66.2(15.2)
(PEDSQL) n, mean (SD)(18 + y)
25, 79.0 (13.1)
13, 81.4 (13.5)
12, 76.4(12.6)
16 (16%)
0 (0%)
16 (50%)
40 (40/95 = 42%)
16 (16/65 = 25%)
24 (24/30 = 80%)
Appetite
Detected serum cannabinoids n (%) Perceived no to low risk of harm with regular smoking of marijuana n (%) Characteristics in marijuana users only Frequency of use, typical pattern past y n = 29 Use less than wkly No use Less than once a mo Once a mo Two or more times a mo Use wkly or more frequently Once a wk Two or more times a wk Once a d More than once a d Number of d used, past 30 d Medical marijuana registry holder n (%)
14 2 9 2 1 15 3 3 3 6 10.8 4
Statistic; P value t (97) = 2.6; P = .011 c2(1) = 0.15; P = .70 c2(1) = 0.54; P = .46 c2(2) = 1.81; P = .404
c2(1) = 0.08; P = .78
t(95) = 1.2; P = .22 t(93) = −.65; P = .52 U = 888.5, P = .83 U = 823.5, P = .44 t(68) = 1.4; P = .14 t(23) = 0.94; P = .36 c2(1) = 40.0; P < .001 c2(1) = 23.8; P < .001
(48%) (7%) (31%) (7%) (3%) (51%) (10%) (10%) (10%) (21%) (SD = 9.0) (13%)
GAD-7, Generalized Anxiety Disorder-7; PedsQL, Pediatric Quality of Life Inventory; PHQ-9, Patient Health Questionnaire-9.
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THE JOURNAL OF PEDIATRICS • www.jpeds.com 17.0, SD = 1.9 years) than the 67 in the never-use group (mean 15.9 SD = 2.2 years; P = .011). The ever- and never-use groups were similar for sex, race, disease type, disease activity, and measures of pain, appetite, quality of life, depression, and anxiety. Serum cannabinoids were detected in 50% (16 of 32) of the ever-use group but in none of the never-use group (0 of 67) (P < .001). For the 32 in the ever-use group, denominators for selfreported data differ because of missing responses and are reported. Thirty of 32 ever-users provided responses to questions about perceptions and motivations, and 29 of 32 provided responses to questions about use patterns. Low to no risk of harm with regular use of marijuana was endorsed by 80% (24 of 30) of ever-users and 25% (16 of 65) of never-users (P < .001; Table I). After adjusting for age, which significantly differed between groups, ever-users were 10.7 times more likely to perceive low to no risk of harm with regular use of marijuana than never-users (OR = 10.7, P < .001). A 3-group analysis (no use, use 13- <18 years of age, and use 18 years+ of age) identified no additional differences. Use at least weekly was reported by 52% (15 of 29), and use at least daily by 31% (9/29). Only 4 reported possession of a medical marijuana registry card (Table I). For questions describing marijuana use, such as source and route of use, participants could select multiple choices if applicable (Table II). Friends (60%) and dealer/black market (17%) were the most commonly reported sources. One-half or more reported smoking (83%) or consuming edibles (50%) with dabbing (40%) and vaping (30%) also being common. At least 1 medical reason for use was endorsed by 57% (17 of 30), with 53% (16 of 30) reporting use to relieve physical pain (Table III). One or more nonmedical recreational or psychological reasons for use were reported by 87% (26 of 30). Most common nonmedical motivations for use were to relax and relieve tension 60% (18 of 30), to feel good 50% (15 of 30), and to have a good time with friends 47% (14 of 30). One or more problems with use was reported by 37% (11 of 30).
Table II. Sources and products/routes of marijuana use (multiple choices allowed) in patients with IBD who report ever using marijuana (N = 30) Sources of marijuana Friends Dealer/black market Parents Siblings Someone else with Medical Registry Card Medical marijuana dispensary Recreational marijuana dispensary Other (“grower/caregiver,” “grandparent”) Products/routes of use Smoking Ingested as edible Dab Vape Oil Other
18 (60%) 5 (17%) 4 (13%) 3 (10%) 3 (10%) 3 (10%) 2 (7%) 2 (7%) 25 (83%) 15 (50%) 12 (40%) 9 (30%) 5 (17%) 1 (3%)
Volume ■■ These 11 reported on average 3.2 (SD = 2.0) problems (range 1-6). Overall, the most common problem was craving or strong desire to use 20% (6 of 30), followed by needing to use more for same effect 17% (5 of 30) and using larger amount for longer than intended 17% (5 of 30).
