Posted on

Cbd oil for pediatric abdominal pain

A critical narrative review of medical cannabis in pediatrics beyond epilepsy, part III: chemotherapy-induced nausea and vomiting and inflammatory bowel disease

Contributions: (I) Conception and design: JS Simonian; (II) Administrative support: None; (III) Provision of study materials or patients: None; (IV) Collection and assembly of data: All authors; (V) Data analysis and interpretation: All authors; (VI) Manuscript writing: All authors; (VII) Final approval of manuscript: All authors.

Correspondence to: Jill S. Simonian, PharmD. University of California, San Diego Skaggs School of Pharmacy and Pharmaceutical Sciences, 9500 Gilman Drive, MC 0657, La Jolla, CA 92093-0657, USA. Email: [email protected] .

Background and Objective: Cannabis may play a role in alleviating chemotherapy-induced nausea and vomiting (CINV) and improving symptoms of inflammatory bowel disease (IBD). With the surge of interest and legalization of cannabis, its medical use in children for these indications was evaluated.

Methods: In this third section of a three-part comprehensive review, PubMed, Embase and Clinicaltrials.gov (1966 to May 2020) searches were conducted using the key search terms pertinent to cannabis, CINV and IBD. Only articles pertaining to cannabis and these disease states were extracted and critically evaluated.

Key Content and Findings: The high emetogenicity of certain chemotherapies prompts the need for an additional antiemetic therapy. Currently, nabilone and dronabinol are approved for adults with refractory CINV, and refractory CINV or AIDS-associated anorexia, respectively. As such, data support the beneficial effects of these synthetic delta-9-tetrahydrocannabinol (THC) medications as adjunctive therapy to partially or completely control CINV. The adverse effects of THC-based products consisted of drowsiness, dizziness, and mood changes. Data for use in IBD remains limited. For symptomatic control of IBD, survey-based studies have demonstrated that various cannabis products improved appetite, abdominal pain, and nausea, but might be accompanied by increased craving, tolerance, lightheadedness, and drowsiness.

Conclusions: Further clinical investigations on its safety and efficacy for CINV (especially for prolonged use and as monotherapy) and IBD are necessary to elucidate the best approach to medically use cannabis in children. Improving healthcare provider knowledge is also important, especially for CINV, to optimize its use.

Keywords: Cannabis; medical marijuana; cannabinoids; pediatrics; inflammatory bowel disease (IBD); nausea; vomiting

Received: 16 July 2020; Accepted: 10 August 2020; Published: 31 August 2020.

Introduction

In the past few decades, a rapid rise has been observed in the awareness and acceptance of cannabis for medical and recreational use, partly due to its legalization in many states in the USA. Coupled to this legalization, the broadening scope of research, and changes to the 2018 Farm Bill, which removed hemp [a cannabis plant with less than 0.3% delta-9-tetrahydrocannabinol (THC)] from the Controlled Substances Act, also contributed to the escalating use of cannabis. Irrespective of the legal status over time, it is clear that millions of people globally use cannabis for a myriad of medical conditions. As research continues to advance, it becomes evident that cannabis has a therapeutic role in many disease states, particularly chronic pain, adjunctive cancer treatment, and epilepsy. However, a growing number of healthcare practitioners, including pediatricians, are recommending cannabis for other medical conditions. Furthermore, adults, young adults and parents of pediatric patients are self-initiating treatment without their practitioner’s knowledge.

With the abundant literature evaluating the use of cannabis for epilepsy, this three-part series details the uses beyond epilepsy of cannabis and cannabis-derived products for medical conditions reported in the pediatric population. Currently, evidenced-based data are limited for the medical use of cannabis for conditions beyond epilepsy due to small studies, a lack of standardized cannabis formulations, variability in dosing, and inconsistent methodology. Moreover, much of the available research has been conducted on adults, underscoring the need for pediatricians to extrapolate data and independently evaluate the risks and benefits of use in childhood and adolescence.

This is the third article in our three-part series and will focus on the use of cannabis in chemotherapy-induced nausea and vomiting (CINV) and inflammatory bowel disease (IBD). The purpose of this series is to provide a critical review of the medicinal properties of cannabis to support pediatric healthcare practitioners in making informed and evidence-based decisions for use in their patients.

Methods

This narrative review was conducted by all authors for the purpose of reviewing the available literature on the use of medical cannabis in pediatric disease states. Due to the robust published studies on the use of cannabinoids for epilepsy, the decision was made to narrow our review to other disease states in which cannabis use was not readily known or studied, in order to illuminate providers regarding potential use for other conditions. Our initial search was wide and endeavored to capture any disease state, other than epilepsy, in which any formulation of cannabis was used in the pediatric population. Our search was then narrowed to the following broad medical conditions: autism, behavioral disorders, oncology, autoimmune diseases, spasticity and pain, and genetic and inherited diseases. Based on the limited search results, we organized our findings to report on studies of (I) neurodevelopmental disorders that included autism spectrum disorder (ASD), Tourette syndrome (TS), spasticity, complex motor disorders, and movement disorders, (II) the congenital skin disorder epidermolysis bullosa (EB), and (III) gastrointestinal disorders that included CINV and IBD. We report our findings regarding cannabis use in neurodevelopmental disorders, movement disorders and epidermolysis bullosa in the second part of this three-part series.

Eligibility

The inclusion criteria were only limited to research conducted on the human, pediatric, adolescent and young adult population in the English language. Due to the paucity of search results, there were no limitations on the type of study included.

Information sources

A search in PubMed, Embase, and clinicaltrials.gov up to May 2020 was conducted. Our search was conducted using MeSH terms describing cannabis and the particular disease states identified above, for example, “cannabis OR cannabinoid OR medical marijuana AND gastrointestinal disorders”. Sources also included websites from relevant regulatory and professional bodies, such as the American Academy of Pediatrics.

The cannabis plant has been used by many different civilizations for a variety of medical conditions; despite this, limited clinical research has been performed, partially due to societal barriers and the classification of marijuana as a Schedule I substance. Several factors, including the recent approval of cannabidiol (CBD) by the United States Food and Drug Administration (FDA) for refractory epilepsy, and the rapid rise of cannabis legalization throughout the United States, have led to a renewed surge of interest in the medical benefits of cannabinoids for many different clinical indications.

As an important component of cancer management, cannabis has been shown to play a role in alleviating side effects of chemotherapy and enhancing palliative care in adults (1). Although there are limited data published on cannabis use in pediatric oncology, a few studies have examined its use for symptomatic management of nausea and vomiting associated with chemotherapy in children, which affects 70% of pediatric patients with cancer (2-5).

Emesis is most commonly caused by a disturbance in the gastrointestinal tract in response to consuming what the body considers a toxin such as bacteria, food, or medications like chemotherapy. In the epithelium of the gastrointestinal tract, the primary trigger of this pathway is the release of serotonin from the enterochromaffin cells, activating 5-HT3 and 5-HT4 receptors in the vagal afferent nerves. When stimulated, this initiates a series of biochemical processes impacting the motor responses and activating the respiratory, gastric, salivary, esophageal, and laryngeal centers in the dorsal vagal complex of the brain (6). The primary neurotransmitters responsible for eliciting emesis behaviors are serotonin, dopamine, and substance P; hence conventional pharmacologic therapy for CINV was developed to target the activity of these neurotransmitters and includes medications that are antagonists of the serotonin, dopamine 2 (D2), and substance P/neurokinin-1 receptors (7).

According to the Children’s Oncology Group Supportive Care Endorsed Guidelines, each stage of increased emetogenicity (low, moderate, high) of chemotherapeutic regimens prompts the need for an additional antiemetic agent. Children receiving moderately emetogenic chemotherapy (MEC) should be treated with a 5-HT3 receptor antagonist (e.g., granisetron, ondansetron, or palonosetron) and a corticosteroid (e.g., dexamethasone). For highly-emetogenic chemotherapy (HEC), the recommended treatment consists of a 5-HT3 antagonist, dexamethasone, and a neurokinin-1 receptor antagonist (e.g., aprepitant). If the patient has a known or suspected hypersensitivity to any of these medications, an alternative agent is suggested (8). D2 antagonists, such as the phenothiazines, have not been considered first line therapy since the introduction of the newer agents as mentioned.

We present the following article in accordance with the Narrative Review reporting checklist (available at https://pm.amegroups.com/article/view/10.21037/pm-20-70/rc).

Mechanistic pathway

The recent discovery of the endocannabinoid system (ECS) has elucidated new ways to regulate the spectrum of anticipatory, acute, delayed, breakthrough, and refractory nausea and vomiting (9). The ECS, comprising the cannabinoid receptors 1 and 2 (CB1 and CB2), the endocannabinoids anandamide (AEA) and 2-arachidonoylglycerol (2-AG), and the enzymes responsible for synthesis and catabolism of AEA and 2-AG, is thought to be involved in the regulation of nausea and vomiting. CB1 is widely distributed in the brain and periphery, including neurons in the brain regions involved in the control of nausea and vomiting, and is thought to also be expressed on enterochromaffin cells in the gut and afferent vagal neurons (6,9). The proximal location of CB1 and 5-HT3 receptors in enterochromaffin cells, vagal afferent nerves, and various regions of the brain suggests that CB1 receptor agonists may be involved with the regulation of emesis. It is postulated that agonists of CB1 receptors in the gastrointestinal epithelium may inhibit the release of serotonin (10), and CB1 expression in the dorsal vagal complex may contribute to mediation of emesis (11). As such, the relationship between the 5-HT3 receptor systems and the CB1 agonists, AEA and THC, suggests that the ECS has the potential to be manipulated for emesis management using exogenous cannabinoids (6).

