Abstract
Background: The effects of cannabis are thought to be mediated by interactions between its constituents and the endocannabinoid system. Delta-9-tetrahydrocannabinol (THC) binds to central cannabinoid receptors, while cannabidiol (CBD) may influence endocannabinoid function without directly acting on cannabinoid receptors. We examined the effects of THC coadministered with different doses of CBD on plasma levels of endocannabinoids in healthy volunteers.
Methods: In a randomized, double-blind, four-arm crossover study, healthy volunteers (n = 46) inhaled cannabis vapor containing 10 mg THC plus either 0, 10, 20, or 30 mg CBD, in four experimental sessions. The median time between sessions was 14 days (IQR = 20). Blood samples were taken precannabis inhalation and at 0-, 5-, 15-, and 90-min postinhalation. Plasma concentrations of THC, CBD, anandamide, 2-arachidonoylglycerol (2-AG), and related noncannabinoid lipids were measured using liquid chromatography-mass spectrometry.
Results: Administration of cannabis induced acute increases in plasma concentrations of anandamide (+ 18.0%, 0.042 ng/mL [95%CI: 0.023–0.062]), and the noncannabinoid ethanolamides, docosatetraenylethanolamide (DEA; + 35.8%, 0.012 ng/mL [95%CI: 0.008–0.016]), oleoylethanolamide (+ 16.1%, 0.184 ng/mL [95%CI: 0.076–0.293]), and N-arachidonoyl-L-serine (+ 25.1%, 0.011 ng/mL [95%CI: 0.004–0.017]) (p < 0.05). CBD had no significant effect on the plasma concentration of anandamide, 2-AG or related noncannabinoid lipids at any of three doses used. Over the four sessions, there were progressive decreases in the preinhalation concentrations of anandamide and DEA, from 0.254 ng/mL [95%CI: 0.223–0.286] to 0.194 ng/mL [95%CI: 0.163–0.226], and from 0.039 ng/mL [95%CI: 0.032–0.045] to 0.027 ng/mL [95%CI: 0.020–0.034] (p < 0.05), respectively.
Discussion: THC induced acute increases in plasma levels of anandamide and noncannabinoid ethanolamides, but there was no evidence that these effects were influenced by the coadministration of CBD. It is possible that such effects may be evident with higher doses of CBD or after chronic administration. The progressive reduction in pretreatment anandamide and DEA levels across sessions may be related to repeated exposure to THC or participants becoming less anxious about the testing procedure and requires further investigation. The study was registered on clinicaltrials.gov (NCT 05170217).
| Original language | English |
|---|---|
| Pages (from-to) | 188-198 |
| Number of pages | 11 |
| Journal | Cannabis and Cannabinoid Research |
| Volume | 9 |
| Issue number | 1 |
| Early online date | 9 Dec 2022 |
| DOIs | |
| Publication status | Published - 12 Feb 2024 |
Funding
This study was fully funded by a Research Grant from the Medical Research Council, United Kingdom (MR/P006841/1). The funder was not involved in the design, data collection, analysis, interpretation, write-up, or the decision of where to publish. A.E. has received speakers' honoraria from GW Pharmaceuticals. A.E.'s position is funded by, and L.A.C., J.H. and J.S. are supported by, the National Institute for Health Research (NIHR) Biomedical Research Centre for Mental Health at South London and Maudsley NHS Foundation Trust and King's College London. R.M.M. has received speakers' honoraria from Janssen, Lundbeck, Otsuka, and Sunovian. All remaining authors report no conflicting interests.
| Funders | Funder number |
|---|---|
| Maudsley Biomedical Research Centre for Mental Health | |
| South London and Maudsley NHS Foundation Trust | |
| Medical Research Council | MR/P006841/1 |
| National Institute for Health and Care Research | |
| King's College London |
Keywords
- 2-arachidonoylglycerol
- anandamide
- cannabis
- CBD
- endocannabinoids
- THC
ASJC Scopus subject areas
- Pharmacology
- Complementary and alternative medicine
- Pharmacology (medical)