Discussion This study of marijuana use by adolescents and young adults with IBD is from a state with legalized recreational marijuana use for adults and medical marijuana use for all. The principal finding in our study of participants 13-22 years of age with IBD is that 32% had ever used marijuana and 9% used daily or almost daily. Furthermore, a substantial proportion reported use for medicinal purpose, use by methods besides smoking, and perceived low risk with regular use. The detection of serum cannabinoids only in the ever-users is consistent with truthful reporting. Our study confirms that marijuana is easily accessible and is consistent with estimates that rates of use among Colorado high school students have had no statistical change from 2005 to present.15 Although a medical reason for use was reported frequently, only 4 had a medical marijuana card and friends and family were the most common source. An increasingly larger percentage of adolescents in Colorado30 and nationally16 perceives safety with regular marijuana use. In our study, 80% of users perceived low risk of harm with regular marijuana use. The National Academy of Sciences has concluded that there is an association between marijuana use frequency during adolescence and progression to developing problem marijuana use.2 Risks of high frequency use include motor vehicle collision6 and fatality24 if driving while intoxicated; drug dependence with higher rates of anxiety, depression, and psychotic disorders31; use of other drugs32; and psychosocial decline (worsening performance on neuropsychological tests).33 There is a need for further understanding of the potential medical benefits of marijuana use in IBD. We found that the most common reasons for using marijuana were to relax and relieve tension, relieve pain, and feel good. Our study did not identify differences between everusers and never-users for clinical measures of IBD severity, quality of life, anxiety, or depression. Theoretically, a different study design such as a randomized controlled trial of marijuana use or placebo could better evaluate the safety and benefit of frequent marijuana use for induction or maintenance of remission, for severe cases, and for those who discontinue established therapies in favor of marijuana alone or marijuana in combination with complementary therapies.34 However, human subject research involving cannabis remains uniquely challenging because cannabis is a schedule 1 drug under federal law.3 Route of use of marijuana by participants with IBD may also be a factor in efficacy and safety. The majority in our study smoke marijuana, like most surveys. However, other routes of use were quite common, with 50% of users reporting ingesting marijuana as an edible. Edible marijuana products have
4
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Table III. Motivations for use and problems with use reported by 30 participants with IBD who reported ever using marijuana
Table III. Continued Problems with use Having problems at school, work, or other obligations (eg, drug-related absences) Spending a great deal of time planning on getting marijuana or getting/using/ recovering from it Being high on marijuana where it increased your chances of getting hurt (eg, driving) Continuing to use marijuana despite reoccurring personal problems (eg, fights with friends, parents, and significant other) Continuing to use marijuana despite physical health problems that could get worse with it Wanting to cut down or quit using marijuana but couldn't Having problems with the law related to marijuana (eg, underage possession)
Motivations for use Medical n = 17 (57%)
Nonmedical: recreational and psychological n = 26 (87%)
Survey question: Do you think you use marijuana . . . (check all that apply) To relieve physical pain To relieve abdominal cramping To relieve nausea To improve appetite To help lose weight To relax and relieve tension To feel good To have a good time with my friends To get high Insomnia: To help me get to sleep To experiment, to see what it is like Because it's fun It helps when I feel depressed or anxious To help when I get sick Life is short. I'll live it to the fullest while I can Attention: So that I can function: study, work, concentrate To feel normal To get away from my problems or troubles Helps me not to get sick Because it helps me to enjoy a party or celebration Because of boredom, nothing else to do Because of anger and frustration To get more energy To cheer me up when I am in a bad mood To get through the day To seek deeper insights and understanding Because it tastes/smells good To help me stay awake To decrease the effects of other drugs To increase the effects of other drugs To fit in with the group I like So I won't feel left out So I'm liked Craving: I am hooked; I feel I must have it To make sex more fun
16 11 8 7 1 18 15 14 13 13 9 9 9 9 7
(53%) (37%) (27%) (23%) (3%) (60%) (50%) (47%) (43%) (43%) (30%) (30%) (30%) (30%) (23%)
Craving or strong desire or urge to use marijuana Needing to use more marijuana than you used to in order to get the same effect Over-doing it: using a larger amount of marijuana or using marijuana for more time than intended Neglecting responsibilities at home, school, or work because of marijuana use Continuing to use marijuana despite psychological problems that could get worse with it Having withdrawal symptoms (eg, craving, feeling irritable, anxious, worried, or depressed, having a low appetite, having trouble sleeping) Giving up or reducing activities (eg, sports) to use marijuana
1 (3%)
1 (3%)
1 (3%)
1 (3%)
0 (0%) 0 (0%)
© 2018 Analice S. Hoffenberg. Data as n, (%).
