Cost-Effectiveness of Medicinal Cannabis for Management of Refractory Symptoms Associated With Chronic Conditions: A Systematic Review of Economic Evaluations.

OBJECTIVES: Although there is a growing body of evidence suggesting that cannabinoids may relieve symptoms of some illnesses, they are relatively high-cost therapies compared with illicit growth and supply. This article aimed to comprehensively review economic evaluations of medicinal cannabis for alleviating refractory symptoms associated with chronic conditions. METHODS: Seven electronic databases were searched for articles published up to September 6, 2020. The quality of reporting of economic evaluations was assessed using the Consolidated Health Economic Evaluation Reporting Standards checklist. The extracted data were grouped into subcategories according to types of medical conditions, organized into tables, and reported narratively. RESULTS: This review identified 12 cost-utility analyses conducted across a variety of diseases including multiple sclerosis (MS) (N = 8), pediatric drug-resistant epilepsies (N = 2), and chronic pain (N = 2). The incremental cost-effectiveness ratio varied widely from cost saving to more than US$451 800 per quality-adjusted life-year depending on the setting, perspectives, types of medicinal cannabis, and indications. Nabiximols is a cost-effective intervention for MS spasticity in multiple European settings. Cannabidiol was found to be a cost-effective for Dravet syndrome in a Canadian setting whereas a cost-utility analysis conducted in a US setting deemed cannabidiol to be not cost-effective for Lennox-Gastaut syndrome. Overall study quality was good, with publications meeting 70% to 100% (median 83%) of the Consolidated Health Economic Evaluation Reporting Standards checklist criteria. CONCLUSIONS: Medicinal cannabis-based products may be cost-effective treatment options for MS spasticity, Dravet syndrome, and neuropathic pain, although the literature is nascent. Well-designed clinical trials and health economic evaluations are needed to generate adequate clinical and cost-effectiveness evidence to assist in resource allocation.

Cannabis and Migraine: It's Complicated.

PURPOSE OF REVIEW: The use of cannabis for the treatment of migraine has become an area of interest with the legalization of medical cannabis in the USA. Understanding the mechanisms of cannabinoids, available studies, and best clinical recommendations is crucial for headache providers to best serve patients. RECENT FINDINGS: Patients utilizing medical cannabis for migraine have reported improvement in migraine profile and common comorbidities. Reduction in prescription medication is also common, especially opioids. Side effects exist, with the majority being mild. Not enough data is available for specific dose recommendations, but THC and CBD appear to mediate these observed effects. The purpose of this article is twofold: review the limited research surrounding cannabis for migraine disease and reflect on clinical management experiences to provide recommendations that best capture the potential use of cannabis for migraine.

Effect of Inhaled Cannabis for Pain in Adults With Sickle Cell Disease: A Randomized Clinical Trial.

Importance: Sickle cell disease (SCD) is characterized by chronic pain and episodic acute pain caused by vasoocclusive crises, often requiring high doses of opioids for prolonged periods. In humanized mouse models of SCD, a synthetic cannabinoid has been found to attenuate both chronic and acute hyperalgesia. The effect of cannabis on chronic pain in adults with SCD is unknown. Objective: To determine whether inhaled cannabis is more effective than inhaled placebo in relieving chronic pain in adults with SCD. Design, Setting, and Participants: This pilot randomized clinical trial included participants with SCD with chronic pain admitted to a single inpatient clinical research center for 2 separate 5-day stays from August 2014 to April 2017. Participants inhaled either vaporized cannabis (4.4% Δ-9-tetrahydrocannabinol to 4.9% cannabidiol) 3 times daily or vaporized placebo cannabis. Pain and pain interference ratings using the Brief Pain Inventory were assessed throughout each 5-day period. Participants with SCD and chronic pain on stable analgesics were eligible to enroll. A total of 90 participants were assessed for eligibility; 56 participants were deemed ineligible, and 34 participants were enrolled. Of these, 7 participants dropped out before randomization. Of 27 randomized participants, 23 completed both treatment arms of the crossover study and were included in the final per protocol analysis. Data analysis was completed in June 2019, with the sensitivity analysis conducted in April 2020. Interventions: Inhalation of vaporized cannabis plant (4.4% Δ-9-tetrahydrocannbinol to 4.9% cannabidiol) or placebo cannabis plant using a vaporizer 3 times daily for 5 days. Main Outcomes and Measures: Daily pain assessed with visual analog scale and Brief Pain Inventory. Results: A total of 23 participants (mean [SD] age, 37.6 [11.4] years; 13 [56%] women) completed the trial. The mean (SD) difference in pain rating assessment between the cannabis and placebo groups was -5.3 (8.1) for day 1, -10.9 (7.0) for day 2, -16.5 (9.2) for day 3, -8.9 (6.7) for day 4, and -8.2 (8.1) for day 5; however, none of these differences were statistically significant. There was no statistically significant mean (SD) difference in pain interference ratings between cannabis and placebo between days 1 and 5 for interference in general activities (day 1: 0.27 [0.35]; day 5: -1.0 [0.5]), walking (day 1: 0.14 [0.73]; day 5: -0.87 [0.63]), sleep (day 1: 0.59 [0.74]; day 5: -1.3 [0.8]), or enjoyment (day 1: 0.23 [0.69]; day 5: -0.91 [0.48]), but there was a statistically significant mean (SD) difference in decrease in interference with mood (day 1: 0.96 [0.59]; day 5: -1.4 [0.6]; P = .02). No differences in treatment-related adverse effects were observed. Use of concomitant opioids was similar during both treatment periods. Conclusions and Relevance: This randomized clinical trial found that, compared with vaporized placebo, vaporized cannabis did not statistically significantly reduce pain and associated symptoms, except interference in mood, in patients with SCD with chronic pain. Trial Registration: ClinicalTrials.gov Identifier: NCT01771731.

