Literature Discussion

NAPE-PLD modulates OEA synthesis (Igarashi, Watanabe, Tsuduki, Kimura, & Kubota, 2018)

FAAH is involved in the degradation of endogenous cannabinoids, including OEA. Targeting FAAH could modulate endocannabinoids during brain injuries (Lin, Metherel, Jones, & Bazinet, 2017). SSR411298, a FAAH inhibitor, showed anxiolytic and antidepressant effects and increased hippocampal levels of AEA, OEA and PEA in mice (Griebel et al., 2018)

OEA is involved in lipid synthesis and lipoprotein assembly through dependent and independent PPARα receptors (Pan, Schwartz, & Hussain, 2018)

OEA has been related ketogenesis through PPARα activation (Misto, Provensi, Vozella, Passani, & Piomelli, 2018)

OEA showed independent PPARα receptor neuroprotective effects against hypoxia insults in cortical neurons (Portavella et al., 2018)

N-acylethanolamines, including AEA, OEA and PEA regulate energy balance, and imbalanced ratios of these cannabinoids have been linked to obesity. These endocannabinoids could be useful as biomarkers for metabolic disorders (Fanelli et al., 2018).

OEA has been associated to modulation of Vascular smooth muscle cell (VSMC) migration and proliferation, suggesting a potential role of OEA to treat restenosis after a percutaneous coronary intervention (PCI) (Zhao et al., 2018)

Stimulation of opioid receptors reduces AEA, PEA, and OEA levels, indicating a cross communication between opioid and endocannabinoid systems (Kaczocha et al., 2018)

OEA, AEA and 2-AG have been related to host immune responses during parasite infections (Batugedara et al., 2018)

Anti-Inflammatory properties

Inhibition of FAAH increases OEA levels in rat brains and its associated to modulation of pro-inflammatory cytokines (Henry et al., 2017)

The anti-inflammatory properties of OEA are mediated by inhibition of T-cell anti-inflammatory factors (Chiurchiù, Leuti, Smoum, Mechoulam, & Maccarrone, 2018)

OEA has been related to inflammatory procesess in the eye of rats (Toguri et al., 2018)

Human and donkey milk showed anti-inflammatory properties in rats and an higher OEA levels in skeletal muscles (Trinchese et al., 2018)

OEA modulates neuroinflammation and neurobehavioral deficits related to Gulf War Illness (Joshi et al., 2018)

ECs 1-AG, OEA, SEA and PEA anti-inflammatory properties could be altered during trauma. Changes of the level of these cannabinoids were found in mothers and their newborns when mothers experienced childhood trauma (Koenig et al., 2018).


Hippocampal Anandamide, OEA and PEA were increased after social exposure (Kerr, Downey, Conboy, Finn, & Roche, 2013) once more stipulating the involvement of the endocannabinoid system in autism.


OEA is actually the strongest endogenous activator of GPR119 and was shown to reduce food intake and weight gain in rodents via PPARα and TRPV1 (Overton et al., 2006).


OEA, PEA, SEA, and 2-AG leves were higher in fibromyalgia women when compared to a control group (Stensson et al., 2018)

Functional Gastro-Intestinal Disorders

In patients with diarrhea-type IBS higher levels of 2AG and lower levels of OEA and PEA were found. In contrast, patients with constipation-type IBS had higher levels of OEA and lower levels of FAAH. Also, PEA levels were inversely correlated with abdominal pain suggesting substantial involvement of the endocannabinoid system in the pathophysiology of IBS (Fichna et al., 2014).

OEA treatment changes microbiota profiles towards a lean-like phenotype microbiota in mice (Di Paola et al., 2018)

OEA showed protective properties against intestinal barrier disfunction after oral ethanol adminsitration to rats (M. Antón et al., 2018)

Hypoxic-ischemic encephalopathy

cannabinoid receptors CB1 and CB2 are upregulated and Endocannabinoids like AEA, 2-AG, OEA and PEA show increased levels after cerebral ischemia (England, Hind, Rasid, & O’Sullivan, 2015; Lara-Celador, Goñi-de-Cerio, Alvarez, & Hilario, 2013).

Experimental in vitro ischemia showed lower AEA, 2-AG, OEA and PEA levels (Sampaio et al., 2018)

Lower degradation OEA derivate, octadecylpropyl sulfamide (SUL), reduces neurodegneration and memory déficits related to hypoxia-ischemia in mice (Kossatz et al., 2018)


In a model of maternal separation, sleep reduction has been related to the endocannabinoid system through the expression of CB1 in the prefrontal cortex and hypothalamus while oleamide improved sleep in adult rats (Reyes Prieto et al., 2012)

obesity and lipid regulation

OEA enhances Long-acting glucagon-like peptide-1 (GLP-1) and exendin-4 (Ex4) proteins stimulation, inducing weight loss in mice (Brown et al., 2018)