6 (20%) 6 (20%) 6 (20%) 6 (20%) 5 (17%) 5 5 5 5 4 3
(17%) (17%) (17%) (17%) (13%) (10%)
3 1 1 0 0 0 0 0 0
(10%) (3%) (3%) (0%) (0%) (0%) (0%) (0%) (0%)
Problems with use n = 11 (37%)
2 (7%)
6 (20%) 5 (17%) 5 (17%)
4 (13%)
4 (13%)
3 (10%)
2 (7%) (continued)
been marketed broadly35 and are popular36 in Colorado. In addition, there is a perception in the community that high CBD content edibles or oils are beneficial for the treatment of chronic diseases such as IBD37 and pediatric epilepsy.38,39 Dabbing and vaping were reported by 40% and 30% of users in our study. Dabbing is a newly popularized form of self-administering high concentrations of THC with a rapid onset of psychoactive effect. Of concern is that users may have higher rates of tolerance and withdrawal, which are symptoms of addiction and dependence.40 Understanding use of dab, oil, vape, and other new forms of marijuana products requires ongoing study. A limitation of this study is that a large proportion of participants (80%) had inactive or mild disease, making it difficult to ascertain a difference in disease activity between groups. Another limitation is the relatively small total number of participants with IBD who endorse use of marijuana. For this reason, we grouped patients with Crohn’s disease and patients with ulcerative colitis together. The only other study of marijuana use by a pediatric gastroenterology group enrolled about one-half as many and included only young adults 18-22 years old receiving infliximab infusions.12 This study found that 70% had used marijuana and one-half did so for medicinal purposes. Additional limitations include that our study did not distinguish between primarily CBD or primarily THC, forms that may have very different biologic effects,41 and we did not assess adherence rates to prescribed IBD therapies. There is no appropriate comparison group for our study. The age distribution of our patients (13-22 years old with mean age of users being 17.0 years) overlaps, but is not the same as the population- based studies that categorize by being in high school in Colorado15 or being in the 12th grade in the US.16 Each of these surveys used different methods for defining frequency of use. Furthermore, none of these studies assessed motivation for medicinal use of marijuana and no standardized tool exists, so we developed our own tool.
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THE JOURNAL OF PEDIATRICS • www.jpeds.com Very little is known about the potential interaction of marijuana with medications used to treat IBD. Cannabinoid metabolism primarily involves the human liver microsomes CYP2C and CYP3A.42 Tacrolimus, sometimes used to treat severe IBD,43 also shares this pathway. The use of marijuana may potentially increase the risk of tacrolimus toxicity, possibly because of altered gut absorption as well as inhibition of CYP2C44 and CYP3A45 clearance of tacrolimus. In conclusion, our study describes the use of marijuana by adolescents and young adults with IBD. Notably 32% have ever used and 9% are using daily or almost daily. The 9% daily or near daily use is clinically important to recognize and to screen for problems with use. Use for medicinal purposes was frequent, and a substantial proportion reported medicinal benefit; they perceived use as safe and beneficial. An additional phenomena that we observed is that in a state with legal pathways to medical and recreational marijuana, users were self-administering marijuana through multiple modalities including vaping, edibles, and oils besides the more traditional route of smoking. These different routes of administration potentially have different effects on the gastrointestinal system. We believe that marijuana use in adolescents and young adults with IBD is prevalent enough to warrant developing guidelines for periodic screening, testing, and counseling. ■
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Submitted for publication Jan 6, 2018; last revision received Feb 15, 2018; accepted Mar 15, 2018
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Reprint requests: Edward J. Hoffenberg, MD, B290 Digestive Health Institute, Children’s Hospital Colorado, 13123 E 16th Ave, Aurora, CO 80045. E-mail: [email protected]
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