A regulatory take on cannabis and cannabinoids for medicinal use in the European Union.

The discovery of the endocannabinoid system has raised public interest in the medicinal use of cannabis, phytocannabinoids, and synthetic cannabinoids, which has always been closely regulated due to their psychotropic effects and potential abuse. The review takes a quick look at the current legal framework in the European Union, which regulates cannabis use and cultivation for medicinal purposes in line with the United Nations Conventions on the production, trade, and use of cannabis, phytocannabinoids, and synthetic cannabinoids. And while the EU legislation precisely defines requirements and marketing authorisation procedures for medicinal products for all EU member states, there is no common regulatory framework for magistral and officinal preparations containing cannabinoids, as they are exempt from marketing authorisation. Instead, their regulation is left to each member state, and it is quite uneven at this point, mainly due to cultural and historical differences between the countries, leading to different access to non-authorised medicinal products. Therefore, to meet great public interest, harmonised approaches on cannabinoid-containing products without marketing authorisation would be welcome to level the playing field in the EU.

Pharmacists and the future of cannabis medicine.

OBJECTIVES: To summarize the history and evolution of cannabis use and policies and to review current therapeutic uses, safety, and the central role pharmacists can play. SUMMARY: Cannabis regulation and use have evolved over the centuries and are becoming more widely accepted, with over two-thirds of states in the United States having an approved cannabis program. However, changing policy and a paucity of controlled clinical trials has led to questions on the safety and effectiveness of cannabinoid therapies. Although there are conditions for which cannabinoids may be helpful, potential contraindications, adverse effects, and drug-drug interactions should be taken into account. CONCLUSION: Pharmacists are in a unique position based on their accessibility, knowledge, and skills to guide product selection, dosing, and discuss drug interactions and adverse effects to educate patients on safe cannabis use, whether it be delta-9-tetrahydrocannabinol, cannabidiol, or a combination thereof. Pharmacists and pharmacy organizations, moreover, should advocate for an integral role in the medical cannabis movement to ensure patient safety and evaluate cannabinoid pharmacology, pharmacokinetics, drug-drug interactions, safety, and efficacy through rigorous investigations.

Oral medicinal cannabinoids to relieve symptom burden in the palliative care of patients with advanced cancer: a double-blind, placebo controlled, randomised clinical trial of efficacy and safety of cannabidiol (CBD).