OEA reduces food intake in mice through intestinal and nodose ganglion PPARα receptors but its effecs on energy epedienture are independent of intestinal and nodose ganglion PPARα receptors (Caillon, Duszka, Wahli, Rohner-Jeanrenaud, & Altirriba, 2018)

endocannabinoids such as OEA bind to GPR119 to increase cAMP (signals high energy/glucose content to a cell), stimulate insulin secretion and cause fat deposition  (Overton et al., 2006) OEA reduced food intake and weight gain in rodents via PPARα and TRPV1 (Overton et al., 2006)

OEA administration caused both anorectic effects and locomotor impaitment in rats. OEA anorectic effects were not mediated by vagal afferents but probably by spinal afferents (Fedele et al., 2018)

OEA levels were reduced in the amygdala and hypothalamus of female rats after high fat diet limitation (Satta et al., 2018)

OEA has been related to hepatic lipid and glucose metabolism in goldfish, suggesting a role in circadian activity and food intake (Gómez-Boronat et al., 2016)

OEA has been related to fat storage and lipid regulation in juncos (Ho et al., 2017)

OEA has been associated with hypophagic effects (Romano et al., 2017)

OEA and PEA plasma concentrations increased after a 2h fat diet in rats (Olatinsu, Sihag, & Jones, 2017)

An animal model of the obesity disease Prader-Willi syndrome (Magel2 KO mice) shows changes in OEA levels. Also, administration of OEA reduces food intake in these animals, suggesting a role of OEA in obesity (Igarashi et al., 2017)

High oleic canola oil and olive oil weight regulation properties are related to high OEA levels (Sihag & Jones, 2018)

OEA changes have been associated to craving behavior in pregnancy woman (Krishnan et al., 2018)

OEA, AEA and PEA levels were reduced in the offspring of pregnant rats who had a dietary restriction (Ramírez-López et al., 2017)

Low OEA and PEA concentrations in breast milk were associated with higher weight of children at 4 months of age (Bruun et al., 2018)

Please, see Bowen et al. (2017) and Brown et al. (2017) for a review of the therapeutic potential of OEA in lipid and weigh control.


In a mouse model of Parkinson’s, OEA (at 5mg/kg) protected dopaminergic neurons from degeneration in a PPARα-dependent way (Gonzalez-Aparicio et al., 2014). Similarly, systemic application of OEA, and to a lesser extent PEA, was found to inhibit pro-inflammatory cytokines and thus to protect against neurodegeneration (Sayd et al., 2014). In another study, OEA reduced L-dopa-induced-dyskinesia in a TRPV1-dependent way (González-Aparicio & Moratalla, 2014).

Stress and depression

OEA has been related to modulation of stress responses (Danandeh et al., 2018)

OEA interacts with histaminergic neurotransmission to exert anti-depressant effects in mice (Costa et al., 2018)

Maternal Deprivation had an effect on the levels of endocannabinoids in rats in a sex dependent manner (Mela et al., 2016)

In a mouse model of depression, chronic unpredictable mild stress causes depression-like behavior, atrophy of hippocampus and frontal cortex and increases corticosterone levels. Oral application of OEA (1.5 – 6 mg/kg) reverted these effects suggesting therapeutic potential for OEA in the treatment of depression (Jin, Yu, Tian-Lan, Zhang, & Quan, 2015).  

PEA levels were elevated in subjects with Burning mouth syndrome when compared to controls and OEA, AEA and PEA levels also correlated with depressive symptoms related to the disease (Barry et al., 2018)


DiNP plastic compound exposition to zebrafish gonades was related to OEA level reduction in this organ (Forner-Piquer et al., 2018)

OEA inhibited melanogenesis in B16 melanoma cells through ERK, AKT and CREB pathways (Zhou et al., 2017)

OEA, PEA, DEA and EPEA have been proposed as biomarkers for different Malaria infections (Surowiec et al., 2017)

Please, see Russo et al. (2018) for a review on how endocannabinoids have been related to pain, inflammation, microbiota and lipid regulation in the gut-brain axis.


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Zhou, J., Ren, T., Li, Y., Cheng, A., Xie, W., Xu, L., … Yang, L. (2017). Oleoylethanolamide inhibits α-melanocyte stimulating hormone-stimulated melanogenesis via ERK, Akt and CREB signaling pathways in B16 melanoma cells. Oncotarget, 8(34), 56868–56879. https://doi.org/10.18632/oncotarget.18097

Synthetic Pathways

Main pathways:

NAT: N-acyltransferase (Ca2+-dependent)

Produces NAPE from phospholipids.

iNAT: N-acyltransferase (Ca2+-independent)

Produces NAPE from phospholipids. Low abundant in brain.

