Acute stress increases circulating anandamide and other N-acylethanolamines in healthy humans

Abstract

Stress plays an important role in psychiatric disorders, and preclinical evidence indicates that the central endocannabinoid system modulates endocrine and neuronal responses to stress. This study aimed to investigate the effect of acute stress on circulating concentrations of endocannabinoids (eCBs) in healthy humans. A total of 71 adults participated in two sessions in which they were exposed to either a standardized psychosocial stress procedure (Trier Social Stress Test) or a control task. Blood samples for eCB and cortisol assays and cardiovascular and subjective measures were obtained before and at regular intervals after the tasks. Serum concentrations of the eCBs, N-arachidonylethanolamine (anandamide, AEA) and 2-arachidonoylglycerol (2-AG), as well as of the N-acylethanolamides (NAEs), N-palmitoylethanolamine (PEA) and N-oleoylethanolamine (OEA), and of the O-acylglycerol, 2-oleoylglycerol (2-OG), were determined. Compared with the control condition, stress increased serum concentrations of AEA and the other NAEs immediately after the stress period. Increases in PEA were positively correlated with increases in serum cortisol after stress. Furthermore, anxiety ratings at baseline were negatively correlated with baseline concentrations of AEA. The sex and menstrual cycle status of the subject affected the NAE responses to stress. Interestingly, subjects of Asian and African-American races exhibited different patterns of stress responses compared with the Caucasian subjects. These results indicate that stress increases circulating NAEs in healthy human volunteers. This finding supports a protective role for eCBs in anxiety. Further research is needed to elucidate the function of these lipid mediators, and to determine the mechanisms that regulate their appearance in the circulation.

Figure 1

Time course of the secondary outcome measures anxiety (a), serum cortisol (b), systolic blood pressure (c), and heart rate (d: bpm refers to beats per minute). To assess the main effect of stress on secondary outcome measures, repeated-measures ANOVAs were performed comparing changes from baseline (−20-min time point) in the no stress and stress sessions (ANOVA; ^***p<0.001).

Figure 2

Serum concentrations as changes from baseline after the no stress (NS) and stress (S) procedures are presented for AEA (a), PEA (b), OEA (c), 2-AG (d), and 2-OG (e). To assess the main effects of stress on circulating lipids, repeated-measures ANOVAs were performed comparing changes from baseline in the no stress and stress sessions (^*p<0.05; ^**p<0.01; ^***p<0.001).

Figure 3

Serum concentrations as changes from baseline after the no stress and stress procedures presented among subgroups of Caucasian, African-American, and Asian subjects; the lipids measured are AEA (a), PEA (b), OEA (c), 2-AG (d), and 2-OG (e). Repeated-measures ANOVAs were performed comparing changes from baseline in the no stress and stress sessions (^**p<0.01; ^***p<0.001).

Figure 4

Serum concentrations as changes from baseline after the no stress and stress procedures presented among subgroups of men, luteal, and follicular women; the lipids measured are AEA (a), PEA (b), OEA (c), 2-AG (d), and 2-OG (e). Repeated-measures ANOVAs were performed comparing changes from baseline in the no stress and stress sessions (^*p<0.05).

Figure 5

Scatterplots showing correlations between pretask baseline (BL: second session) concentrations of the N-acylethanolamines and anxiety. The three panels show correlations between pretask baseline concentrations of Anxiety and pretask baseline concentrations of (a) AEA, (b) PEA, and (c) OEA (^*p<0.05).

Figure 6

Scatterplots showing correlations between stress-induced concentrations of the N-acylethanolamines and stress-induced cortisol concentrations. The three panels show correlations between stress-induced cortisol concentrations and stress-induced concentrations of (a) AEA, (b) PEA, and (c) OEA. Values are derived by subtracting no-stress session values from stress session values (^**p<0.01, Cfbl: change from baseline).