BACKGROUND: Despite improvements in medical care, patients with advanced cancer still experience substantial symptom distress. There is increasing interest in the use of medicinal cannabinoids, but there is little high quality evidence to guide clinicians. This study aims to define the role of cannabidiol (CBD) in the management of symptom burden in patients with advanced cancer undergoing standard palliative care. METHODS AND DESIGN: This study is a multicentre, randomised, placebo controlled, two arm, parallel trial of escalating doses of oral CBD. It will compare efficacy and safety outcomes of a titrated dose of CBD (100 mg/mL formulation, dose range 50 mg to 600 mg per day) against placebo. There is a 2-week patient determined titration phase, using escalating doses of CBD or placebo to reach a dose that achieves symptom relief with tolerable side effects. This is then followed by a further 2-week assessment period on the stable dose determined in collaboration with clinicians. DISCUSSION: A major strength of this study is that it will target symptom burden as a whole, rather than just individual symptoms, in an attempt to describe the general improvement in wellbeing previously reported by some patients in open label, non controlled trials of medicinal cannabis. Randomisation with placebo is essential because of the well-documented over reporting of benefit in uncontrolled trials and high placebo response rates in cancer pain trials. This will be the first placebo controlled clinical trial to evaluate rigorously the efficacy, safety and acceptability of CBD for symptom relief in advanced cancer patients. This study will provide the medical community with evidence to present to patients wishing to access medicinal cannabis for their cancer related symptoms. TRIAL REGISTRATION NUMBER: ALCTRN12618001220257 Registered 20/07/2018.

[Position paper on medical cannabis and cannabis-based medicines in pain medicine]. / Ein Positionspapier zu medizinischem Cannabis und cannabisbasierten Medikamenten in der Schmerzmedizin.

Since March 2017, the prescription of medical cannabis at the expense of the statutory health insurance is possible after approval by the respective medical services. Chronic pain is the most common indication, as health claims data and the accompanying survey show. From the point of view of the law, a prescription is indicated in cases of serious illness, missing or not indicated established therapeutic approaches and a not entirely remote prospect of improvement of the illness or its symptoms. This describes a broader indication spectrum than can currently be based on randomised controlled clinical trials. There is weak evidence of low efficacy for neuropathic pain. For pain related to spasticity and cancer-related pain there is evidence of improvements in quality of life, but effects on pain are of little relevance. For all other indications, only an individual therapeutic trial can be justified based on the available external evidence. However, this usually corresponds to the demand of "a not entirely remote prospect" of a noticeably positive effect of medical cannabis. It is also problematic that almost no long-term studies for the application and efficacy of flowers and extracts are available.Current knowledge on the use of cannabis-based drugs and, more clearly, medical cannabis for chronic pain is insufficient. The increase in the number of countries with marketing authorisations or exemptions for medicinal cannabis or cannabis-based drugs for chronic pain will also pave the way for larger empirical and population-based studies that will further improve the evidence base of research and clinical use.

Surveys of pharmacy students and pharmacy educators regarding medical marijuana.

INTRODUCTION: In this study, a cohort of Ohio pharmacy students were surveyed about knowledge and attitudes regarding medical marijuana (MMJ). Pharmacy educators in legalized states were asked how MMJ education was incorporated into pharmacy curricula. METHODS: Pharmacy students from six colleges were emailed surveys. Pharmacy educators from 79 colleges in states with legal MMJ programs were emailed regarding curricular content covering MMJ. RESULTS: A total of 319 student respondents received scores between 50 and 60% on knowledge-based questions. Students favored legalization of medical, but not recreational marijuana; they are not confident in ability to counsel; they believe little education on MMJ is provided in pharmacy school; and feel that more education is needed on MMJ. Students supporting MMJ were more likely to support recreational use of marijuana (p < 0.001), and education about MMJ (p < 0.001). Students in advanced years were less willing to dispense medical marijuana (p < 0.01), and less likely to support pharmacist availability for counseling (p < 0.05). Sixty-two percent of colleges who responded to the survey in legalized states provided education on MMJ to pharmacy students. Sixty-four percent of colleges responding who provided MMJ education offered a required course; 84.6% educated on indications and misuse/abuse; 92.3% on side effects, and adverse drug reactions; 53.8% on drug interactions. CONCLUSION: Ohio pharmacy student knowledge regarding medical marijuana is low. Students believe pharmacists should be available for counseling on MMJ; they feel unprepared to dispense MMJ, and would like more education on MMJ. Some colleges of pharmacy in the US report providing MMJ education; extent is unknown.

[Cannabis for medicinal use: development of pharmacopoeia monographs as a quality standard]. / Cannabis für medizinische Zwecke: Entwicklung von Arzneibuchmonographien als Qualitätsstandard.