Clinical studies of synthetic delta-9-tetrahydrocannabinol (THC)

As potential antiemetic agents, THC and THC analogues have been the most investigated of the cannabinoids. Many of the earlier published studies investigated nabilone (Cesamet TM Valeant, Costa Mesa, CA), an oral synthetic cannabinoid analogue of THC, with a molecular structure slightly different from that of THC. Nabilone has demonstrated fewer episodes of nausea and vomiting in adults receiving MEC (6), shown to be comparably effective for HEC (12) when compared to D2 receptor antagonists, and was approved by the FDA in 1985 for adults with CINV refractory to conventional antiemetic therapy (13).

Ekert et al. investigated the use of oral THC 10- to 15-mg/m 2 versus metoclopramide or prochlorperazine 5- to 10-mg for the relief of CINV in children in two double-blind randomized controlled trials. Both trials demonstrated reduced nausea and vomiting in the participants receiving THC (14) (Table 1). Chan et al. conducted a double-blind, randomized, crossover study of 30 children receiving two courses of identical chemotherapy, measuring the rate of reduction of retching and vomiting, and the overall rate of improvement of retching and vomiting as subjectively characterized by the subject and their parents. Results showed that subjects experienced a 70% overall rate of improvement of vomiting with nabilone 0.5- to 2-mg twice daily, in contrast to 30% with 2.5- to 10-mg twice daily prochlorperazine (P=0.003). Interestingly, 66% of participants demonstrated a preference for nabilone, while 17% preferred prochlorperazine (P=0.015). The most common side effects reported were dizziness and drowsiness (15) (Table 1). A similarly designed study evaluated the efficacy of oral nabilone 0.5-mg twice daily compared to oral domperidone 1-mg three times daily in 18 children receiving chemotherapy. On a scale of 0–3 (with 3 being the worst), patients reported a statistically significant reduction in nausea with nabilone compared to domperidone (P=0.01) as well as a reduction in mean number of vomiting episodes (P<0.01) As in the Chan trial, study participants demonstrated a preference for nabilone over domperidone. Drowsiness was the most common adverse effect (16) (Table 1).

Table 1

Author(s) N Population Mean age (range), years Study design Dose § Dosing regimen Adverse effects ‡ Outcomes
Ekert et al., 1979 19 PM † 11.0 ¶ (5 to 19) DB RCT, crossover THC 10 mg/m 2 ; metoclopramide 5 or 10 mg (by BSA) −2, 4, 8, 16, 24 hours around CTX; placebo given at +4 hours None reported Reduced nausea and vomiting compared to metoclopramide
Ekert et al., 1979 14 PM † 14.0 ¶ (6 to 19) DB RCT, crossover THC 10 mg/m 2 ; prochlorperazine 5 or 10 mg (by BSA) −2, 4, 8, 16, 24 hours around CTX; Placebo given at 4 hours None reported Reduced nausea and vomiting compared to prochlorperazine
Chan et al., 1987 30 PM † , history of CINV 11.8 (3.5 to 17.8) DB RCT, crossover Nabilone 0.5–1 mg (by weight); prochlorperazine 2.5–5 mg (by weight) 8–12 hours prior to CTX then BID or TID Drowsiness (67%), dizziness (50%), euphoria, ocular irritation, hypotension Reduced retching and vomiting (60%), overall improvement of retching and vomiting (21%), patients’ drug preference (20%), compared to prochlorperazine
Dalzell et al., 1986 23 PM † , 2 identical cycles scheduled 7.9 (0.8 to 17) DB RCT, crossover Nabilone 0.5–2 mg (by weight); domperidone 5–15 mg (by weight) 24 hours prior to CTX then nabilone BID or TID, or domperidone TID Drowsiness (55%), dizziness (35%), elevated mood, hallucinations (n=1) Reduced nausea severity and vomiting compared to domperidone
Polito et al., 2018 110 PM † 14.0 (1.1 to 18) 5-year retrospective chart review Nabilone 0.019/kg initial dose with 5-HT3 antagonist Once daily (5%); BID (83%); TID (3%) Sedation (20%), dizziness, euphoria Complete control of vomiting in ≥50% of children; 31.8% partial control
Elder and Knoderer, 2015 58 PM † 13.9 (6 to 18) 10-year retrospective chart review Dronabinol ≤2.5 mg/m 2 Scheduled in 55%; PRN in 45% None reported Positive response (0–1 episodes of vomiting) in 60% of children
Abrahamov et al., 1995 8 PM † , hematological 6.6 (3 to 13) Open-label Delta-8-THC 18 mg/m 2 , 4 total doses 2 hours prior to CTX then QID Irritability (n=2), euphoria (n=1) Complete success preventing nausea and vomiting

† , any pediatric malignancy; ‡ , listed in descending order of frequency; percentages only listed if ≥20%; § , oral monotherapy unless otherwise indicated; ¶ , median ages reported as mean ages not reported. BID, two times daily; CTX, chemotherapy; PM, pediatric malignancy; PO, by mouth; PRN, as needed; QID, four times daily; TID, three times daily.

A 5-year, multicenter, retrospective review described the safety and efficacy of nabilone as adjuvant treatment for CINV prophylaxis in children receiving >1 dose of chemotherapy. Most of the participants (109/110) who received MEC or HEC were treated with a combination of nabilone and 5-HT3 antagonists, and 58% of those were also given an additional antiemetic. Results demonstrated that over 50% of all patients experienced complete chemotherapy-induced vomiting control while 31.8% had partial control. Adverse effects were experienced by 37 (34%) patients who reported sedation and dizziness as the most common effects (17) (Table 1). The contribution of the therapeutic effect of nabilone was difficult to determine, since all patients were treated with multiple antiemetics.

Dronabinol (Marinol ® Solvay Pharmaceuticals, Marietta GA) was the second synthetic THC medication approved by the FDA for adults with CINV, differing from nabilone in that its structure is identical to THC (18). Similar to nabilone, dronabinol has demonstrated fewer episodes and shorter durations of nausea and vomiting when compared with D2 receptor antagonists as monotherapy and in combination for MEC. In a 10-year retrospective chart review of 55 children receiving MEC or HEC and more than one dose of dronabinol, response to dronabinol was measured as good, fair, or poor, based on the number of emesis events. A median of 3.5 doses were received per patient per hospital visit (range, 1–129). Regardless of the emetogenic risk of regimen, 60% of patients reported a good response, 13% had a fair response, and 27% were poor responders. Tolerability, indirectly measured by continuation as outpatients, was reported by 62% of patients. Although there were limitations in this review, including the absence of nausea severity rating and lack of control of concomitant antiemetics, this retrospective study demonstrates the potential use of cannabinoid-based therapy in the pediatric CINV population (19) (Table 1). It is notable that although the dosing guidelines state 5 mg/m 2 , the most common dose was 2.5 mg/m 2 , suggesting perhaps that future studies could investigate lower doses for efficacious therapy in pediatric CINV (18).

Delta-8-THC is an isomer of delta-9-THC, differing in structure only by the location of a double bond, incurring enhanced chemical stability and reduced intoxicating effects. Although also naturally occurring in the cannabis plant, the quantities of delta-8-THC produced are so limited that the chemical is usually prepared in a laboratory using various techniques (20,21). It has been hypothesized that higher doses of delta-8-THC (18 mg/m 2 ) used in children with CINV may optimize therapeutic benefit with minimal side effects associated with the same doses of delta-9-THC (21). One study investigated the use of delta-8-THC in eight pediatric patients with CINV (21) (Table 1). Preliminary results indicated that when delta-8-THC was initiated as a pre-medication two hours before chemotherapy and repeated every six hours, prevention of vomiting was observed during 480 cycles. Despite this promising observation, these conjectures need to be further explored in clinical studies to ascertain the benefits of delta-8-THC over delta-9-THC.

The primary nabilone and dronabinol studies described above were conducted over 30 years ago, prior to the advent of more current antiemetics. To date, there are no pediatric studies comparing the efficacy of synthetic THC against either 5-HT3 or neurokinin-1 receptor antagonists, nor is there any evidence for the use of other cannabis products, including plant-derived cannabis and CBD, for CINV management in children.

See also  Cbd oil for aches

Summary statement

The high emetogenicity of chemotherapy, severely affecting pediatric oncology patients, has led to research efforts to evaluate if cannabinoids are effective as agents for the use in CINV. Current clinical studies are limited and the few trials that have been conducted have been restricted to the FDA approved agents, nabilone and dronabinol, with one study evaluating the THC isomer, delta-8-THC. There are no current studies evaluating a plant-derived cannabis product. Albeit their optimal use remains unknown, nabilone and dronabinol have shown promising results in the prevention of CINV, either partially or completely, when used in children as mono- or adjunctive therapy. Importantly, patients often report a subjective preference for the THC product when compared to another antiemetic.

