Abstract
Meyer P, Langos M, Brenneisen R: Human pharmacokinetics and adverse effects of pulmonary and intravenous THC-CBD formulations. Med Cannabis Cannabinoids 2018;1:36–43.
Owing to variable absorption and extensive first-pass metabolism, the bioavailability of oral delta-9-tetrahydrocannabinol (THC) and cannabidiol (CBD) is low, and, therefore, alternative application forms are necessary. In this open-label 2-period phase-1 study on 11 healthy volunteers, a combination of THC and CBD was compared by pulmonary (inh) and intravenous (iv) application. The liquid aerosol was produced by an in vitro validated pressurized metered-dose inhaler (pMDI) device, releasing 41–44% of the cannabinoid dose, enabling a dosage of 81 μg THC and 87 μg CBD per actuation. Three subjects (pilot trial, low-dose session) received 324 and 348 μg THC and CBD, respectively, and eight subjects (main trial, high-dose session) received 648 and 696 μg THC and CBD, respectively. The addition of the local anesthetic lidocaine to the inh preparation was used in an effort to prevent airways irritation and coughing. Adverse effects were monitored by visual analog scales and measuring vital functions. Results demonstrated that after low inh doses, THC and CBD were not measurable in plasma longer than 20 and 40 minutes after administration, respectively. Therefore, only plasma levels resulting after high doses were further evaluated. After inh and iv administration, THC plasma peaks were observed five minutes postdrug, with THC peak concentrations ranging from 3 to 22 ng/mL and from 13 to 40 ng/mL, respectively. CBD peaks were also measured five minutes after inh and iv administration, with concentrations ranging from 2 to 17 ng/mL and from 14 to 26 ng/mL, respectively. The elimination half-lives was 7 and 11 minutes after inh and 22 and 24 minutes after iv administration for THC and CBD, respectively. The mean inh bioavailability (calculated vs. iv) was 55% ± 37% and 59% ± 47% for THC and CBD, respectively. Conjugated 11-carboxy-THC was the main THC metabolite. The nebulized aerosol was generally well tolerated with little or no coughing and only slight psychological adverse effects. These were more distinct after iv administration, especially irritations and hallucinations. Besides moderate tachycardia, the vital functions stayed unchanged. The authors conclude that a THC–CBD inh aerosol shows favorable pharmacokinetic properties, which are similar to those of an iv preparation. Adding a local anesthetic is recommended to prevent coughing, which decreases absorption. The negligible psychoactivity may be due to an antipsychotic effect of CBD, the low THC dosage, and/or the decreased formation of the psychoactive metabolite 11-hydroxy-THC. Therefore, the inhalation through a pMDI is a viable, safe, and well-tolerated alternative to the oral administration.
Lintzeris N, Bhardwaj A, Mills L, et al.: Nabiximols for the treatment of cannabis dependence: A randomized clinical trial. JAMA Int Med 2019. [E-pub ahead of print]; DOI:10.1001/jamainternmed.2019.1993.
The objective of this study was to examine the safety and efficacy of nabiximols in the treatment of patients with cannabis dependence. The study was a parallel double-blind randomized clinical trial comparing nabiximols with placebo in a 12-week multisite outpatient study. Participants were recruited from February 3, 2016, to June 14, 2017, at four outpatient specialist alcohol and drug treatment services in New South Wales, Australia. Participants had cannabis dependence (as defined by the International Statistical Classification of Diseases and Related Health Problems, Tenth Revision) and were seeking treatment, were nonresponsive to prior treatment attempts, were 18–64 years of age, had no other substance use disorder, had no severe medical or psychiatric conditions, were not pregnant, were not mandated by a court to undergo treatment, and provided informed consent. Participants received 12-week treatment involving weekly clinical reviews, structured counseling, and flexible medication doses—up to 32 sprays daily (THC, 86.4 mg, and CBD, 80 mg), dispensed weekly. A total of 128 participants (30 women and 98 men; mean [standard deviation; SD] age, 35.0 [10.9] years) were randomized and received at least one dose of study medication. Participants had used a mean (SD) of 2.3 (2.1) g of cannabis on a mean (SD) of 25.7 (4.5) days in the past 28 days. Treatment retention was comparable for the 2 groups (placebo, 30 of 67 participants [44.8%]; nabiximols, 30 of 61 participants [49.2%]), and both groups used similar mean (SD) doses (placebo, 18.5 [9.5] sprays daily; nabiximols, 17.6 [9.5] sprays daily, equivalent to a mean [SD] of 47.5 [25.7] mg of THC and 44.0 [23.8] mg of CBD). For the primary end point, the placebo group reported significantly more days using cannabis during the 12 weeks (mean [SD], 53.1 [33.0] days) than the nabiximols group (mean [SD], 35.0 [32.4] days; estimated difference, 18.6 days; 95% confidence interval, 3.5–33.7 days; p = 0.02). Both groups showed comparable improvements in health status, with no substantial changes in other substance use. Medication was well tolerated with few adverse events. The authors conclude that this study demonstrated that cannabinoid agonist treatment, in this case using nabiximols, in combination with psychosocial interventions is a safe approach for reducing cannabis use among individuals with cannabis dependence who are seeking treatment.