Herbal drugs and extracts, like all pharmaceutical starting materials used in the manufacture of medicinal products, must have an appropriate pharmaceutical quality. Corresponding quality standards are described in the individual monographs of the pharmacopoeia according to § 55 of the German Drug Law. This includes information on ingredients and active substance content, among other things. This article describes the development of the Cannabis Flower Monograph for the German Pharmacopoeia (DAB) and the quality requirements and storage conditions contained therein. The state of development of monographs for the European Pharmacopoeia is also presented.After it was announced that there would be new legal regulations for the medical use of cannabis flowers and cannabis extracts, the first work on the cannabis flower monograph for the DAB began as early as 2015. First, a monograph on cannabis flowers was published in May 2016 in the German Drug Codex (DAC). The monograph was replaced in May 2017 by the publication of the DAB monograph. A revised version of the DAB monograph has been in force since April 2018 as a national quality standard.A harmonised cannabis flower monograph for the European Pharmacopoeia is currently being prepared to replace national quality standards. In addition, the German Pharmacopoeia and subsequently the European Pharmacopoeia develops monographs for preparations from cannabis flowers. In future, harmonised monographs in the European Pharmacopoeia will make it possible to avoid multiple testing according to the respective national standards and to facilitate analyses in laboratories and pharmacies.

The Role of Cannabis in the Management of Inflammatory Bowel Disease: A Review of Clinical, Scientific, and Regulatory Information.

There is significant interest among patients and providers in using cannabis (marijuana) and its derivatives to treat a number of chronic illnesses, including inflammatory bowel disease. Despite the Schedule I classification of cannabis by the federal government, state governments have sought ways to make cannabis available for specific medical conditions, and some states have legalized cannabis outright. This white paper summarizes the preclinical data, clinical data, safety data, and the regulatory landscape as they apply to medical cannabis use in inflammatory bowel disease. Animal models of cannabinoid chemistry and physiology give evidence of anti-inflammatory, antidiarrheal, and nociceptive-limiting properties. Human studies have found benefit in controlling symptoms and improving quality of life, but no studies have established true disease modification given the absent improvement in biomarker profiles or endoscopic healing. Finally, this review describes the legal, regulatory, and practical hurdles to studying the risks and benefits of medical cannabis in the United States. 10.1093/ibd/izy319_video1 izy319.video1 5852852028001.

Barriers to Achieving Optimal Success with Medical Cannabis: Opportunities for Quality Improvement.

This commentary describes the clinician experience of certifying patients for medical cannabis (MC) in a north suburban Chicago integrative family medicine practice. The physician and research assistant performed a comprehensive chart review of the first 166 MC patients certified in the practice. Based on this review, barriers and opportunities were elucidated to improve delivery of MC therapy in Illinois within the existing framework of regulation, licensing, certification, and distribution. The following factors have posed challenges for the Illinois Medical Cannabis Pilot Program. These factors are interrelated and include: (1) inadequate scientific knowledge regarding effectiveness, dosage, delivery mechanism, indications, and drug interactions in humans; (2) lack of educational standards for dispensary and medical staff training; (3) lack of communication and coordination of patient care; (4) complexity and inconsistent availability of dosing options; and (5) barriers to access for patients seeking this therapy.

Implementation of a generic SFC-MS method for the quality control of potentially counterfeited medicinal cannabis with synthetic cannabinoids.

In this study, we describe the development of a SFC-MS method for the quality control of cannabis plants that could be potentially adulterated with synthetic cannabinoids. Considering the high number of already available synthetic cannabinoids and the high rate of development of novel structures, we aimed to develop a generic method suitable for the analysis of a large panel of substances using seventeen synthetic cannabinoids from multiple classes as model compounds. Firstly, a suitable column was chosen after a screening phase. Secondly, optimal operating conditions were obtained following a robust optimization strategy based on a design of experiments and design space methodology (DoE-DS). Finally, the quantitative performances of the method were assessed with a validation according to the total error approach. The developed method has a run time of 9.4 min. It uses a simple modifier composition of methanol with 2% H2O and requires minimal sample preparation. It can chromatographically separate natural cannabinoids (except THC-A and CBD-A) from the synthetics assessed. Also, the use of mass spectrometry provides sensitivity and specificity. Moreover, this quality by design (QbD) approach permits the tuning of the method (within the DS) during routine analysis to achieve a desirable separation since the future compounds that should be analyzed could be unknown. The method was validated for the quantitation of a selected synthetic cannabinoid in fiber-type cannabis matrix over the range of 2.5% - 7.5% (w/w) with LOD value as low as 14.4 ng/mL. This generic method should be easy to implement in customs or QC laboratories in the context of counterfeit drugs tracking.

Mapping regulatory models for medicinal cannabis: a matrix of options.