The safety profiles of the THC-based products were consistent among studies, with drowsiness and dizziness reported as the most relevant side effects (14-17,22). However, the lack of studies comparing cannabis to conventional antiemetic regimens, such as newer 5-HT3 antagonists or aprepitant, and the absence of the evaluation of other cannabis products, including CBD, for emesis control, prompts the need for further investigation, especially integrating larger sample sizes. Specifically, further research is needed to determine the optimal dose, dosage form, drug-drug interactions, and safety of prolonged use of the products in the pediatric population.

The American Academy of Pediatrics opposes pediatric cannabis use in nearly all circumstances; however, they support its use in “children with life-limiting or seriously debilitating conditions”, which may arguably include CINV. The negative impact of CINV on a child’s life should not be underestimated as up to two-thirds of the patients may experience CINV (23). While current studies are inconclusive, the medical use of cannabis in children with CINV is largely based on clinical discretion (5). As such, the healthcare provider-patient relationship as well as the provider’s knowledge of cannabis use in childhood cancer are crucial to prescribe cannabis in specific patients who may most likely benefit. Interestingly, Ananth and colleagues surveyed 634 provider perspectives on medical cannabis in children with cancer, and reported that 33% received inquiries regarding cannabis each month and 92% were willing to consider it as a supportive therapy (24). This underlines the importance and need for practitioners to be educated on the benefits and harm of medical use of cannabis.

IBD is an immune-mediated chronic intestinal condition consisting of two primary types: ulcerative colitis (UC) and Crohn’s disease (CD). The pathogenic hypothesis is a dysregulation of the three major components of gut homeostasis: microbiota, intestinal epithelial cells, and immune cells in the tissues. Primary symptomatology includes diarrhea, rectal bleeding, anemia, abdominal pain, and nausea and vomiting (25). Pediatric practitioners must not only focus on simply treating IBD itself, but also consider pediatric attributes such as growth, proper weight gain, skeletal development and puberty, as 20–25% of patients develop it in childhood or adolescence (26).

Currently, gastroenterologists rely on a stepwise approach using FDA approved medications to treat IBD, following the American Gastroenterological Association (AGA) guidelines characterizing drug therapy depending on the type and severity of disease. These include aminosalicylates (i.e., sulfasalazine, mesalamine), glucocorticoids, thiopurines (i.e., 6-mercaptopurine, azathioprine) and biologics (i.e., TNF-α antagonists, such as infliximab) (27,28). Unfortunately, these regimens are often unsuccessful, prohibitively expensive, and are accompanied by a high risk of adverse events, such as immunosuppression, infection, malignancy, and anaphylaxis.

Mechanistic pathway

Evidence suggests a correlation between ECS tone and IBD pathology. As reviewed extensively by Gyires et al. (29), CB1 receptors have been identified in the colonic epithelium, smooth muscle, and the submucosal myenteric plexus. Similarly, CB2 receptors have been located in the gut epithelium, subepithelial macrophages, and plasma cells. Expression of both receptors has been shown to be elevated in the inflamed gut. In addition, endocannabinoid expression, particularly anandamide (AEA), is also altered in patients with IBD. It has been shown that AEA levels are increased in colonic samples of UC patients in early disease, and reduced at later time points, suggesting the protective role of AEA in early inflammatory processes, but a deteriorating role in later disease (30). It is likely that AEA levels are reduced in prolonged inflammation due to the decreased expression of the AEA precursor and increased expression of fatty acid amide hydrolase (FAAH), the enzyme required for AEA degradation (31,32). Furthermore, the absence of alterations in the levels of a second endocannabinoid, 2-arachidonoylglycerol, in gut inflammation implies the lack of importance of this endocannabinoid in IBD (30,32). Overall, evidence is suggestive of a role of exogenous cannabinoids in the manipulation of the ECS for the potential treatment of IBD symptomatology (33). In particular, CBD has been shown to display anti-inflammatory properties in animal models (34). Because CBD is known to have little to no affinity for the CB receptors, it is suggested that its anti-inflammatory effects are due to the disruption of the enzymatic breakdown of AEA by FAAH, leading to elevated AEA levels, resulting in the indirect activation of CB1 and CB2 receptors. In addition, CBD reduces neutrophil proliferation and inhibition of proinflammatory cytokine release, such as interleukin-1, interleukin-6, and interferon gamma from microglial cells (34).

Clinical studies of various cannabis products

Although the AGA does not provide guidance on cannabis use, patients frequently supplement their IBD therapy independently with the perception of added medical benefits to control their symptoms (35). Research on the use of cannabis in adults has shown promise for symptom relief; however, clinical trials in the pediatric population are lacking (36,37). Although one small study showed safety, but not efficacy when using low dose CBD for patients aged 20–75 with Crohn’s disease (38), there are currently no retrospective or prospective controlled studies for IBD in pediatric patients. Following is a review of three survey and questionnaire studies that evaluated cannabis use in pediatric IBD patients.

Hoffenberg et al., in 2018, conducted a descriptive cross-sectional study of 99 adolescents and young adults with IBD. Patients completed questionnaires that included self-report data on appetite, pain, quality of life, depression, anxiety, and cannabis use. Approximately 32% of subjects reported cannabis use in the past six months and/or ever and were designated as ‘ever-users’. Twenty-nine of these ‘ever-users’ provided responses to the use-pattern questions, with 82% reporting using cannabis daily or weekly. Furthermore, 57% of the 30 ‘ever-user’ patients acknowledged cannabis use for at least one medical condition and reported symptomatic relief for improved appetite (23%), pain (53%), abdominal cramping (37%), and nausea (27%). The most common mode of cannabis consumption was smoking, followed by edibles, dabbing, and vaping. One or more problems were reported by 37% of patients and included craving (20%), tolerance (17%), and using larger amounts for longer than intended (17%) (39).

In a second survey-based study, Hoffenberg et al. evaluated a subset of the same group of IBD patients, comparing those who had used oral or sublingual cannabis oil with those who were cannabis non-users in the prior six months. Cannabis oil was used by 15% of 99 patients who were enrolled. Nine of the 15 subjects who responded to the survey endorsed better sleep, decreased nausea, and increased appetite, while two reported improved mood and decreased anxiety. There was no consistency with concentration ratios of CBD and THC or routes of administration (sublingual, oral pills, tinctures, and beverages) (40).

In a prospective survey conducted in 2017, Phatak et al. reported on cannabis use in 53 young adults diagnosed with IBD. Thirty-seven (70%) patients used cannabis either currently or in the past, and of those, 70% did not discuss use with their healthcare provider. The most common method of consumption was smoking, followed by edibles. Twenty-four of 37 (65%) patients indicated a medical condition for use and most reported either moderate or complete symptomatic relief for poor appetite, abdominal pain, nausea, and diarrhea. Adverse effects were reported by seven of 37 (19%) and were identified as fear, paranoia, lightheadedness, laziness, drowsiness, loss of focus, poor diet, lethargy, and addiction (41).

Summary statement

The descriptive studies of cannabis use, based on self-reported questionnaires, were deficient in both objective measures of efficacy that incorporated biomarkers and measures of concomitant prescription IBD therapy. However, these surveys highlight the fact that, regardless of healthcare provider consultation or knowledge, adolescents and young adults are using cannabis for IBD symptom relief and associated use with a perceived improvement in symptoms and quality of life. As such, it is imperative not only to advocate the need for and conduct clinical studies, but to ensure adequate knowledge of healthcare providers in order to provide comprehensive care of patients.

Guidance on cannabis use from professional organizations, such as the AGA, is non-existent. Although the American Academy of Pediatrics opposes cannabis use for all diseases outside of the FDA-approved regulatory process, there are provisions for debilitating conditions in which current therapies are inadequate (42). Despite documentation of the involvement of cannabinoids and the ECS in gut homeostasis and the apparent self-treatment of patients, clinical evidence at this time does not support the recommendation of cannabis products for the treatment of IBD in the pediatric population. However, care providers are urged to communicate openly with their pediatric patients and their caregivers to determine if cannabis supplementation is being used. Informed providers can then discuss the benefits and risks of use, as well as monitor for side effects and drug interactions. Informed providers can also assist patients in obtaining a reliable product from a reliable source and educate about the benefits of choosing an oral or sublingual product over smoking.

Conclusions

Current published literature indicates a surge of interest in the use of cannabis for symptomatic management of CINV and IBD. Pharmacological evidence demonstrating the intricate network of endocannabinoids and cannabinoid receptors in areas of the central and peripheral nervous systems involved with CINV, and the gastrointestinal tract suggest the need for further research into cannabis for treatment considerations. Based on the studies reviewed in this paper, it is reasonable to consider cannabis as adjunctive therapy to accompany conventional CINV regimens; however, more research is needed to determine its use as monotherapy. The published literature remains too limited to recommend cannabis-derived products for IBD. The safety profile of cannabis-derived medications has shown to be acceptable, with few reported side effects.

