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 1:1 delta-9-tetrahydrocannabinol (THC) and 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 little high-quality evidence to guide clinicians. This study aims to define the role of a 1:1 delta-9-tetrahydrocannabinol/cannabidiol (THC/CBD) cannabinoid preparation in the management of symptom burden in patients with advanced cancer undergoing standard palliative care. METHODS AND DESIGN: One hundred fifty participants will be recruited from five sites within the Queensland Palliative Care Research Group (QPCRG) and randomly assigned to an active treatment or placebo group. This study is a pragmatic multicentre, randomised, placebo-controlled, two-arm trial of escalating doses of an oral 1:1 THC/CBD cannabinoid preparation. It will compare efficacy and safety outcomes of a titrated dose (10 mg/10 mg/mL oral solution formulation, dose range 2.5 mg/2.5 mg-30 mg/30 mg/day) against placebo. There is a 2-week patient-determined titration phase, using escalating doses of 1:1 THC/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. The primary objective is to assess the effect of escalating doses of a 1:1 THC/CBD cannabinoid preparation against placebo on change in total symptom score, with secondary objectives including establishing a patient-determined effective dose, the change in total physical and emotional sores, global impression of change, anxiety and depression, opioid use, quality of life and adverse effects. DISCUSSION: This will be the first placebo-controlled clinical trial to rigorously evaluate the efficacy, safety and acceptability of 1:1 THC/CBD for symptom relief in advanced cancer patients. This study will allow the medical community to have some evidence to present to patients wishing to access cannabis for their symptoms caused by advanced malignancy. TRIAL REGISTRATION: ACTRN, ACTRN12619000037101 . Registered on 14 January 2019. Trial Sponsor: Mater Misericordiae Limited (MML) and Mater Medical Research Institute Limited (MMRI)-Raymond Terrace, South Brisbane, Brisbane, QLD, Australia.

Does Unit-Dose Packaging Influence Understanding of Serving Size Information for Cannabis Edibles?

OBJECTIVE: Edible cannabis products have increased in popularity, particularly in jurisdictions that have legalized nonmedical cannabis. Rates of adverse events from cannabis edibles have also increased, in part because of difficulties identifying and titrating tetrahydrocannabinol (THC) levels. The current study tested whether packaging cannabis in separate units enhances consumer understanding of serving sizes. METHOD: An experimental task was conducted as part of the 2018 International Cannabis Policy Study online survey. Participants were recruited from the Nielsen Global Insights Consumer Panel. A total of 26,894 participants (61.5% female) ages 16-65 years from Canada and the United States were randomly assigned to view a cannabis brownie packaged according to one of three conditions: (a) multiserving edible ("control condition"), (b) single-serving edible, and (c) single-serving edible packaged separately ("unit-dose packaging"). Participants were asked to identify a standard serving based on information on the product label. Logistic regression was used to test the influence of packaging condition on the likelihood of a correct response, adjusting for key covariates. RESULTS: Compared with the multiserving edible control (50.6%), participants were significantly more likely to correctly identify the serving size in the single-serving edible condition (55.3%; adjusted odds ratio = 1.22, CI [1.15, 1.29], p < .001) and the unit-dose packaging condition (54.3%; adjusted odds ratio = 1.17, CI [1.10, 1.24], p < .001). CONCLUSIONS: Packaging in which each product unit contained one dose of THC enhanced consumers' ability to identify how much of a product constitutes a standard serving or dose. Packaging products as individual doses eliminates the need for mental math and could reduce the risk of accidental overconsumption of cannabis.

Cannabis labelling and consumer understanding of THC levels and serving sizes.

OBJECTIVE: As part of cannabis legalization in Canada and several US states, regulations specify how THC levels should be labelled on products; however, there is little evidence on the extent to which consumers understand and use THC labelling to inform consumption amounts. The current study was designed to assess comprehension of cannabis-related information including communication of dose and strength of product on different labelling designs among young Canadians. METHODS: Two experiments were conducted in October 2017 among Canadian youth and young adults aged 16-30 years as part of an online cross-sectional survey (N = 870). Experiment 1 randomized respondents to one of three labelling conditions (1=No Label, 2=mgTHC, 3=Doses). Respondents interpreted a recommended serving and number of servings contained in the package. Experiment 2 randomized respondents to one of four labelling conditions communicating THC level (1=No Label, 2=%THC, 3=mgTHC, 4=Traffic Light System). Respondents determined level of THC in the product. RESULTS: Labelling the number of doses per package was associated with the greatest proportion of correct responses (54.1 %) when respondents had to determine a recommended serving compared with the no-label control condition (7.4 %) and THC mg condition (13.4 %). When cannabis products were labelled using a traffic light system, participants were more likely to identify THC level: low THC (85.1 %) or high THC (86.4 %) than the control condition (2.0 % and 5.2 % respectively). CONCLUSION: Few consumers can understand and apply quantitative THC labelling; in contrast, THC labels that provide 'interpretive' information, such as descriptors, symbols, or references to servings have greater efficacy.

