Thank you for visiting nature. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser or turn off compatibility mode in Internet Explorer. In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript. Animal models indicate that the endocannabinoid system ECS plays a modulatory role in stress and reward processing, both crucially impaired in addictive disorders. Preclinical findings showed endocannabinoid-modulated synaptic plasticity in reward brain networks linked to the metabotropic-glutamate-5 receptor mGluR5 , contributing to drug-reinforcing effects and drug-seeking behavior. Although animal models postulate a link between ECS and cocaine addiction, human translational studies are lacking. Our results corroborate animal findings suggesting an alteration of the ECS in cocaine dependence and an association between peripheral 2-AG levels and cerebral mGluR5 in humans. Therefore, the ECS might be a promising pharmaco-therapeutic target for novel treatments of cocaine dependence. Impaired reward behavior and inadequate stress response drive drug addiction development and maintenance. Accordingly, long-term maladaptive functional and structural synaptic plasticity caused by repeated drug exposure have been reported in brain networks related to reward behavior and stress response \\\\[ 1 , 2 \\\\]. Cocaine, as a non-selective monoamine transporter inhibitor, leads to elevated dopamine DA levels within the brain regions of the mesolimbic reward network in animals and humans including projections from the ventral tegmental area \\\\[VTA\\\\] to the nucleus accumbens \\\\[NAc\\\\] , which has been linked to the highly addictive properties of cocaine \\\\[ 3 , 4 \\\\]. Animal models have shown that acute cocaine-induced activation of DA neurons in the NAc is specifically associated with the drug-reinforcing effects enhancing motivated and drug-seeking behavior \\\\[ 5 , 6 , 7 \\\\]. Moreover, preclinical evidence suggests that repeated cocaine use entails drug-induced neuroplastic adaptations in mesolimbic DA neurons, causing drug-cue-related hyper-sensitivity and subsequently contributing to cocaine use maintenance and drug relapse even after a prolonged time of abstinence \\\\[ 8 , 9 , 10 \\\\]. In recent years, accumulating evidence mainly from preclinical studies indicates that the endocannabinoid system ECS plays a major role in reward processing. Specifically, long-term depression LTD causing synaptic plasticity in the mesolimbic DA network has been linked to the ECS underpinning drug-seeking and addictive behavior \\\\[ 21 , 22 , 23 , 24 \\\\]. They act as retrograde neurotransmitters by activating presynaptic CB 1 receptors entailing inhibition of presynaptic neurotransmitter release \\\\[ 25 , 26 , 27 , 28 , 29 \\\\]. CB 1 receptors are highly expressed throughout the mesolimbic DA network localized on terminals of glutamatergic and GABAergic neurons but not on DA neurons itself \\\\[ 30 , 31 , 32 \\\\]. Preclinical findings showed that acute and repeated cocaine administration facilitates endocannabinoid-mediated LTD at GABAergic interneurons and abolishes endocannabinoid-mediated LTD at glutamatergic neurons, both resulting in increased DA release in the VTA and its projection to the NAc, contributing to the drug reinforcing effects \\\\[ 36 , 37 , 38 \\\\]. Moreover, cocaine-induced activation of the endocannabinoid-LTD mechanism in the VTA has been recently linked to motivational behavior in rats, while the CB 1 receptor inverse agonist rimonabant was able to block reward-seeking behavior \\\\[ 39 \\\\]. In the NAc, a single in vivo cocaine administration in mice has been shown to abolish endocannabinoid-mediated LTD at terminals of glutamatergic neurons resulting in increased glutamate release and subsequently in increased excitation of DA cells \\\\[ 40 \\\\]. Synaptic plasticity induced by endocannabinoid-mediated LTD has been further related to activation of postsynaptic metabotropic glutamate receptor 5 mGluR5 in various brain regions in rodents \\\\[ 41 , 42 , 43 \\\\]. Notably, a single administration of cocaine in mice has been shown to alter the functional interaction of endocannabinoid-mediated LTD and mGluR5 \\\\[ 40 \\\\]. Only one human study has investigated plasma endocannabinoids in individuals with cocaine use so far reporting elevated levels of AEA and the structurally related N-acylethanolamines NAEs palmitoylethanolamide PEA , and oleoylethanolamide