Acknowledgments

Footnote

Reporting Checklist: The authors have completed the Narrative Review Reporting checklist. Available at https://pm.amegroups.com/article/view/10.21037/pm-20-70/rc

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://pm.amegroups.com/article/view/10.21037/pm-20-70/coif). JL serves as an unpaid editorial board member of Pediatric Medicine from Oct 2019 to Sept 2021. The authors have no other conflicts of interest to declare.

Ethical Statement: All authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

References

  1. Cotter J. Efficacy of crude marijuana and synthetic delta-9-tetrahydrocannabinol as treatment for chemotherapy-induced nausea and vomiting: a systematic literature review. Oncol Nurs Forum 2009;36:345-52. [Crossref] [PubMed]
  2. Mechoulam R, Hanus L. The Cannabinoids: An Overview. Therapeutic Implications in Vomiting and Nausea After Cancer Chemotherapy, in Appetite Promotion, in Multiple Sclerosis and in Neuroprotection. Pain Res Manag 2001;6:67-73. [Crossref] [PubMed]
  3. Dupuis LL, Sung L, Molassiotis A, et al. 2016 updated MASCC/ESMO consensus recommendations: Prevention of acute chemotherapy-induced nausea and vomiting in children. Support Care Cancer 2017;25:323-31. [Crossref] [PubMed]
  4. Wong SS, Wilens TE. Medical Cannabinoids in Children and Adolescents: A Systematic Review. Pediatrics 2017;140:e20171818. [PubMed]
  5. Rod Rassekh S. Urgent need for “EBMM” in pediatric oncology: Evidence based medical marijuana. Pediatr Hematol Oncol 2019;36:253-4. [Crossref] [PubMed]
  6. Sharkey KA, Darmani NA, Parker LA. Regulation of nausea and vomiting by cannabinoids and the endocannabinoid system. Eur J Pharmacol 2014;722:134-46. [Crossref] [PubMed]
  7. Hesketh PJ. Understanding the pathobiology of chemotherapy-induced nausea and vomiting. Providing a basis for therapeutic progress. Oncology 2004;18:9-14. [PubMed]
  8. Patel P, Robinson PD, Thackray J, et al. Guideline for the Prevention and Treatment of Anticipatory Nausea and Vomiting due to Chemotherapy in Pediatric Cancer Patients. Pediatr Blood Cancer 2017;64:e26542. [Crossref]
  9. Parker LA, Rock EM, Limebeer CL. Regulation of nausea and vomiting by cannabinoids. Br J Pharmacol 2011;163:1411-22. [Crossref] [PubMed]
  10. Hu DL, Zhu G, Mori F, et al. Staphylococcal enterotoxin induces emesis through increasing serotonin release in intestine and it is downregulated by the cannabinoid receptor 1. Cell Microbiol 2007;9:2267-77. [Crossref] [PubMed]
  11. Mackie K. Distribution of cannabinoid receptors in the central and peripheral nervous system. Handb Exp Pharmacol 2005;299-325. [Crossref] [PubMed]
  12. Crawford SM, Buckman R. Nabilone and metoclopramide in the treatment of nausea and vomiting due to cisplatin: a double blind study. Med Oncol Tumor Pharmacother 1986;3:39-42. [PubMed]
  13. Nabilone. Package insert. Valeant Pharmaceuticals International, 1985.
  14. Ekert H, Waters K, Jurk I, et al. Amelioration of cancer chemotherapy-induced nausea and vomiting by delta-9-tetrahydrocannabinol. Med J Aust 1979;2:657-9. [Crossref] [PubMed]
  15. Chan HS, Correia JA, MacLeod SM. Nabilone versus prochlorperazine for control of cancer chemotherapy-induced emesis in children: a double-blind, crossover trial. Pediatrics 1987;79:946-52. [PubMed]
  16. Dalzell AM, Bartlett H, Lilleyman JS. Nabilone: an alternative antiemetic for cancer chemotherapy. Arch Dis Child 1986;61:502-5. [Crossref] [PubMed]
  17. Polito S, MacDonald T, Romanick M, et al. Safety and efficacy of nabilone for acute chemotherapy-induced vomiting prophylaxis in pediatric patients: A multicenter, retrospective review. Pediatr Blood Cancer 2018;65:e27374. [Crossref] [PubMed]
  18. Dronabinol. Package insert: AbbVie Inc., 1985.
  19. Elder JJ, Knoderer HM. Characterization of dronabinol usage in a pediatric oncology population. J Pediatr Pharmacol Ther 2015;20:462-7. [Crossref] [PubMed]
  20. Muchtar S, Almog S, Torracca MT, et al. A Submicron Emulsion as Ocular Vehicle for Delta-8-Tetrahydrocannabinol: Effect on Intraocular Pressure in Rabbits. Ophthalmic Res 1992;24:142-9. [Crossref] [PubMed]
  21. Abrahamov A, Abrahamov A, Mechoulam R. An efficient new cannabinoid antiemetic in pediatric oncology. Life Sci 1995;56:2097-102. [Crossref] [PubMed]
  22. Phillips RS, Friend AJ, Gibson F, et al. Antiemetic medication for prevention and treatment of chemotherapy-induced nausea and vomiting in childhood. Cochrane Database Syst Rev 2016;2:CD007786. [PubMed]
  23. Fernández-Ortega P, Caloto MT, Chirveches E, et al. Chemotherapy-induced nausea and vomiting in clinical practice: impact on patient’s quality of life. Support Care Cancer 2012;20:3141-8. [Crossref] [PubMed]
  24. Ananth P, Ma C, Al-Sayegh H, et al. Provider Perspectives on Use of Medical Marijuana in Children With Cancer. Pediatrics 2018;141:e20170559. [Crossref] [PubMed]
  25. Friedman S, Blumberg RS. Inflammatory Bowel Disease. In: Jameson J, Fauci AS, Kasper DL (eds), et al. Harrison’s Principles of Internal Medicine, 20e New York, NY: McGraw-Hill. Available online: http://accessmedicine.mhmedical.com/content.aspx?bookid=2129&sectionid=19228250
  26. Lahad A, Weiss B. Current therapy of pediatric Crohn’s disease. World J Gastrointest Pathophysiol 2015;6:33-42. [Crossref] [PubMed]
  27. Feuerstein JD, Isaacs KL, Schneider Y, et al. AGA Clinical Practice Guidelines on the Management of Moderate to Severe Ulcerative Colitis. Gastroenterology 2020;158:1450-61. [Crossref] [PubMed]
  28. Ko CW, Singh S, Feuerstein JD, et al. AGA Clinical Practice Guidelines on the Management of Mild-to-Moderate Ulcerative Colitis. Gastroenterology 2019;156:748-64. [Crossref] [PubMed]
  29. Gyires K, Zádori ZS. Role of Cannabinoids in Gastrointestinal Mucosal Defense and Inflammation. Curr Neuropharmacol 2016;14:935-51. [Crossref] [PubMed]
  30. D’Argenio G, Valenti M, Scaglione G, et al. Up-regulation of anandamide levels as an endogenous mechanism and a pharmacological strategy to limit colon inflammation. FASEB J 2006;20:568-70. [Crossref] [PubMed]
  31. Storr MA, Keenan CM, Emmerdinger D, et al. Targeting endocannabinoid degradation protects against experimental colitis in mice: involvement of CB1 and CB2 receptors. J Mol Med 2008;86:925-36. [Crossref] [PubMed]
  32. Di Sabatino A, Battista N, Biancheri P, et al. The endogenous cannabinoid system in the gut of patients with inflammatory bowel disease. Mucosal Immunol 2011;4:574-83. [Crossref] [PubMed]
  33. Couch DG, Cook H, Ortori C, et al. Palmitoylethanolamide and Cannabidiol Prevent Inflammation-induced Hyperpermeability of the Human Gut In Vitro and In Vivo—A Randomized, Placebo-controlled, Double-blind Controlled Trial. Inflamm Bowel Dis 2019;25:1006-18. [Crossref] [PubMed]
  34. Burstein S. Cannabidiol (CBD) and its analogs: a review of their effects on inflammation. Bioorg Med Chem 2015;23:1377-85. [Crossref] [PubMed]
  35. Hasenoehrl C, Storr M, Schicho R. Cannabinoids for treating inflammatory bowel diseases: where are we and where do we go? Expert Rev Gastroenterol Hepatol 2017;11:329-337. [Crossref] [PubMed]
  36. Ambrose T, Simmons A. Cannabis, Cannabinoids, and the Endocannabinoid System—Is there Therapeutic Potential for Inflammatory Bowel Disease? J Crohns Colitis 2019;13:525-35. [Crossref] [PubMed]
  37. Irving PM, Iqbal T, Nwokolo C, et al. A Randomized, Double-blind, Placebo-controlled, Parallel-group, Pilot Study of Cannabidiol-rich Botanical Extract in the Symptomatic Treatment of Ulcerative Colitis. Inflamm Bowel Dis 2018;24:714-24. [Crossref] [PubMed]
  38. Naftali T, Mechoulam R, Marii A, et al. Low-dose cannabidiol is safe for not effective in the treatment of Crohn’s disease, a randomized controlled trial. Dig Dis Sci 2017;62:1615-20. [Crossref] [PubMed]
  39. Hoffenberg EJ, Mcwilliams SK, Mikulich-Gilbertson SK, et al. Marijuana Use by Adolescents and Young Adults with Inflammatory Bowel Disease. J Pediatr 2018;199:99-105. [Crossref] [PubMed]
  40. Hoffenberg EJ, Mcwilliams S, Mikulich-Gilbertson S, et al. Cannabis Oil Use by Adolescents and Young Adults With Inflammatory Bowel Disease. J Pediatr Gastroenterol Nutr 2019;68:348-52. [Crossref] [PubMed]
  41. Phatak UP, Rojas-Velasquez D, Porto A, et al. Prevalence and Patterns of Marijuana Use in Young Adults With Inflammatory Bowel Disease. J Pediatr Gastroenterol Nutr 2017;64:261-4. [Crossref] [PubMed]
  42. Committee on Substance Abuse, Committee on Adolescence. Committee on Substance Abuse Committee on Adolescence. The impact of marijuana policies on youth: clinical, research, and legal update. Pediatrics 2015;135:584-7. [Crossref]