Validation of a liquid chromatography tandem mass spectrometry (LC-MS/MS) method to detect cannabinoids in whole blood and breath.

Background The widespread availability of cannabis raises concerns regarding its effect on driving performance and operation of complex equipment. Currently, there are no established safe driving limits regarding ∆9-tetrahydrocannabinol (THC) concentrations in blood or breath. Daily cannabis users build up a large body burden of THC with residual excretion for days or weeks after the start of abstinence. Therefore, it is critical to have a sensitive and specific analytical assay that quantifies THC, the main psychoactive component of cannabis, and multiple metabolites to improve interpretation of cannabinoids in blood; some analytes may indicate recent use. Methods A liquid chromatography tandem mass spectrometry (LC-MS/MS) method was developed to quantify THC, cannabinol (CBN), cannabidiol (CBD), 11-hydroxy-THC (11-OH-THC), (±)-11-nor-9-carboxy-Δ9-THC (THCCOOH), (+)-11-nor-Δ9-THC-9-carboxylic acid glucuronide (THCCOOH-gluc), cannabigerol (CBG), and tetrahydrocannabivarin (THCV) in whole blood (WB). WB samples were prepared by solid-phase extraction (SPE) and quantified by LC-MS/MS. A rapid and simple method involving methanol elution of THC in breath collected in SensAbues® devices was optimized. Results Lower limits of quantification ranged from 0.5 to 2 µg/L in WB. An LLOQ of 80 pg/pad was achieved for THC concentrations in breath. Calibration curves were linear (R2>0.995) with calibrator concentrations within ±15% of their target and quality control (QC) bias and imprecision ≤15%. No major matrix effects or drug interferences were observed. Conclusions The methods were robust and adequately quantified cannabinoids in biological blood and breath samples. These methods will be used to identify cannabinoid concentrations in an upcoming study of the effects of cannabis on driving.

'Standard THC units': a proposal to standardize dose across all cannabis products and methods of administration.

BACKGROUND AND AIMS: Cannabis products are becoming increasingly diverse, and vary considerably in concentrations of ∆9 -tetrahydrocannabinol (THC) and cannabidiol (CBD). Higher doses of THC can increase the risk of harm from cannabis, while CBD may partially offset some of these effects. Lower Risk Cannabis Use Guidelines currently lack recommendations based on quantity of use, and could be improved by implementing standard units. However, there is currently no consensus on how units should be measured or standardized among different cannabis products or methods of administration. ARGUMENT: Existing proposals for standard cannabis units have been based on specific methods of administration (e.g. joints) and these may not capture other methods, including pipes, bongs, blunts, dabbing, vaporizers, vape pens, edibles and liquids. Other proposals (e.g. grams of cannabis) cannot account for heterogeneity in THC concentrations among different cannabis products. Similar to alcohol units, we argue that standard cannabis units should reflect the quantity of primary active pharmacological constituents (dose of THC). On the basis of experimental and ecological data, public health considerations and existing policy, we propose that a 'standard THC unit' should be fixed at 5 mg THC for all cannabis products and methods of administration. If supported by sufficient evidence in future, consumption of standard CBD units might offer an additional strategy for harm reduction. CONCLUSIONS: Standard ∆9 -tetrahydrocannabinol (THC) units can potentially be applied among all cannabis products and methods of administration to guide consumers and promote safer patterns of use.

[Cannabis-based medicines for chronic pain: indications, selection of drugs, effectiveness and safety : Experiences of pain physicians in Saarland]. / Cannabispräparate bei chronischen Schmerzen: Indikationen, Präparateauswahl, Wirksamkeit und Sicherheit : Erfahrungen der saarländischen Schmerztherapeuten.