OEA but lower 2-AG levels in abstinent individuals with cocaine use disorder CUD compared to healthy controls. Inclusion and exclusion criteria are described in the supplementary materials. All participants provided written informed consent and were financially compensated for their participation. Blood plasma samples were taken after the psychiatric interviews. Because lipids such as endocannabinoids can readily cross the blood brain barrier, plasma endocannabinoid levels give reliable information about levels in the brain \\\\[ 55 , 56 \\\\]. PET imaging acquisition and preprocessing have been previously described in detail \\\\[ 45 \\\\]. For more information see supplementary materials. All procedures were kept consistent on the baseline, follow-up, and PET testing days, when blood samples were taken see supplementary materials. The influence of current alcohol dependence was specifically considered here given previously reported impact of co-morbid AUD on the association of 2-AG with CUD \\\\[ 48 \\\\]. False discovery rate FDR was applied to account for multiple comparisons when needed \\\\[ 64 \\\\]. Bars represent means including individual data points, and error bars reflect standard error of the mean SEM ; corrected for age, sex, recent cannabis use, and alcohol dependence. All three groups showed stable 2-AG levels over the twelve months period even if cocaine use was increased or decreased see Supplementary materials Figure S2. Association within recreational and dependent CU are shown in Supplementary Fig. S3a , and regression parameters of the models are shown in Supplementary Table S3. More precisely, results indicate that the association between cocaine craving and 2-AG was only present in dependent CU co-morbid with alcohol dependence see supplementary materials Figure S3b. Additional LMM including cannabis dependence in the model was not significant see supplementary materials Table S4. Additional stepwise linear regression analyses forward and backward were performed to check for potential confounding effects of cannabis use on 2-AG over all subjects and within groups. However, this regressor became non-significant after controlling for age, sex, recent cannabis use THC and CBD plasma levels , and alcohol dependence in the model see Supplementary materials Table S5. Distributions of cannabis use in the last 6 months for each group are shown in the Supplementary materials Fig. Correlation analyses yielded significant positive correlations between 2-AG and region-specific mGluR5 VOIs within chronic CU showing significantly different correlation coefficients compared to controls for the brain structures insula, ACC, MCC, amygdala, thalamus, caudate , and hippocampal regions see Table 2. Positive interactions within chronic CU are shown in Fig. After controlling for multiple comparisons using FDR, only the correlation p -value of the thalamus region remained significant see Table 2 while the other regions did not reach the significant threshold anymore even though showing clear statistical trends. After controlling for tobacco use and age, the interaction between 2-AG and mGluR5 was specifically evident in chronic cocaine users for the brain structures amygdala a , thalamus b , as well as hippocampal region c , and as trend levels for the other brain structures d — g. To formally address whether the relationship between 2-AG and mGluR5 density was unique to chronic CU even after controlling for confounding variables age and smoking, we used binary logistic regression models with GROUP as the dependent variable. All logistic regression models are shown in the supplementary materials Table S6. Our findings indicate alterations of the ECS in individuals with cocaine dependence. Specifically, basal 2-AG was elevated in cocaine dependence compared to controls and at a trend level also to recreational users. In contrast, the latter two groups did not differ in basal 2-AG plasma concentration. Our findings suggest that 2-AG might play a crucial role in cocaine dependence in humans. This is consistent with recent animal models showing elevated 2-AG levels in the VTA after cocaine administration, contributing to the positive reinforcing and motivation-enhancing effects of the substance \\\\[ 36 , 39 , 67 \\\\]. Whereas a previous study did not find correlations between AEA levels in cerebrospinal fluid CSF and serum \\\\[ 68 \\\\], recent human findings indicate