doi: 10.21037/pm-20-70
Cite this article as: Simonian JS, Varanasi S, Richards GJ, Nguyen AV, Diaz-Fong JP, Le J. A critical narrative review of medical cannabis in pediatrics beyond epilepsy, part III: chemotherapy-induced nausea and vomiting and inflammatory bowel disease. Pediatr Med 2020;3:12.

See also  Cbd facial oil for stress

Cannabis and pediatric inflammatory bowel disease: change blossoms a mile high

Corresponding author: Edward J. Hoffenberg MD, Children’s Hospital Colorado, B290 Digestive Health Institute, 13123 E 16 th Ave, Aurora CO 80045, 720-777-6669; 720-777-7277 (fax), [email protected]

Abstract

The trend towards decriminalization of cannabis (marijuana) continues sweeping across the United States. Colorado has been a leader of legalization of medical and recreational cannabis use. The growing public interest in the medicinal properties of cannabis and its use by patients with a variety of illnesses including inflammatory bowel disease (IBD) makes it important for pediatric gastroenterologists to understand this movement and its potential impact on patients. This article describes the path to legalization and “medicalization” of cannabis in Colorado as well as the public perception of safety despite the known adverse health effects of use. We delineate the mammalian endocannabinoid system and our experience of caring for children and adolescents with IBD in an environment of increasing awareness and acceptance of its use. We then summarize the rationale for considering that cannabis may have beneficial as well as harmful effects for IBD patients. Finally, we highlight the challenges federal laws impose on conducting research on cannabis in IBD. The intent of this article is to inform health care providers about the issues around cannabis use and research in adolescents and young adults with IBD.

Keywords: cannabis, marijuana, inflammatory bowel disease, cannabidiol (CBD), tetrahydrocannabinol (THC), research, pediatric

Cannabis legalization in Colorado

As of fall 2015, Colorado was one of 24 states that legalized cannabis use for medical purposes and one of 4 states that allowed adult use for recreational purposes 1 . The passage of Amendment 20 in 2000 allowed adult Colorado residents with valid social security numbers and diagnosed with certain debilitating conditions or undergoing treatment for specific conditions to have possession of up to 2 ounces, and to grow up to 6 cannabis plants, for medicinal purposes . An identification card was required, as well as a doctor recommendation to use cannabis as treatment for these conditions ( Table 1 ). A minor could receive a cannabis recommendation with consent of both parents and documentation from two physicians 2 . Parents could then apply for a medical marijuana card on behalf of their child, be listed as the child’s caregiver on the card, and have permission to transport medical marijuana from a medical marijuana dispensary to their child. In this way, Colorado voters defined cannabis as an acceptable treatment for a number of chronic conditions that produce subjective symptoms such as severe pain or nausea, and for cachexia 3 .

Table 1

Approved conditions for medical cannabis (marijuana) use per Colorado Constitution as of February 2016 46

With abolishment of the limitation of 5 “patients” to 1 “caregiver” and the U.S. Department of Justice indicating they would not likely prosecute individuals in compliance with state laws, applications for medical marijuana increased from 6000 in 2008 to 100,000 in 2012 and there were about 500 licensed dispensaries providing legal medical marijuana 4 . In the vast majority (> 90%) the medical indication was severe pain. In 2012, Colorado voters enacted state constitutional Amendment 64 which legalized recreational cannabis use for those over 21 years old and provided for a system for regulation, taxation, and distribution, similar to alcohol. The expansion of the cannabis industry began in earnest in 2013. The first retail stores opened on January 1, 2014. In 2015, Colorado had $1 billion in sales, generating an expected $100 million in tax revenue, double that of 2014 5 . For 2015, about 40% of revenue came from medical, and 60% from recreational use. Recreational cannabis, because of additional excise taxes designated to provide funds for schools and other projects, is more expensive than medical cannabis. Many habitual users still purchase the cheaper medical marijuana.

There is a process by which cannabis may be given to children under 18 years of age in Colorado. Two physicians must diagnose the patient with a qualifying debilitating condition, one of which must explain the possible risks and benefits in writing (there are no state guidelines on what this should include), and a parent must be a primary care giver. The state then provides the parent with a medical marijuana minor patient card. The amount that may be possessed is much higher for medical than for recreational purposes. A number of families have moved to Colorado, specifically to obtain cannabidiol (CBD) oil to treat severe seizures and neurologic conditions in their children 6 .

Colorado has embarked on a social experiment “medicalizing” cannabis use and ending prohibition on recreational use. In its current state, the industry may be viewed as much like a pharmaceutical company that is in both production and retail. The product, however, is not one well-tested drug, but may contain over 100 chemicals in varying amounts, provided in different types of delivery systems (smoking, vaping, edibles, patches, oils, etc.), and with mainly anecdotal data on efficacy for treating human disease and an absence of information on safety and drug interactions. Health care providers will be asked by patients to discuss the medical marijuana issues 7 .

Public Perception of Risk and Adverse Effects

The public perception of risk is quite low. In the “Monitoring the Future” report, the proportion of high school seniors who view regular use of cannabis as not having great risk was 60% in 2014, a figure that has been increasing steadily since 2004 8 . However, substantial literature supports the view of significant adverse health effects with both short-term and long-term use, mainly on neurologic, cognitive, and mental health ( Table 2 ) 9 . There may be acute psychotic symptoms during intoxication and several cases of apparent acute intoxication have been widely reported in the local media, including one 19 year old who jumped off a hotel balcony to his death, and a husband who shot his wife 10 . Impaired adolescent driving while intoxicated with cannabis, especially in combination with alcohol, is another important issue. There has been an increase in the potency of THC content in marijuana from about 3% in the 1980s to 12% in 2012 11 , raising concerns about the impact of this increased potency on the potential adverse effects of marijuana use. Another major concern is that cannabis ingested in an edible form is more difficult to titrate, unlike vaping or inhaling, as the effect may be delayed, and therefore higher doses may be consumed leading to intoxication. Heavy users have impaired memory for at least 1 week after abstinence; hyperemesis syndrome has been well described as have withdrawal symptoms. Addiction risk may be higher for those beginning heavy use in adolescence, and this behavior may predict progression to harder drugs 9, 12 . These negative effects have both immediate and long term implications, leading the American Academy of Pediatrics 13 and the Academy of Child and Adolescent Psychiatry 14 to officially oppose the legalization of marijuana. These issues have not been widely reported in the public media. There are however particular challenges in interpreting the literature on cannabis use, as the data are often derived from studies of heavy and/or long term users where there are other potential confounding factors, such as use of other drugs, psychosocial and economic adversity 9 . Further, the retrospective and correlational methodologies used do not allow for inferences of causality for any adverse outcomes associated with cannabis use.

Table 2

Adverse health effects reported with use of cannabis (marijuana) and level of evidence 47,9

Substantial Moderate Limited Mixed
Impaired memory to at
least 7 days abstinence
(heavy users)
Depression
(regular users)
Impaired decision-
making up to 2
days after last use
(regular users)
Impaired executive
functioning after
short abstinence
Acute psychotic
symptoms during
intoxication
Gateway Drug

Clinical Use of Cannabinoids and Side Effects

A rigorously conducted meta-analysis of randomized clinical trials (RCTs) of cannabinoids across a broad range of conditions found only 4 of 79 RCTs to have a low risk of bias 15 , with 70% of studies having a high risk of bias, typically due to incomplete outcome data. The large majority of trials evaluated chemotherapy related nausea and vomiting, chronic pain and spasticity due to multiple sclerosis or paraplegia. Use of cannabinoids for chronic pain and spasticity was supported by moderate-quality evidence. Improvements in chemotherapy related nausea and vomiting, weight gain in HIV, sleep disorders and Tourette syndrome, was supported by low-quality evidence. Overall cannabinoids were associated with an increased risk of adverse effects, with an odds ratio (OR) of any adverse effect of 3.03 (95% CI: 2.42-3.80) and serious adverse effects, OR of 1.41 (95% CI: 1.04-1.92). There is a dearth of evidence related to clinical trials of cannabis itself, including associated adverse effects. As public acceptance of cannabis expands, some states have included in the legalization process that tax funds be allocated to address the lack of scientific knowledge on potential beneficial as well as harmful effects of use.

