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The endocannabinoid system in humans: significant associations between anandamide, brain function during reward feedback and a personality measure of reward dependence


Preclinical evidence indicates that the endocannabinoid system is involved in neural responses to reward. This study aimed to investigate associations between basal serum concentrations of the endocannabinoids anandamide (AEA) and 2-arachidonylglycerol (2-AG) with brain functional reward processing. Additionally, a personality measure of reward dependence was obtained. Brain functional data were obtained of 30 right-handed adults by conducting fMRI at 3 Tesla using a reward paradigm. Reward dependence was obtained using the subscale reward dependence of the Tridimensional Personality Questionnaire (TPQ). Basal concentrations of AEA and 2-AG were determined in serum. Analyzing the fMRI data, for AEA and 2-AG ANCOVAs were calculated using a full factorial model, with condition (reward > control, loss > control) and concentrations for AEA and 2-AG as factors. Regression analyses were conducted for AEA and 2-AG on TPQ-RD scores. A whole-brain analysis showed a significant interaction effect of AEA concentration by condition (positive vs. negative) within the putamen (x = 26, y = 16, z = −8, F13.51, TFCE(1, 54) = 771.68, k = 70, PFWE = 0.044) resulting from a positive association of basal AEA concentrations and putamen activity to rewarding stimuli, while this association was absent in the loss condition. AEA concentrations were significantly negatively correlated with TPQ reward dependence scores (rspearman = −0.56, P = 0.001). These results show that circulating AEA may modulate brain activation during reward feedback and that the personality measure reward dependence is correlated with AEA concentrations in healthy human volunteers. Future research is needed to further characterize the nature of the lipids’ influence on reward processing, the impact on reward anticipation and outcome, and on vulnerability for psychiatric disorders.

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Fig. 1: Coronal and transversal view (Montreal -Neurological -Institute coordinate x = 22; z = −3) depicts the interaction effect on whole-brain level of AEA concentration by condition (reward vs. loss) within the putamen (x = 26, y = 16, z = −8, F13.51, TFCE(1, 54) = 771.68, k = 70, PFWE = 0.044), resulting from an increased putamen activity in reaction to rewarding stimuli in subjects with higher AEA concentration, while this association was absent in the loss condition (color bar: TFCE Score, PFWE = 0.05).
Fig. 2: Scatter plot depicting the associations between anandamide (AEA) concentrations and Tridimensional Personality Questionnaire (TPQ) reward dependence scores.


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We thank Kathrin Schwarte for her skillful technical support. We offer many thanks to the participants.

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CR and AD have both contributed equally to the present work and should therefore both be regarded as first authors. UD and RR have supervised this work equally and should therefore both be regarded as last authors. AD, KD, VA, RR, and UD have substantially contributed to the conception and design of the work as well as the analysis and the interpretation of the data. In particular, CR but also VE and KF were involved in subject recruitment and data acquisition. DK helped with subject screening and running the study sessions. MH and SP carried out the endocannabinoid analyses. CR, AD, RR, and UD drafted and revised the work for important intellectual content. All authors gave their final approval of the version to be published and the agreement to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

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Correspondence to Andrea Dlugos.

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Redlich, C., Dlugos, A., Hill, M.N. et al. The endocannabinoid system in humans: significant associations between anandamide, brain function during reward feedback and a personality measure of reward dependence. Neuropsychopharmacol. 46, 1020–1027 (2021).

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