BACKGROUND: There are uncertainties among physicians with respect to the indications, selection of drugs, effectiveness and safety of cannabis-based medicines for chronic pain. METHODS: All statutory health insurance pain physicians in Saarland were asked to complete a self-developed questionnaire assessing their experiences with cannabis-based medicines, which they prescribed between 10 March 2017 and 30 November 2018 for adult patients with chronic cancer and non-cancer pain. RESULTS: All statutory health insurance pain physicians participated in the survey and 13 out of 20 reported having prescribed cannabis-based medicines. The most frequent reasons for prescriptions in 136 patients (1.9% of the patients of the institutions) were failure of established treatment (73%) and desire of the patient (63%). In 35% of patients the type of pain was nociceptive, in 34% neuropathic, in 29% nociceptive and neuropathic and in 13% nociplastic. Dronabinol was prescribed for 95% of the patients and 71% were responders (clinically relevant reduction of pain or of other symptoms). In 29% of patients treatment was terminated due to either a lack of efficacy or adverse events. CONCLUSION: Statutory health insurance pain physicians in Saarland were reluctant to prescribe cannabis-based medicines. Dronabinol was effective and well-tolerated in the majority of the highly selected patients.

[European Union regulatory and quality requirements for botanical drugs and their implications for Chinese herbal medicinal products development].

This paper introduces regulatory pathways and characteristic quality requirements for marketing authorization of herbal medicinal products in the European Union（EU）, and the legal status and applications of "European Union list of herbal substances, preparations and combinations" and "European Union herbal monographs". Also introduced are Chinese herbs that have been granted the EU list entry, those with EU herbal monographs, and registered EU traditional herbal medicinal products with Chinese herbs as active ingredients. Special attention is paid to the technical details of three authorized EU herbal medicinal products (Veregen, Sativex and Episalvan) in comparison with Andrographis paniculata extract HMPL-004 that failed the phase Ⅲ clinical trial for ulcerative colitis. The paper further emphasizes the importance of enriching active fractions of herbal extracts and taking regulatory and quality considerations into account in early stage of botanical drug development.

Stability of dronabinol capsules when stored frozen, refrigerated, or at room temperature.

PURPOSE: Results of a study to determine the 90-day stability of dronabinol capsules stored under various temperature conditions are reported. METHODS: High-performance liquid chromatography (HPLC) with ultraviolet (UV) detection was used to assess the stability of dronabinol capsules (synthetic delta-9-tetrahydrocannabinol [Δ9-THC] mixed with high-grade sesame oil and other inactive ingredients and encapsulated as soft gelatin capsules) that were frozen, refrigerated, or kept at room temperature for three months. The dronabinol capsules remained in the original foil-sealed blister packs until preparation for HPLC-UV assessment. The primary endpoint was the percentage of the initial Δ9-THC concentration remaining at multiple designated time points. The secondary aim was to perform forced-degradation studies under acidic conditions to demonstrate that the HPLC-UV method used was stability indicating. RESULTS: The appearance of the dronabinol capsules remained unaltered during frozen, cold, or room-temperature storage. Regardless of storage condition, the percentage of the initial Δ9-THC content remaining was greater than 97% for all evaluated samples at all time points over the three-month study. These experimental data indicate that the product packaging and the sesame oil used to formulate dronabinol capsules efficiently protect Δ9-THC from oxidative degradation to cannabinol; this suggests that pharmacies can store dronabinol capsules in nonrefrigerated automated dispensing systems, with a capsule expiration date of 90 days after removal from the refrigerator. CONCLUSION: Dronabinol capsules may be stored at room temperature in their original packaging for up to three months without compromising capsule appearance and with minimal reduction in Δ9-THC concentration.

Cannabis for the Management of Pain: Assessment of Safety Study (COMPASS).