Mammalian endocannabinoid system

Cannabis affects humans through cross-reactivity with an endogenous mammalian cannabinoid sensing system known as the endocannabinoid system. This system includes receptors active in the central and peripheral nervous system (where they modulate appetite, pain, mood, and memory) as well as in many peripheral organs, including the gastrointestinal tract (where it may impact motility and secretion via acetylcholine) 16 ( Fig1 ).

Main effects of cannabinoid receptor CB1 and CB2 activation in the gastrointestinal tract. Adapted from 16

The most well-known receptors are the G-protein coupled cannabinoid-1(CB1) and cannabinoid-2 (CB2) receptors. The CB1 receptor expression is found primarily in the nervous system, while CB2 receptors may be found on immune cells where they modulate immune cell function. Additional atypical receptors, such as TRPV1 and GPR55 have been reported to be responsive to endocannabinoids, but their functions are still being clarified. The primary endogenous ligand for the CB1 receptor is anandamide, and the primary endogenous ligand for the CB2 receptor is 2- arachidonoylglycerol (2-AG) 17 . THC has greater affinity for the CB1 receptor than for the CB2 receptor and CBD has a weak affinity for CB2 receptor. Both anandamide and 2-AG are metabolized by the arachidonic acid pathway 16 ( Fig 2 ).

Diagram of cannabinoid receptors CB1 and CB2 in the intestinal tract. Adapted from 16

What is in cannabis?

The cannabis plant is comprised of stem, leaves, nodes, and male or female flowers. The male cannabis flowers pollinate the female plants, while female flowers provide the cannabinoids for consumption. There are over 106 known phytocannabinoid chemicals identified from the cannabis plant 18 . The two main active ingredients of cannabis are tetrahydrocannabinol (THC), the primary psychoactive substance, and cannabidiol (CBD), a largely non-psychoactive substance. Not only may plant products be present, but pesticides and fungi sometimes are found as well 19 .

Depending on whether there are buds, leaves, and stems, the amount of THC, CBD, and other chemical components varies greatly. Many strains for recreational use have an abundance of THC, which induces both psychoactive and soporific effects, while CBD abundant strains such as Charlotte’s Web are less common, but gaining popularity due to the anti-seizure, anxiolytic, non-psychotropic effects. Epidiolex, a liquid formulation from GW Pharmaceuticals that contains pure, plant-derived CBD has received Fast Track designation from the Food and Drug Administration due to its very promising investigation trial in Dravet syndrome, a severe, refractory, infantile-onset form of epilepsy.

Pediatric IBD patients use cannabis

Patients and parents ask our opinion about trying cannabis for their IBD symptoms. From surveys we have conducted, we know that some of our patients in the pediatric IBD center at Children’s Hospital Colorado use cannabis 20 . They report to us trying cannabis in multiple forms, including smoking, edibles, and CBD oil. Patients and parents tell us they feel it helps treat their IBD beyond improved coping, decreased pain, and better appetite. Furthermore, patients have asked us for a medical marijuana card, however, none in our group have completed a Physician Certification form required to formally recommend medical marijuana 3 .

It seems logical that as care providers for children and adolescents with IBD, we should seek to know more about the medical effects of cannabis. Questions include: Is it really beneficial? What are the risks? How should we evaluate special considerations in IBD? Do our IBD patients use cannabis differently than those who use it for recreational use? Are IBD patients at greater risk for addiction (i.e. combined use with narcotics after surgery or for chronic pain)? What impact does intestinal inflammation or dysmotility have on absorption of edibles? And how do the chemicals in cannabis affect other medications used to treat IBD?

Do our IBD patients use cannabis similarly to peers without chronic illness?

Given our IBD patient’s interest in and use of legal medical and recreational cannabis in Colorado, we conducted a pilot study to measure use in 65 pediatric IBD subjects and 100 subjects without chronic illness 20 . Using the validated CIDI-SAM questionnaire, 21 we found that frequency of ever using cannabis was similar between the groups (IBD 31% and control 40%, p= NS). However, IBD users reported weekly or more use much more frequently (IBD 55% and control 26%, OR 3.54 95% CI 1.14-11.05, p=0.03). Motivation for use was also different; the IBD group reported cannabis use more frequently for treatment of physical symptoms.

How do our results compare to state and national data? The Healthy Kids Colorado Survey (HKCS) 22 and the Youth Risk Behavioral Survey (YRBS) 23 provide this information. In 2013, both Colorado and National data show that about 40% of high school students had ever used cannabis, similar to our IBD and control groups. In terms of intensity of use, the HKCS and YRBS report about 20-25% use weekly or more. Again, our study’s comparison group, at 26%, was consistent with these data, while our IBD group, at 55%, was much higher. There are alarming national data 24 that daily or almost daily use of cannabis among 12-17yr olds is increasing rapidly. In 2003, 4.9M Americans 12 years and older reported daily cannabis use for the past month; by 2013 it was 8.1M.

We can summarize U.S. trends for cannabis use:

pediatric IBD patients who use cannabis may do so more intensely and for physical reasons, compared to peers without chronic illness.

Cannabis for treatment of IBD

We could identify no studies evaluating cannabis for the treatment of IBD in children and data in adults are limited. There are 3 observational studies of about 300 adult subjects which suggest that use of cannabis is associated with subjective relief of symptoms 25,26,27 .

A single placebo-controlled clinical trial of THC was conducted for treatment of Crohn’s disease. Patients smoked cigarettes with known THC content or placebo, and at 8 weeks, 10 of 11 in the cannabis group showed a response with a drop in CDAI, compared to 4 of 10 in the placebo group (p = 0.028) 28 . Whether there is a disease modifying benefit, as opposed to an enhanced quality of life is unknown. And whether the effect is long lasting has also not been studied.

Potential beneficial mechanisms of cannabis in IBD

Cannabis can potentially be used to alleviate a number of IBD-associated intestinal symptoms, including reducing nausea, stool frequency and abdominal pain, while improving appetite and weight gain 29,7, 30 . This in turn may indirectly influence intestinal inflammation and possibly microbiome. However, it remains unclear whether or not it has any direct impact on the underlying disease pathogenesis. We do know that the endogenous cannabinoid system (including cannabinoid receptors and the cognate ligand anandamide) is up-regulated in ulcerative colitis patients 31, 32 suggesting a role in disease regulation. Moreover, anandamide has been shown to suppress proliferation and cytokine release from primary human T-lymphocytes mainly via the CB2 receptor 33 . CBD may exert anti-inflammatory effects through inhibition of fatty acid amidohydrolase (FAAH), which leads to increased concentrations of anandamide 34 .

The primary psychoactive ingredient in cannabis, THC, acts mainly as a weak CB1 receptor agonist. Through this pathway, THC can also inhibit human T cell proliferation, preferentially targeting the same pro-inflammatory IFNγ-producing Th1 cells that are heavily implicated in IBD pathogenesis 35,36 . However, THC also increases the concentration of regulatory T cell-associated cytokines, IL-10 and TGFβ, in unfractionated human T cell cultures 37,38 suggesting that the capacity of THC to reduce T cell proliferation may actually reflect the ability to enhance regulatory T cell suppressive function. This could be particularly beneficial in the context of IBD given the established impaired regulatory T cell suppressive function associated with this disease 39 . One concern with the administration of cannabinoids in the context of inflammation and increased endocannabinoid production is the potential for receptor desensitization which can occur in the case of the human immune-associated CB2 receptor 40 . While anandamide and THC might both have beneficial effects in isolated short-term cell culture experiments, it remains to be seen if the chronic combination has synergistic or contradictory effects in vivo.

In addition to potential T cell targeted anti-inflammatory mechanisms, cannabinoids have also been shown to impair cytokine production by human neutrophils, and in particular the IBD-associated pro-inflammatory cytokine TNFα 41 . Human neutrophil transmigration in vitro is also impaired by treatment with a synthetic cannabinomimetics, although the mechanism, while unclear, does not appear to be mediated via the CB1 or CB2 receptor suggesting that it may have been an indirect effect. While neutrophils are relatively short-lived, they are widely considered to be critical to the acute phase of intestinal injury associated with IBD.

Clearly, our overall understanding of potential anti-inflammatory mechanisms of cannabis is relatively poor. This is compounded by the wide array of biologically active components found in cannabis which include agonists, antagonists, partial agonists, positive allosteric modulators and negative allosteric modulators. A clinical trial sponsored by Bial, a pharmaceutical company in Portugal, and conducted by the French company Biotrial, studied the effect in human volunteers of a fatty acid amide hydrolase (FAAH) inhibitor, an enzyme that is thought to break down endocannabinoids in the brain. The study was aborted after 5 of 6 subjects receiving the highest doses developed significant neurologic side effects including one death 42 . While this effect was not believed to be a drug class effect, it highlights that further study is essential to determine the possible impact and safety of cannabinoids prior to their use for the treatment of IBD.

