Investigating the acute effects of cannabinoids consumption on circulating levels of endocannabinoids.

Cannabis remains the most commonly used drug of abuse worldwide and the legalization in several states caused a drastic change in the variety of products available on the market. Over the past few years, several studies reported that the average concentration of Δ9-tetrahydrocannabinol (THC) drastically increased as well as the availability of products containing different combinations of THC and other cannabinoids, mainly cannabidiol (CBD). However, little is known about the acute effects of THC and/or CBD on the lipidome and more specifically the endocannabinoid system. The aim of the present study was to examine the acute effects of three cannabis flower chemovars with different THC to CBD ratios, in order to test whether chemovars with a higher CBD content produce different subjective effects and analyze their influence on the circulating levels of endocannabinoids.

Participants were randomly assigned to ad libitum administration of one of three chemovars (THC-dominant: 24% THC, 1% CBD; THC+CBD: 9% THC, 10% CBD; CBD-dominant: 1% THC, 23% CBD); plasma samples were collected in a mobile pharmacology laboratory before, immediately after and 1hour after ad libitum administration of their assigned chemovar. Twelve cannabinoids and 14 endocannabinoids were quantified using liquid chromatography tandem mass spectrometry assays previously published and validated by our group. Statistical analysis was performed using SPSS and MetaboAnalyst.

One hundred and six participants were included in the study; 29 were assigned to the THC-dominant chemovar, 37 to the CBD-dominant chemovar and 40 to the THC+CBD chemovar. A total of 318 plasma samples were analyzed for both cannabinoids and endocannabinoids concentrations. Results were divided in 9 sub-groups based on the chemovar used and the time after consumption. Across the different time points, significant changes were noted for docosatetraenoyl ethanolamide (DEA), palmitoyl ethanolamide (PEA), stearoyl ethanolamide (SEA), linoleoyl ethanolamide (LEA) and oleoyl ethanolamine (OEA). Interestingly, anandamide (AEA) concentrations were significantly decreased only after consumption of the CBD-dominant chemovar and the THC+CBD chemovar. The mean AEA concentrations in the CBD-dominant group dropped from 0.74±0.24ng/mL before consumption to 0.54±0.17ng/mL one hour after use (P<0.001) and from 0.70±0.18ng/mL to 0.53±0.17ng/mL in the THC+CBD chemovar group (P<0.001).

Chronic cannabis abuse can lead to damaging effects in humans and some authors examined whether components of the endocannabinoid system will undergo alterations and have shown decreased anandamide levels in CSF and an alteration of serum anandamide was not observed in the same study. Others reported increased levels of anandamide upon CBD treatment, mostly in Schizophrenia patients. These studies focused on long-term effects (14, 28days). To our knowledge, this is the first study to assess the acute effects of different cannabis chemovars (THC-dominant, CBD-dominant and THC+CBD chemovar) on the circulating levels of endocannabinoids in healthy frequent user volunteers. It is very interesting that upon CBD consumption a decrease in AEA was observed. This decrease might alter the effect of THC, since AEA and THC both bind to CB1 receptors.

Further studies are needed to better understand the acute effects of cannabis consumption on the circulating levels of endocannabinoids and potentially explain the differences in endocannabinoid patterns after acute versus chronic consumption as well as the potential indirect effect of CBD on THC's mechanism of action.