Human Pharmacokinetics and Adverse Effects of Pulmonary and Intravenous THC-CBD Formulations

Abstract

Background: Due 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. 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.

CBD and THC: Do They Complement Each Other Like Yin and Yang?

“…It is important to note that the pharmacokinetic profile of intravenous cannabinoids given under experimental conditions does not mirror the pharmacokinetics of oral administration, as evident by plasma concentrations. The pharmacokinetic profiles of intravenous preparations are similar to that of inhaled and smoked THC‐CBD preparations, which are much more consistent than, and thus more favorable to, oral preparations 29 . C max also increases and is reached faster under intravenous, inhaled, and smoked administration 25 .…”

“…Englund and colleagues’ and Haney and colleagues’ studies utilized similar administration paradigms, with oral CBD administered before THC, which was provided by intravenous or smoked, respectively 28,30 . Given that intravenous and smoked administrations demonstrate similar pharmacokinetic profiles, 29 it would be expected that Haney and colleagues’ results would confirm the findings of the prior study. However, this is not the case as Haney and colleagues found no significant attenuation of THC‐induced effects.…”

“…The pharmacokinetic profiles of intravenous preparations are similar to that of inhaled and smoked THC-CBD preparations, which are much more consistent than, and thus more favorable to, oral preparations. 29 C max also increases and is reached faster under intravenous, inhaled, and smoked administration. 25 In order to account for this variability among their dosing methods, Englund and colleagues administered the intravenous THC at a later timepoint than the oral CBD.…”

Cannabidiol (CBD) repurposing as antibacterial: promising therapy of CBD plus polymyxin B against superbugs

“…However, the oral bioavailability of CBD is low (6-25%), highly variable and increased with coadministration of a high-fat meal (42,44,45). Additionally, CBD bioavailability (59%) could be higher through pulmonary administration (46).…”

“…However, considering that CBD shows low water solubility (12.6 mg/L) and high lipophilicity (logP of 6.3), this present a limitation for the development of an IV pharmaceutical formulation compatible with the doses proposed here (50). Nevertheless, a study presented a simple formulation of both CBD and delta-9-tetrahydrocannabinol (THC) 1.6 mg IV, which was administered in eight healthy individuals (46).…”