Challenges with cannabis in human subject research

With the legalization of medical and recreational cannabis and implementation of a regulatory system, one would expect that this recent change to the law would open new opportunities for human subject research involving cannabis. In fact, we have obtained a grant from the Colorado Department of Public Health and Environment to perform an observational study to evaluate cannabis in pediatric inflammatory bowel disease. However, academic researchers in Colorado now face some paradoxical challenges because under federal law, cannabis continues to remain a Schedule 1 drug.

To start with, there is still some uncertainty about the future of legalized cannabis in Colorado. On August 29th, 2013, the Department of Justice released an update to the Marijuana Enforcement Policy 43 , restating its efforts on enforcement priorities related to cannabis and the Department’s expectation that States that legalize cannabis would establish strict regulatory schemes that protect these federal enforcement priorities. This policy was based on assurance from the Colorado governor that these schemes will be in strict adherence and include strong state-based enforcement efforts that are backed by adequate funding. But the Department of Justice clearly states that it reserves the right to challenge the State’s legalization in the future.

There is also a continuing risk to be involved in litigation. Throughout 2015, several Colorado private businessmen operating cannabis businesses that were authorized under State law, as well as businesses that financed, insured, built and funded these businesses, were sued under the allegation that they constitute criminal enterprises under the Racketeer Influenced and Corrupt Organization (RICO) Act 44 .

Furthermore, a careful review of funding sources for research involving cannabis is critical because the Controlled Substances Act and other laws, such as the Anti-Money Laundering (AML) law, prohibit everyone from dealing with the proceeds from Controlled Substances, or from engaging in financial transactions with these proceeds.

For universities receiving Title IV federal student aid funding, the Drug Free Schools and Campuses Regulations (EDGAR Part 86) require the implementation of a program to prevent the unlawful possession, use or distribution of illicit drugs and alcohol by students and employees, and a policy that stipulates that a student or employee who violates the alcohol and other drugs policy is subject to both the institution’s sanction and to criminal sanctions provided by federal, state and local law. This again creates a challenging environment for academic researchers who want to study health effects of cannabis.

Researchers who plan to conduct a scientifically designed, interventional study with cannabis have additional challenges. First, in the United States, NIDA (National Institute on Drug Abuse) the federal agency overseeing marijuana for human subject research, contracts with the University of Mississippi to grow the only current supply of marijuana for use in human research studies 45 . Second, even when following and completing all required regulatory steps for this research, including investigational new drug application (IND) from Food and Drug Administration (FDA), Drug Enforcement Agency (DEA) researcher registration, institutional review board (IRB) approval, the Colorado State Board of Pharmacy does not allow any involvement of hospital pharmacists in research with cannabis, and the research cannot be performed under the hospital’s DEA license. Hence implementation of scientifically designed, interventional research requires the development of new processes, including new drug storage and dispensing processes, to conduct the research in a manner that is compliant with all applicable laws and policies. Lastly, many observational studies would benefit from having a quantitative analysis of the various cannabinoids in the product(s) used by the end users. Due to the challenges listed above, academic researchers are not allowed to have patients bring their cannabis products on campus for chemical analysis, and the state certified laboratories only perform testing for licensed cannabis growers.

Given all of the above challenges, our institution developed still evolving guidelines for human subject research involving cannabis ( Table 3 ). We also identified a number of important issues that have yet to be resolved ( Table 4 ). We recommend ongoing monitoring of federal and state laws as the field evolves.

Table 3

University of Colorado School of Medicine guidelines for human subject research involving cannabis (marijuana) as of February 2016

For all studies:
Cannot accept funding for research from cannabis industry
For observational studies:
Can survey or evaluate subjects who are already using drug for medical or recreational
purposes (e.g. can ask subject to come in for a blood draw 1 hour after taking drug)
Should obtain federal Certificate of Confidentiality for the study
Cannot subsidize the purchase of the cannabis products
Cannot pay subjects to participate in the study
Cannot bring to campus cannabis products to test level of cannabinoids (e.g. from grower or
retailer)
Cannot advise or prescribe to start taking the drug, or manage it in any way.
Cannot dictate when the drug is to be given (e.g. specific times to enable pharmacokinetic
studies)
Cannot ask users to stop cannabis use to be eligible to participate in a study (e.g. no baseline
studies)
Cannot ask to stop using drug for a washout period
Cannot have subjects smoke or ingest drug anywhere on campus prior to being interviewed
or evaluated for research
Cannot advise or prescribe to start taking the drug
Cannot move people higher on waiting list for a certain product at the dispensary if they
agree to participate in a study
For interventional studies (including animal studies):
Must be conducted under an IND from the FDA
Can only use cannabis purchased from NIDA or a cannabis-derived product that has an FDA
record (FDA approved, or under IND)
Must apply for a DEA Researcher registration
Cannot add marijuana to clinical DEA license
Must use specifically designed and dedicated locations for storage and administration of the
drug
Must post study on ClinicalTrials.gov posting as Applicable Clinical Trial. Study results need to
be posted no later than 12 months after the final collection of the primary outcome data

Table 4

Issues on cannabis research that have been identified but are yet to be resolved

Should observational studies that include minors be limited to those with medical marijuana
license? Should clinical researchers obtain a copy of the medical marijuana license?
How close are the chemical concentrations and ratios from an individual cannabis sample to
those in the grower’s profile for the harvest batch? Can researchers rely on the profile values?
If not, how can they obtain quick and inexpensive chemical analyses done without violating any
regulations and policies?
How can clinical researchers get continuous pre- and post-administration pharmacokinetic data
without violating any regulations and policies?
Even if listed as caregiver of a minor child, what might be the risk to parents who give cannabis
or cannabis-derived products to their child?

Conclusion

Use of recreational and medical cannabis use is increasing in the United States. There is an incorrect public perception of the safety of regular use. Approximately 30-40% of adolescents and young adults with IBD will try cannabis and some report benefit for their IBD. There is some rationale for considering a possible immune modifying effect of cannabis on IBD. The possible benefits and significant risks need to be better understood. However, the current regulatory environment imposes unique challenges on performing rigorous research into cannabis use. Care providers should become familiar with the issues around cannabis use and maintain open communication with their pediatric IBD patients.

What is known on this subject

Cannabis use is increasingly accepted across the United States.

There is public perception of the medical benefits of cannabis to treat many chronic diseases including IBD, but little concern about safety.

What this study adds

Approximately one quarter of adolescents and young adults with IBD in Colorado use cannabis regularly.

Although there is rationale for considering that cannabis might be helpful, there are unique aspects to conducting research on cannabis in pediatric IBD patients.

Acknowledgments

Financial Disclosure statement:

Edward Hoffenberg has a grant from Colorado Department of Public Health and Environment to study the benefits of marijuana in pediatric and adolescent IBD

Colm Collins: supported by funding from NIH NIDDK K01

Funding source: none

Abbreviations

IBD inflammatory bowel disease
CBD cannabidiol
THC tetrahydrocannabinol

Footnotes

Potential conflicts of interest: the authors have no conflicts of interest relevant to this article to disclose.

Note: term cannabis used primarily, but marijuana used when referring to state or federal programs using the term

References

2. Secretary of State of Colorado Medical Use of Marijuana. Colorado Department of Public Health and Environment, Health and Environmental Information and Statistics Division. 2012 [Google Scholar]

3. >Colorado Department of Public Health and E. Physician Certification. MMR1002. Colorado Medical Marijuana Registry. 2015 [Google Scholar]

4. Rocky Mountain High Intensity Drug Trafficking Area (RMHIDTA) Youth and Adult Marijuana Use. 2016:13. [Google Scholar]

5. Baca R. Denver Post. Denver Post; Denver: 2016. Colorado marijuana sales skyrocket to more than $996 million in 2015. [Google Scholar]

6. Young S. Medical Marijuana Refugees: ‘This was our only hope’. CNN Health + 2014; 2016 U.S. Edition ed: Cable News Network. [Google Scholar]

7. Gerich ME, Isfort RW, Brimhall B, Siegel CA. Medical Marijuana for Digestive Disorders: High Time to Prescribe? Am J Gastroenterol. 2014 [PubMed] [Google Scholar]

8. Johnston L, O’Malley P, Miech R, Bachman J, Schulenberg J. Monitoring the Future: National Survey Results on Drug Use 1975-2013 Overview, Key findings on Adolescent Drug Use. Institute for Social Research; University of Michigan: Ann Arbor: 2014. p. 13. [Google Scholar]

9. Volkow ND, Baler RD, Compton WM, Weiss SR. Adverse health effects of marijuana use. N Engl J Med. 2014; 370 :2219–27. [PMC free article] [PubMed] [Google Scholar]

10. Rocky Mountain High Intensity Drug Trafficking Area (RMHIDTA) Center RMHIDTA Investigative Support Center. Vol. 2. Denver: 2014. The Legalization of Marijuana in Colorado The Impact. [Google Scholar]