Shah A, Hayes CJ, Lakkad M, Martin BC: Impact of medical marijuana legalization on opioid use, chronic opioid use, and high-risk opioid use. J Gen Intern Med 2019;34:1419–1426.
The objective of this study was to determine the association of medical marijuana legalization with prescription opioid utilization. A 10% sample of a nationally representative database of commercially insured population was used to gather information on opioid use, chronic opioid use, and high-risk opioid use for the years 2006–2014. Adults with pharmacy and medical benefits for the entire calendar year were included in the population for that year. Multilevel logistic regression analyses, controlling for patient, person-year, and state-level factors, were used to determine the impact of medical marijuana legalization on the three opioid use measures. Subgroup analyses among cancer-free adults and cancer-free adults with at least one chronic noncancer pain condition in the particular year were conducted. Alternative regression models were used to test the robustness of our results, including a fixed effects model, an alternative definition for start date for medical marijuana legalization, a person-level analysis, and a falsification test. Results demonstrated that the final sample included a total of 4,840,562 persons translating into 15,705,562 person years. Medical marijuana legalization was found to be associated with a lower odds of any opioid use, chronic opioid use, and high-risk opioid use. The findings were similar in both the subgroup analyses and all the sensitivity analyses. The falsification tests showed no association between medical marijuana legalization and prescriptions for antihyperlipidemics or antihypertensives. The authors conclude that in states where marijuana is available through medical channels, a modestly lower rate of opioid prescribing and high-risk opioid prescribing were observed. They suggest that policy makers could consider medical marijuana legalization as a tool that may modestly reduce chronic and high-risk opioid use. However, further research assessing risk versus benefits of medical marijuana legalization and head-to-head comparisons of marijuana versus opioids for pain management is required.
Luba R, Earleywine M, Farmer S, Slavin M: Cannabis in end-of-life care: Examining attitudes and practices of palliative care providers. J Psychoactive Drugs 2018;50:348–354.
Medical cannabis research has become quite extensive, with indications ranging from glaucoma to chemotherapy-induced nausea. Despite increased interest in cannabis' potential medical uses, research barriers, cannabis legislation, stigma, and lack of dissemination of data contribute to low adoption for some medical populations. Of interest, cannabis use appears low in palliative care settings, with few guidelines available to palliative care providers. This study sought to examine the attitudes, beliefs, and practices of palliative care providers regarding the use of cannabis for terminally ill patients. Palliative care providers (N = 426) completed a one-time online survey assessing these attitudes, beliefs, and practices. Results demonstrated that palliative care providers endorse cannabis for a wide range of palliative care symptoms, end-of-life care generally, and as an adjuvant medication. Nevertheless, the gap between these beliefs and actual recommendation or prescription appears vast. Many who support the use of cannabis in palliative care do not recommend it as a treatment. The authors note that these data suggest recommendations for health care providers and palliative care organizations.
Monte AA, Shelton SK, Mills E, et al.: Acute illness associated with cannabis use, by route of exposure: An observational study. Ann Intern Med 2019;170:531–537.
The objective of this retrospective study was to describe and compare adult emergency department (ED) visits related to edible and inhaled cannabis exposure. The design involved chart review of ED visits between January 1, 2012, and December 31, 2016, at a large urban academic medical hospital in Colorado. Adults with ED visits with a cannabis-related International Classification of Diseases, Ninth or 10th Revision, Clinical Modification (ICD-9-CM or ICD-10-CM) code, were reviewed. Patient demographic characteristics, route of exposure, dose, symptoms, length of stay, disposition, discharge diagnoses, and attribution of visit to cannabis were all recorded. Results demonstrated that there were 9973 visits with an ICD-9-CM or ICD-10-CM code for cannabis use. Of these, 2567 (25.7%) visits were at least partially attributable to cannabis, and 238 of those (9.3%) were related to edible cannabis. Visits attributable to inhaled cannabis were more likely to be for cannabinoid hyperemesis syndrome (18.0% vs. 8.4%), and visits attributable to edible cannabis were more likely to be due to acute psychiatric symptoms (18.0% vs. 10.9%), intoxication (48% vs. 28%), and cardiovascular symptoms (8.0% vs. 3.1%). Edible products accounted for 10.7% of cannabis-attributable visits between 2014 and 2016, but represented only 0.32% of total cannabis sales in Colorado (in kilograms of THC) during that period. The authors conclude that visits attributable to inhaled cannabis are more frequent than those attributable to edible cannabis, although the latter is associated with more acute psychiatric visits and more ED visits than expected.