NAPE-PLD: N-acyl-phosphatidylethanolamine (NAPE)-hydrolyzing phospholipase D

Produces Anandamide from NAPE

Additional pathways:

ABDH4: α/β-hydrolase 4

Lyso-PLD: lyso-phospholipase D

GDE1: glycerophosphodiester phosphodiesterase 1

PTPN22: protein tyrosine phosphatase, non-receptor type 22


Degradation Pathways

FAAH-1: fatty acid amide hydrolase-1

FAAH-2: fatty acid amide hydrolase-2

NAAA: N-acylethanolamine-hydrolyzing acid amidase  


Clinical Trials

60 day treatment with OEA suplementation (250mg/day) reduced weight, body mass index, waist circumference, fat percent, hunger, the desire to eat, and cravings for sweet foods and increased fullness sensation in a clinical trial with 56 subjects. OEA effect was associated to anti-inflammatori and antioxidant properties and reduced PPARα expression. This study suggests that OEA could be effective in treating obesity (Laleh et al., 2018; Payahoo, Khajebishak, Asghari Jafarabadi, & Ostadrahimi, 2018)

AEA and OEA levels increased after isometric exercise and were associated with pain reduction in a sample of 58 subjects. Blocking opioid receptors blocked endocannabinoids level rise, suggesting that both endocannabinoid and opioid systems interact between each other (Crombie, Brellenthin, Hillard, & Koltyn, 2018a)

Several clinical trials have tested the therapeutic potential of cannabinoids after Stroke. Meta-analysis revealed that both endocannabinoids like AEA, OEA or PEA and plant cannabinoids like THC or CBD can significantly reduce neuronal degeneration after Stroke (England, Hind, Rasid, & O’Sullivan, 2015). Specifically activating CB1 and/or CB2 receptors had the strongest protective effect but other receptors such as 5-TH1a and PPARα are also likely to be involved.

AEA, 2-AG, and OEA have been associated to metabolic disorders through their role in energy expenditure regulation, as shown in a sample of 35 obese native american subjects (Heinitz et al., 2018)

OEA, PEA and AEA plasma levels were elevated in alcohol binge drinkers and these also correlated with mRNA expression of anti-inflammatory markers (Antón et al., 2017)

Plasma OEA and PEA levels were higher in patients with chronic widespread pain conditions, but these did not correlate with inflammatory biomarkers (Stensson, Ghafouri, Gerdle, & Ghafouri, 2017)

AEA, 2-AG and OEA levels increased in two different groups of subjects (PTSD vs Control) after 30 minutes aerobic exercise (Crombie, Brellenthin, Hillard, & Koltyn, 2018b)


Antón, M., Rodríguez-González, A., Rodríguez-Rojo, I. C., Pastor, A., Correas, Á., Serrano, A., … Orio, L. (2017). Increased plasma oleoylethanolamide and palmitoleoylethanolamide levels correlate with inflammatory changes in alcohol binge drinkers: the case of HMGB1 in women. Addiction Biology. https://doi.org/10.1111/adb.12580

Crombie, K. M., Brellenthin, A. G., Hillard, C. J., & Koltyn, K. F. (2018a). endocannabinoid and Opioid System Interactions in Exercise-Induced Hypoalgesia. pain Medicine (Malden, Mass.), 19(1), 118–123. https://doi.org/10.1093/pm/pnx058

Crombie, K. M., Brellenthin, A. G., Hillard, C. J., & Koltyn, K. F. (2018b). Psychobiological Responses to Aerobic Exercise in Individuals With Posttraumatic Stress Disorder. Journal of Traumatic Stress, 31(1), 134–145. https://doi.org/10.1002/jts.22253

England, T. J., Hind, W. H., Rasid, N. A., & O’Sullivan, S. E. (2015). cannabinoids in experimental Stroke: a systematic review and meta-analysis. Journal of Cerebral Blood Flow and Metabolism: Official Journal of the International Society of Cerebral Blood Flow and Metabolism, 35(3), 348–358. https://doi.org/10.1038/jcbfm.2014.218

Heinitz, S., Basolo, A., Piaggi, P., Piomelli, D., Jumpertz von Schwartzenberg, R., & Krakoff, J. (2018). Peripheral endocannabinoids Associated With Energy Expenditure in Native Americans of Southwestern Heritage. The Journal of Clinical Endocrinology and Metabolism, 103(3), 1077–1087. https://doi.org/10.1210/jc.2017-02257

Laleh, P., Yaser, K., Abolfazl, B., Shahriar, A., Mohammad, A. J., Nazila, F., & Alireza, O. (2018). Oleoylethanolamide increases the expression of PPAR-Α and reduces appetite and body weight in obese people: A clinical trial. Appetite, 128, 44–49. https://doi.org/10.1016/j.appet.2018.05.129

Payahoo, L., Khajebishak, Y., Asghari Jafarabadi, M., & Ostadrahimi, A. (2018). Oleoylethanolamide Supplementation Reduces Inflammation and Oxidative Stress in Obese People: A Clinical Trial. Advanced Pharmaceutical Bulletin, 8(3), 479–487. https://doi.org/10.15171/apb.2018.056

Stensson, N., Ghafouri, B., Gerdle, B., & Ghafouri, N. (2017). Alterations of anti-inflammatory lipids in plasma from women with chronic widespread pain - a case control study. Lipids in Health and Disease, 16(1), 112. https://doi.org/10.1186/s12944-017-0505-7