Objective The aim of the present study was to develop a framework for assessing regulatory options for medicinal cannabis in Australia. Methods International regulatory regimes for medicinal cannabis were reviewed with a qualitative policy analysis approach and key policy features were synthesised, leading to a conceptual framework that facilitates decision making across multiple dimensions. Results Two central organising dimensions of medicinal cannabis regulation were identified: cannabis supply and patient authorisation (including patient access). A number of the different supply options can be matched with a number of different patient authorisation options, leading to a matrix of possible regulatory regimes. Conclusions The regulatory options, as used internationally, involve different forms of cannabis (synthetic and plant-based pharmaceutical preparations or herbal cannabis) and the varying extent to which patient authorisation policies and procedures are stringently or more loosely defined. The optimal combination of supply and patient authorisation options in any jurisdiction that chooses to make medicinal cannabis accessible will depend on policy goals. What is known about the topic? Internationally, regulation of medicinal cannabis has developed idiosyncratically, depending on formulations that were made available and local context. There has been no attempt to date in the scientific literature to systematically document the variety of regulatory possibilities for medicinal cannabis. What does this paper add? This paper presents a new conceptual schema for considering options for the regulation of medicinal cannabis, across both supply and patient authorisation aspects. What are the implications for practitioners? The design of regulatory systems in Australia, whether for pharmaceutical or herbal products, is a vital issue for policy makers right now as federal and state and territory governments grapple with the complexities of medicinal cannabis regulation. The conceptual schema presented herein provides a tool for more systematic thinking about the options.

Comprehensive quality evaluation of medical Cannabis sativa L. inflorescence and macerated oils based on HS-SPME coupled to GC-MS and LC-HRMS (q-exactive orbitrap®) approach.

There are at least 554 identified compounds in C. sativa L., among them 113 phytocannabinoids and 120 terpenes. Phytocomplex composition differences between the pharmaceutical properties of different medical cannabis chemotype have been attributed to strict interactions, defined as 'entourage effect', between cannabinoids and terpenes as a result of synergic action. The chemical complexity of its bioactive constituents highlight the need for standardised and well-defined analytical approaches able to characterise the plant chemotype, the herbal drug quality as well as to monitor the quality of pharmaceutical cannabis extracts and preparations. Hence, in the first part of this study an analytical procedures involving the combination of headspace-solid-phase microextraction (HS-SPME) coupled to GC-MS and High Resolution Mass-Spectrometry LC-HRMS (Orbitrap®) were set up, validated and applied for the in-depth profiling and fingerprinting of cannabinoids and terpenes in two authorised medical grade varieties of Cannabis sativa L. inflorescences (Bedrocan® and Bediol®) and in obtained macerated oils. To better understand the trend of all volatile compounds and cannabinoids during oil storage a new procedure for cannabis macerated oil preparation without any thermal step was tested and compared with the existing conventional methods to assess the potentially detrimental effect of heating on overall product quality.

Race/ethnicity and marijuana use in the United States: Diminishing differences in the prevalence of use, 2006-2015.

BACKGROUND: Marijuana use has been decreasing in the past several years among adolescents, though variation in the extent and rate of decrease across racial/ethnic groups is inadequately understood. METHODS: The present study utilized nationally-representative data in Monitoring the Future from 2006 to 2015 to examine trends over time in past 30-day marijuana use. We examine whether differences in trends over time by race and ethnicity also differ by individual-level, school-level, and state-level factors. Sample included 131,351 8th grade students, 137,249 10th grade students, and 123,293 12th grade students; multi-level models and difference-in-differences tests were used. RESULTS: In 10th grade, Black students had a positive linear increase in marijuana use (est=0.04, SE=0.01, p<0.001), and the magnitude of the increase was significantly greater than among non-Hispanic White students (est=0.38, SE=0.009, p<0.001). The increase trend among Black students was greater among those in large class sizes. In 12th grade, all racial ethnic groups except non-Hispanic Whites demonstrated a linear increase in prevalence across time. The magnitude of the increase among Hispanic students was greater among those in urban areas and large class sizes. The magnitude of the increase among Black students was greater in states with a medical marijuana law before 2006 (est=0.06, SE=0.03, p=0.02), among other state-level covariates. CONCLUSION: Together these results suggest that the next stage of public health approaches to reducing the harms associated with adolescent drug use should attend to shifting demographic patterns of use among adolescents and ensure that services and programmatic approaches to adolescent prevention are applied equitably.