11. ElSohly M. Vol. 123. National Center for Natural Products Research; University of Mississippi: 2014. Potency Monitoring Program quarterly report no. 123-reporting period: 9/16/2013-12/15/2013. [Google Scholar]

12. Simonetto DA, Oxentenko AS, Herman ML, Szostek JH. Cannabinoid hyperemesis: a case series of 98 patients. Mayo Clin Proc. 2012; 87 :114–9. [PMC free article] [PubMed] [Google Scholar]

13. AAP Committee on Substance Abuse and AAP Committee on Adolescence The impact of marijuana policies on youth: clinical, research, and legal update. Pediatrics. 2015; 135 :584–7. [PubMed] [Google Scholar]

14. AACAP Committee on Substance Abuse and Committee on Adolescence AACAP Marijuana Legalization Policy Statement: American Academy of Child and Adolescent Psychiatry. 2014 [Google Scholar]

15. Whiting PF, Wolff RF, Deshpande S, Di Nisio M, Duffy S, Hernandez AV, Keurentjes JC, Lang S, Misso K, Ryder S, Schmidlkofer S, Westwood M, Kleijnen J. Cannabinoids for Medical Use: A Systematic Review and Meta-analysis. JAMA. 2015; 313 :2456–73. [PubMed] [Google Scholar]

16. Izzo AA, Camilleri M. Emerging role of cannabinoids in gastrointestinal and liver diseases: basic and clinical aspects. Gut. 2008; 57 :1140–55. [PubMed] [Google Scholar]

17. Massa F, Storr M, Lutz B. The endocannabinoid system in the physiology and pathophysiology of the gastrointestinal tract. J Mol Med (Berl) 2005; 83 :944–54. [PubMed] [Google Scholar]

18. Huestis MA. Human cannabinoid pharmacokinetics. Chem Biodivers. 2007; 4 :1770–804. [PMC free article] [PubMed] [Google Scholar]

19. Baca R, Migoya D. Denver Post. Denver Post; Denver: 2015. Marijuana products pulled in Denver in largest pesticide recalls. [Google Scholar]

20. Hoffenberg A, Hopfer C, Markson J, Garling T, Guerrero-Baez J, Hoffenberg E. Marijuana use in Adolescents and Young Adults with and without Inflammatory Bowel Disease. J Pediatr Gastroenterol Nutr. 2013; 57 e 64 #227. [Google Scholar]

21. Cottler LB. Composite International Diagnostic Interview-Substance Abuse Module (SAM) Department of Psychiatry, Washington University School of Medicine. 2000 [Google Scholar]

22. Gruber K, Anderson A, Calanan R, VanDyke M, Barker L, Burris D, Tolliver R. Colorado Department of Public Health and Environment. March Denver; 2015. Marijuana Use Among Adolescents in Colorado: Results from the 2013 Healthy Kids Colorado Survey; p. 10. [Google Scholar]

23. Kann L, Kinchen S, Shanklin S. Youth Risk Behavior Surveillance-United States, 2013. MMWR. 2014; 63 :172. [PubMed] [Google Scholar]

24. Substance Abuse and Mental Health Services Administration (SAMHSA) Substance Use and Mental Health Services Administration; Rockville, MD: 2014. Results from the 2013 National Survey on Drug Use and Health: Summary of National Findings. [Google Scholar]

25. Lal S, Prasad N, Ryan M, Tangri S, Silverberg MS, Gordon A, Steinhart H. Cannabis use amongst patients with inflammatory bowel disease. Eur J Gastroenterol Hepatol. 2011; 23 :891–6. [PubMed] [Google Scholar]

26. Ravikoff Allegretti J, Courtwright A, Lucci M, Korzenik JR, Levine J. Marijuana use patterns among patients with inflammatory bowel disease. Inflamm Bowel Dis. 2013; 19 :2809–14. [PMC free article] [PubMed] [Google Scholar]

27. Storr M, Devlin S, Kaplan GG, Panaccione R, Andrews CN. Cannabis use provides symptom relief in patients with inflammatory bowel disease but is associated with worse disease prognosis in patients with Crohn’s disease. Inflamm Bowel Dis. 2014; 20 :472–80. [PubMed] [Google Scholar]

28. Naftali T, Bar-Lev Schleider L, Dotan I, Lansky EP, Sklerovsky Benjaminov F, Konikoff FM. Cannabis induces a clinical response in patients with Crohn’s disease: a prospective placebo-controlled study. Clin Gastroenterol Hepatol. 2013; 11 :1276–1280. e1. [PubMed] [Google Scholar]

29. Dejesus E, Rodwick BM, Bowers D, Cohen CJ, Pearce D. Use of Dronabinol Improves Appetite and Reverses Weight Loss in HIV/AIDS-Infected Patients. J Int Assoc Physicians AIDS Care (Chic) 2007; 6 :95–100. [PubMed] [Google Scholar]

30. Schicho R, Storr M. IBD: Patients with IBD find symptom relief in the Cannabis field. Nat Rev Gastroenterol Hepatol. 2014; 11 :142–3. [PMC free article] [PubMed] [Google Scholar]

31. Marquez L, Suarez J, Iglesias M, Bermudez-Silva FJ, Rodriguez de Fonseca F, Andreu M. Ulcerative colitis induces changes on the expression of the endocannabinoid system in the human colonic tissue. PLoS One. 2009; 4 :e6893. [PMC free article] [PubMed] [Google Scholar]

32. D’Argenio G, Valenti M, Scaglione G, Cosenza V, Sorrentini I, Di Marzo V. Up-regulation of anandamide levels as an endogenous mechanism and a pharmacological strategy to limit colon inflammation. FASEB J. 2006; 20 :568–70. [PubMed] [Google Scholar]

33. Cencioni MT, Chiurchiu V, Catanzaro G, Borsellino G, Bernardi G, Battistini L, Maccarrone M. Anandamide suppresses proliferation and cytokine release from primary human T-lymphocytes mainly via CB2 receptors. PLoS One. 2010; 5 :e8688. [PMC free article] [PubMed] [Google Scholar]

34. Burstein SH, Zurier RB. Cannabinoids, endocannabinoids, and related analogs in inflammation. AAPS J. 2009; 11 :109–19. [PMC free article] [PubMed] [Google Scholar]

35. McCulloch C, Searle S, Neuhaus J. Generalized, linear, and mixed models. John Wiley and Sons. 2008 [Google Scholar]

36. Strober W, Fuss IJ. Proinflammatory cytokines in the pathogenesis of inflammatory bowel diseases. Gastroenterology. 2011; 140 :1756–67. [PMC free article] [PubMed] [Google Scholar]

37. Wittchen HU. Reliability and validity studies of the WHO–Composite International Diagnostic Interview (CIDI): a critical review. J Psychiatr Res. 1994; 28 :57–84. [PubMed] [Google Scholar]

38. Pacifici R, Zuccaro P, Pichini S, Roset PN, Poudevida S, Farre M, Segura J, De la Torre R. Modulation of the immune system in cannabis users. JAMA. 2003; 289 :1929–31. [PubMed] [Google Scholar]

39. Boschetti G, Nancey S, Sardi F, Roblin X, Flourie B, Kaiserlian D. Therapy with anti-TNFalpha antibody enhances number and function of Foxp3(+) regulatory T cells in inflammatory bowel diseases. Inflamm Bowel Dis. 2011; 17 :160–70. [PubMed] [Google Scholar]

40. Shoemaker JL, Joseph BK, Ruckle MB, Mayeux PR, Prather PL. The endocannabinoid noladin ether acts as a full agonist at human CB2 cannabinoid receptors. J Pharmacol Exp Ther. 2005; 314 :868–75. [PubMed] [Google Scholar]

41. Kusher DI, Dawson LO, Taylor AC, Djeu JY. Effect of the psychoactive metabolite of marijuana, delta 9-tetrahydrocannabinol (THC), on the synthesis of tumor necrosis factor by human large granular lymphocytes. Cell Immunol. 1994; 154 :99–108. [PubMed] [Google Scholar]

42. Enserik M. Science News. Vol. 2016. American Academy for the Advancement of Science; New York: 2016. More details emerge on fateful French drug trial. [Google Scholar]

43. Cole JM. Department of Justice. Office of the Deputy Attorney General; Washington, DC: 2013. Guidance Regarding Marijuana Enforcement. [Google Scholar]

44. Cole JM. Department of Justice. Office of the Deputy Attorney General; Washington, DC: 2014. Guideline Regarding Marijuana Related Financial Crimes. [Google Scholar]

45. US Food and Drug Administration . Marijuana Research with Human Subjects. Vol. 2016. U.S. FDA; Washington, D.C.: 2015. [Google Scholar]

46. Secretary of State, State of Colorado . Colorado Department of Public Health and Environment. Vol. 5. Secretary of State; Colorado: 2015. Medical Use of Marijuana. CCR 1006-2. [Google Scholar]

47. The Retail Marijuana Public Health Advisory Committee . Changes in marijuana use patterns, systematic literature review, and possible marijuana-related health effects. Colorado State Board of Health; Denver: 2015. Monitoring Health Concerns Related to Marijuana in Colorado: 2014. [Google Scholar]

See also  Cbd oil 250mg dose for dag