UNLABELLED: Cannabis is widely used as a self-management strategy by patients with a wide range of symptoms and diseases including chronic non-cancer pain. The safety of cannabis use for medical purposes has not been systematically evaluated. We conducted a prospective cohort study to describe safety issues among individuals with chronic non-cancer pain. A standardized herbal cannabis product (12.5% tetrahydrocannabinol) was dispensed to eligible individuals for a 1-year period; controls were individuals with chronic pain from the same clinics who were not cannabis users. The primary outcome consisted of serious adverse events and non-serious adverse events. Secondary safety outcomes included pulmonary and neurocognitive function and standard hematology, biochemistry, renal, liver, and endocrine function. Secondary efficacy parameters included pain and other symptoms, mood, and quality of life. Two hundred and fifteen individuals with chronic pain were recruited to the cannabis group (141 current users and 58 ex-users) and 216 controls (chronic pain but no current cannabis use) from 7 clinics across Canada. The median daily cannabis dose was 2.5 g/d. There was no difference in risk of serious adverse events (adjusted incidence rate ratio = 1.08, 95% confidence interval = .57-2.04) between groups. Medical cannabis users were at increased risk of non-serious adverse events (adjusted incidence rate ratio = 1.73, 95% confidence interval = 1.41-2.13); most were mild to moderate. There were no differences in secondary safety assessments. Quality-controlled herbal cannabis, when used by patients with experience of cannabis use as part of a monitored treatment program over 1 year, appears to have a reasonable safety profile. Longer-term monitoring for functional outcomes is needed. STUDY REGISTRATION: The study was registered with www.controlled-trials.com (ISRCTN19449752). PERSPECTIVE: This study evaluated the safety of cannabis use by patients with chronic pain over 1 year. The study found that there was a higher rate of adverse events among cannabis users compared with controls but not for serious adverse events at an average dose of 2.5 g herbal cannabis per day.

Preformulation studies of a prodrug of Delta9-tetrahydrocannabinol.

Preformulation studies were performed on a hemiglutarate ester prodrug of Delta(9)-tetrahydrocannabinol (THC-HG), to facilitate the development of stable formulations by hot-melt methods. The various studies performed included solid-state thermal characterization, pKa, logP, aqueous and pH dependent solubility, pH stability and effect of moisture, temperature and oxygen on solid-state stability. A hot-melt method was utilized to fabricate THC-HG incorporated poly (ethylene oxide) (PEO) matrices and the bioadhesive properties, release profiles and post-processing stability of these matrices were assessed as a function of the polymer molecular weight. The prodrug exhibited a T (g) close to 0 degrees C, indicating its amorphous nature. Thermogravimetric analysis revealed a rapid weight loss after 170 degrees C. The prodrug exhibited a seven-fold higher aqueous solubility as compared to the parent drug (THC). Also, the solubility of the compound increased with increasing pH, being maximum at pH 8. The prodrug exhibited a v-shaped pH-rate profile, with the degradation rate minimum between pH 3 and 4. The moisture uptake and drug degradation increased with an increase in relative humidity. Solid-state stability indicated that the prodrug was stable at -18 degrees C but demonstrated higher degradation at 4 degrees C, 25 degrees C and 40 degrees C (51.6%, 74.5% and 90.1%, respectively) at the end of 3-months. THC-HG was found to be sensitive to the presence of oxygen. The release of the active from the polymeric matrices decreased, while bioadhesion increased, with an increase in molecular weight of PEO.

A peek into Pandora's box: the medical excuse marijuana controversy.

The smoking of marijuana for medicinal applications is a volatile and difficult issue for the medical and regulatory communities which has reached the forefront of discussions of public policy. Any consideration of this issue must take into account the substantial toxicity, impurity, and morbidity associated with marijuana use. Several states have passed ballot initiatives or legislation that allow a medical excuse for possession of marijuana. These initiatives bypass the Food and Drug Administration process of proving safety and efficacy, and they have created serious regulatory dilemmas for state regulatory boards. Several examinations of the issue have consistently drawn question to the validity of smoking an impure substance while voicing concern for the well being of patients in need. The historical, social, medical, and legal issues are examined.

Preparation and certification of standard reference material 1507: 11-nor-delta 9-tetrahydrocannabinol-9-carboxylic acid in freeze-dried urine.

The National Institute of Standards and Technology (NIST) has prepared and certified SRM 1507, a freeze-dried urine fortified with 11-nor-delta 9-tetrahydrocannabinol-9-carboxylic acid (THC-9-COOH), the major urinary metabolite of marijuana. The certified concentration of 20 +/- 1 ng/mL for the analyte was obtained from the concordant results of analyses of the material by gas chromatography/mass spectrometry (GC/MS) and high-performance liquid chromatography with electrochemical detection (HPLC-EC). Solid-phase extraction was used to prepare the sample for GC/MS analyses, and liquid-liquid extraction was used for the HPLC-EC analyses. The multistep HPLC method was developed at NIST to circumvent interferences from urinary constituents. The results of a round robin test on this material among five Department of Defense laboratories involved in drug testing are reported.