Safety and pharmacokinetics of oral cannabidiol when administered concomitantly with intravenous fentanyl in humans

Abstract

Objectives: Cannabidiol (CBD) is hypothesized as a potential treatment for opioid addiction, with safety studies an important first step for medication development. We determined CBD safety and pharmacokinetics when administered concomitantly with a high-potency opioid in healthy subjects.

Methods: This double-blind, placebo-controlled cross-over study of CBD, coadministered with intravenous fentanyl, was conducted at the Clinical Research Center in Mount Sinai Hospital, a tertiary care medical center in New York City. Participants were healthy volunteers aged 21 to 65 years with prior opioid exposure, regardless of the route. Blood samples were obtained before and after 400 or 800 mg of CBD pretreatment, followed by a single 0.5 (session 1) or 1.0 μg/kg (session 2) of intravenous fentanyl dose. The primary outcome was the Systematic Assessment for Treatment Emergent Events (SAFTEE) to assess safety and adverse effects. CBD peak plasma concentrations, time to reach peak plasma concentrations (tmax), and area under the curve (AUC) were measured.

Results: SAFTEE data were similar between groups without respiratory depression or cardiovascular complications during any test session. After low-dose CBD, tmax occurred at 3 and 1.5 hours in sessions 1 and 2, respectively. After high-dose CBD, tmax occurred at 3 and 4 hours in sessions 1 and 2, respectively. There were no significant differences in plasma CBD or cortisol (AUC P = NS) between sessions.

Conclusions: Cannabidiol does not exacerbate adverse effects associated with intravenous fentanyl administration. Coadministration of CBD and opioids was safe and well tolerated. These data provide the foundation for future studies examining CBD as a potential treatment for opioid abuse.

Conflict of interest statement

Declarations of Interest: None.

Figures

Figure 1. Experimental flowchart per study day for each subject

This flowchart outlines the session timeline to assess safety of cannabidiol (CBD) and fentanyl co-administration. Participants were provided a light meal 2 hours prior to CBD administration. Fentanyl was administered 60 minutes after administration of the CBD/placebo. A standard meal was provided 4 hours after CBD/placebo administration. Solid arrows indicate the time points when blood (10 mL) samples were collected. Vital signs, SAFTEE, VAS, PANAS and OVAS were also assessed at the times indicated by the solid arrows except for the 3h time point (denoted by a star). Dashed arrows indicate times for urine collection (45 min, 2,4,6, and 8h). Abbreviations: OVAS, opioid specific visual analog scales, PANAS = positive and negative affect schedule, SAFTEE = systematic assessment for treatment emergent events, VAS = visual analog scale.

Figure 2. Plasma CBD Concentrations

Mean (± SEM) plasma CBD concentrations across time (in hrs) were not significantly affected by Fentanyl dose (AUC Wilcoxon p=NS). Mean (± SEM) plasma CBD concentrations for Low-Dose (400 mg) CBD are in Panel A and High-Dose (800 mg) CBD is in Panel B. Panel C represents the combined curves for all Groups (0, 400mg and 800 mg CBD) across the two Fentanyl sessions. Abbreviations: NS = not significant; SEM = standard error of the mean; * indicates significant difference between groups at one given time point (t-test p