Dose-dependent effects of oral cannabidiol and delta-9-tetrahydrocannabinol on serum anandamide and related N-acylethanolamines in healthy volunteers

Abstract

Background: The mental health benefits of cannabidiol (CBD) are promising but can be inconsistent, in part due to challenges in defining an individual's effective dosage. In schizophrenia, alterations in anandamide (AEA) concentrations, an endocannabinoid (eCB) agonist of the eCB system, reflect positively on treatment with CBD. Here, we expanded this assessment to include eCBs alongside AEA congeners, comparing phytocannabinoids and dosage in a clinical setting.

Methods: Liquid chromatography-tandem mass spectrometry quantified changes in serum levels of AEA, 2-arachidonoylglycerol (2-AG), alongside AEA-related compounds oleoylethanolamide (OEA) and palmitoylethanolamide (PEA), which were attained from two independent, parallel-designed, clinical trials investigating single, oral CBD (600 or 800 mg), delta-9-tetrahydrocannabinol (Δ⁹-THC, 10 or 20 mg) and combination administration (CBD|800 mg+Δ⁹-THC|20 mg) in healthy volunteers (HVs, n=75). Concentrations were measured at baseline (t=0), 65 and 160 min post administration.

Results: CBD-led increases in AEA (1.6-fold), OEA and PEA (1.4-fold) were observed following a single 800 mg (p_corr<0.05) but not 600 mg dosage. Declining AEA was observed with Δ⁹-THC at 10 mg (-1.3-fold) and 20 mg (-1.4-fold) but restored to baseline levels by 160 min. CBD+Δ⁹-THC yielded the highest increases in AEA (2.1-fold), OEA (1.9-fold) and PEA (1.8-fold) without reaching a maximal response.

Conclusion: CBD-administered effects towards AEA, OEA and PEA are consistent with phase II trials reporting clinical improvement for acute schizophrenia (CBD≥800 mg). Including Δ⁹-THC appears to enhance the CBD-induced response towards AEA and its congeners. Our results warrant further investigations into the potential of these lipid-derived mediators as metabolic measures for CBD dose prescription and co-cannabinoid administration.

Keywords: Data Interpretation, Statistical; PSYCHIATRY; Schizophrenia & psychotic disorders.

Figure 1. Consolidated Standards of Reporting Trials diagram of study designs and participant’s serum collection from respective phase I clinical trials (GEI-TCP-II and LOGIN-TS4). CBD, cannabidiol; Δ⁹-THC, delta-9-tetrahydrocannabinol; PLA, placebo.

Figure 2. Measured endocannabinoids and N-acylethanolamines in human serum following acute administration with CBD|800 mg (blue triangle), CBD|600 mg (green circle), Δ⁹-THC|20 mg (maroon crossed-square), Δ⁹-THC|10 mg (red square), in-combination (CBD|800 mg+Δ⁹-THC|20 mg, teal triangle) and placebo (black diamond). Box and whisker plots display concentrations (pmol/mL) for (A) CBD, (B) Δ⁹-THC, (C) AEA, (D) 2-AG, (E) OEA and (F) PEA at baseline (t=0), as well as 65 and 160 min post dose. Statistical significance was determined by two-way repeated measures analysis of variance, which were adjusted for multiple comparisons using Benjamini-Krieger-Yekutieli false discovery rate (*p_corr<0.05, **p_corr<0.01, ***p_corr<0.001, ****p_corr<0.0001 represent significant changes at 65 and 160 min, compared with t=0; ns, not significant). AEA, anandamide; 2-AG, 2-arachidonoylglycerol; CBD, cannabidiol; OEA, oleoylethanolamide; PEA, palmitoylethanolamide; Δ9-THC, delta-9-tetrahydrocannabinol.

Figure 3. Associations of CBD with changes to baseline levels (t=0) of (A,B) AEA, (C,D) OEA and (E,F) PEA. The differences at 65 and 165 min are presented on the y-axis (Δ pmol/mL) against CBD concentrations for same time-points on the x-axis (pmol/mL) for (A,C,E) CBD|800 mg and (B,D,F) CBD|800mg+Δ⁹-THC|20 mg. Correlations were determined by Spearman analysis at a CI of 95%. The coefficient of correlation (r) and p values are shown. AEA, anandamide; CBD, cannabidiol; OEA, oleoylethanolamide; PEA, palmitoylethanolamide; Δ9-THC, delta-9-tetrahydrocannabinol.