that peripheral endocannabinoid plasma concentrations might reflect brain levels. Translational evidence from humans and mice indicate a similar relationship between fear behavior and AEA concentrations, genetically manipulated by the FAAH polymorphism, in both, the periphery as well as in the amygdala and prefrontal cortex \\\\[ 69 \\\\]. Therefore, we speculate that the elevated 2-AG levels found in individuals with cocaine dependence indicate higher response to the cocaine-rewarding effects as well as higher motivated behavior resulting in increased vulnerability to developing cocaine dependence. Given that i cocaine use intensity i. Accordingly, no correlations between 2-AG and cocaine addiction severity variables have been previously shown in abstinent cocaine users \\\\[ 48 \\\\]. In contrast to our findings, the same study found reduced 2-AG plasma levels and elevated NAE levels in abstinent individuals with CUD compared to healthy controls. However, lower 2-AG plasma levels were only significantly different from controls in abstinent cocaine users with co-morbid AUD as the authors reported in the supplements, whereas AUD had no influence on NAE levels. Importantly, ROC curves showed that CUD was only a significant predictor for NAEs but not 2-AG indicating that the findings regarding lower 2-AG plasma levels in abstinent cocaine users might not be related to chronic cocaine use per se. However, the question of whether elevated 2-AG levels in individuals with cocaine dependence is due to long-term changes in synaptic plasticity caused by repeated cocaine use, as previously shown in animal models, or whether it is a pre-existing phenomenon, and 2-AG is thus a biomarker of vulnerability to cocaine dependence, requires further investigation. Our present analyses with follow-up data suggest stable 2-AG plasma levels over a period of at least 12 months, independent of increased or decreased cocaine use, which might be indicative of 2-AG being a biomarker i. Future studies should, therefore, address our assumption that individuals with elevated basal 2-AG levels are more prone to the rewarding effects of cocaine e. Although we found higher basal 2-AG plasma levels in the cocaine-dependent group, cocaine craving was negatively associated with 2-AG plasma levels in dependent CU initially. This result would have been in contrast to previous animal findings reporting a positive association between stress-induced cocaine craving and phasic 2-AG response \\\\[ 71 , 72 \\\\]. However, the additional LMM showed that the relationship between 2-AG and cocaine craving was primarily driven by alcohol dependence and only found in individuals with co-morbid cocaine and alcohol dependence but not with cocaine dependence alone. Genetic and pharmacological downregulation of 2-AG signaling in rodent brain regions responsible for stress and affect regulation e. However, no reliable measures of withdrawal and anxiety symptoms neither for cocaine nor for alcohol were available for the present dataset and future human studies should investigate the influence of alcohol and cocaine withdrawal on 2-AG and craving in AUD alone and co-morbid with CUD. In fact, since the relationship between 2-AG and cocaine craving was no longer evident in dependent CU without co-morbid alcohol dependence, the present results support our suggestion of elevated 2-AG levels as a stable biomarker unique for cocaine dependence. Here, we found for the first time a relationship between 2-AG and mGluR5 density in humans, including brain regions involved in processing reward behavior and affect regulation i. This association was evident only in chronic CU but not in healthy controls and was strongest in the thalamus, where the correlation survived FDR-correction despite the small sample size. Our present results are in line with previous animal models showing an involvement of mGluR5 and 2-AG in LTD throughout various brain regions \\\\[ 41 , 42 , 43 \\\\] and are consistent with the notion of drug-induced long-term synaptic plasticity \\\\[ 1 \\\\]. Notably, single in vivo cocaine administration has been previously reported to affect mGluR5 and endocannabinoid-LTD in mice \\\\[ 40 \\\\], which might in the long run lead to alterations in this system mechanism and may further explain that our finding of the statistical interaction between 2-AG and mGluR5 was only evident in chronic CU. These findings are consistent with