Human Pharmacokinetics and Adverse Effects of Pulmonary and Intravenous THC-CBD Formulations
Pascale Meyer, Manuela Langos, Rudolf Brenneisen
Medical Cannabis and Cannabinoids, 2018, 1, 36–43
Preclinical Science and Clinical Studies – Research Article
Background : Due to variable absorption and extensive firstpass metabolism, the bioavailability of oral delta-9-tetrahydrocannabinol (THC) and cannabidiol (CBD) is low, and, therefore, alternative application forms are necessary.
Methods : In an 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 8 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 should prevent airways irritation and coughing. The pharmacokinetic evaluation was based on plasma profiles acquired by gas chromatography-mass spectrometry. Adverse effects were monitored by visual analog scales and measuring vital functions.
Results : After low inh doses, THC and CBD were not measurable in plasma longer than 20 and 40 min after administration, respectively. Therefore, only plasma levels resulting after high doses were further evaluated. After inh and iv administration, THC plasma peaks were observed 5 min post-drug, with THC peak concentrations ranging from 3 to 22 and from 13 to 40 ng/mL, respectively. CBD peaks were also measured 5 min after inh and iv administration, with concentrations ranging from 2 to 17 and from 14 to 26 ng/ mL, respectively. The elimination half-lives were 7 and 11 min after inh and 22 and 24 min 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.
Conclusions : We 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 via a pMDI is a viable, safe, and well-tolerated alternative to the oral administration.
Keywords : Delta-9-tetrahydrocannabinol · Cannabidiol · Phase-1 study · Inhalation · Injection · Pharmacokinetics · Adverse effects
Due to variable, erratic absorption and extensive first-pass metabolism, but also dependent on ingested food and type of oral formulation, the bioavailability of oral delta-9-tetrahydrocannabinol (THC) is low, with only 5–20% reaching the systemic circulation [1–3]. Thus, alternative application forms are necessary. The pulmonary delivery of drugs to treat systemic diseases has the advantage of reproducible absorption kinetics and is independent of dietary complications, extracellular enzymes, and inter-patient metabolic differences that affect gastrointestinal absorption . In a previous study, the pharmacokinetics of THC were determined after pulmonary (inh) delivery of an aqueous aerosol nebulized by a pressure-driven device (Pari Master®) and after intravenous (iv) injection . The mean inh bioavailability was about 28 ± 23%, and the peak plasma concentration (Cmax) was already reached after 10 min. The level of the metabolite 11-hydroxy-THC (11-OHTHC), which is known to be as psychoactive as THC, was lower after inh than after oral application . The tolerability of the inh aerosol was good, but some coughing and irritation of the upper airways were seen, influencing the efficiency of the inhalation process and, thus, bioavailability. There is increasing evidence of the polypharmacological mechanisms of action and therapeutic potential of cannabidiol (CBD) [7–9]. For example, it shows anticonvulsive, antianxiolytic, antipsychotic, antiemetic, and antirheumatic effects. Some authors even claim the existence of a synergy or “entourage effect” between CBD and THC . In this sense, a THC-CBD combination seems to be justified to optimize the therapeutic range. Consequently, a further study was carried out in which the pharmacokinetic properties and tolerance of inh THC-CBD were compared to an iv administration. The THC-CBD combination was applied in the form of an aerosol nebulized by a pressurized metered- dose inhaler (pMDI).