both previous preclinical results and recent human findings reporting impaired glutamate homeostasis in the NAc in chronic CU \\\\[ 76 , 77 \\\\]. Although we were not able to assess mGluR5 density in the ventral striatum i. Our results extend previous findings from our lab \\\\[ 45 \\\\], indicating that cocaine use disorder might be rather linked to 2-AG and its interaction with mGluR5 than exclusively to mGluR5 density per se, which has been reported previously \\\\[ 46 , 47 \\\\]. Future studies should address this issue and our assumption by using PET imaging techniques with selective tracers for enzymes and lipids related to 2-AG in both sexes. We recently reported lower tonic OEA and PEA hair concentration in a subgroup of the present chronic CU compared to healthy controls, specifically pronounced in individuals showing cocaine dependence \\\\[ 49 \\\\]. Moreover, reported findings might also be related to phasic vs. The present findings are novel in the field of cocaine use disorder in humans and crucially contribute to a better mechanistic understanding of the role of the ECS in cocaine dependence. 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The pharmacology of palmitoylethanolamide and first data on the therapeutic efficacy of some of its new formulations. Endocannabinoid and perceived stress: association analysis of endocannabinoid levels in hair versus levels in plasma and urine. Biol Psychol. Download references. We thank Avery Nelson for his preliminary statistical analyses with parts of the present data set. Sara L. Kroll, Lea M. Markus Leweke. You can also search for this author in PubMed Google Scholar. SLK analyzed the data and wrote the paper. BBQ designed initial research and revised the paper. MRB performed the toxicological hair analysis. Correspondence to Sara L. CR is a shareholder of lero bioscience UG Ltd. BBQ received funding from Gilead Sciences. All other authors declare no conflict of interest. Reprints and permissions. Kroll, S. Plasma endocannabinoids in cocaine dependence and their relation to cerebral metabotropic glutamate receptor 5 density. Transl Psychiatry 13 , Download citation. Received : 17 June Revised : 28 September Accepted : 06 October Published : 19 October Anyone you share the following link with will be able to read this content:. Sorry, a shareable link is not currently available for this article. Provided by the Springer Nature SharedIt content-sharing initiative. Skip to main content Thank you for visiting nature. Download PDF. Subjects Addiction Molecular neuroscience. Abstract Animal models indicate that the endocannabinoid system ECS plays a modulatory role in stress and reward processing, both crucially impaired in addictive disorders. Lower brain fatty acid amide hydrolase in treatment-seeking patients with alcohol use disorder: a positron emission tomography study with \\\\[C\\\\]CURB Article 07 January Exploring regulation and function of dopamine D3 receptors in alcohol use disorder. Links between central CB1-receptor availability and peripheral endocannabinoids in patients with first episode psychosis Article Open access 26 August Introduction Impaired reward behavior and inadequate stress response drive drug addiction development and maintenance. Analysis of N-acylethanolamines and phyto-cannabinoids in plasma Blood plasma samples were taken after the psychiatric interviews. PET imaging and analysis PET imaging acquisition and preprocessing have been previously described in detail \\\\[ 45 \\\\]. Table 1 Demographic data means and standard deviations. Full size table. Full size image. Discussion Our findings indicate alterations of the ECS in individuals with cocaine dependence. Google Scholar Cohen J. Google Scholar Download references. Acknowledgements We thank Avery Nelson for his preliminary statistical analyses with parts of the present data set. Quednow Authors Sara L. Kroll View author publications. View author publications. Supplementary information. Supplementary Materials. About this article. Cite this article Kroll, S. Copy to clipboard. This article is cited by Endocannabinoids and related lipids linked to social exclusion in individuals with chronic non-medical prescription opioid use Sara L. Kroll Philip Meier Boris B. Search Search articles by subject, keyword or author. Show results from All journals This journal. Advanced search.

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