Novel findings regarding the role of the endocannabinoid system in pediatric functional gastrointestinal disorders
Division of Gastroenterology, Hepatology, and Nutrition, Department of Pediatrics, Virginia Commonwealth University, Richmond, VA, USA
Department of Neurology, Medical College of Wisconsin, Milwaukee, WI, USA
Division of Quantitative Health Sciences, Department of Pediatrics, Medical College of Wisconsin, Milwaukee, WI, USA
Department of Surgery, Department of Anesthesia Medical Faculty, Clinical Pain Research Laboratories, CHUS Research Center, Sherbrooke University, Sherbrooke, Canada
Neuroscience Research Center, Medical College of Wisconsin, Milwaukee, WI, USA
Department of Neurology, Virginia Commonwealth University, Richmond, VA, USA
Abstract
The role of the endocannabinoid system in functional gastrointestinal disorders is not well understood. Serum palmitoylethanolamide and N-oleoylethanolamide are increased in these patients compared to controls.
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Keywords: Endocannabinoids, Functional gastrointestinal disorders, Pain modulation system, Peroxisome proliferator–activated receptors
Abstract
Introduction:
Pain constitutes the chief complaint of some functional gastrointestinal disorders (FGIDs). The endocannabinoid (EC) and peroxisome proliferator–activated receptors (PPARs) agonist systems have not been explored as possible contributors.
Objective:
To determine if EC and PPAR agonist abnormalities occur in adolescents with FGID.
Methods:
Institutional Review Board approved study compared 33 children (12-18 years) with a FGID to 18 healthy controls (HC). Clinical measures: functional disability inventory and pediatric pain questionnaire (PPQ). Endocannabinoid and PPAR agonist concentrations were determined in serum from blood. Data were analyzed using Mann–Whitney and Fisher exact tests (2-sided P < 0.05 considered significant).
Results:
When compared to HC, FGID subjects used different terms to describe their pain, which also occurred in more body areas. Functional gastrointestinal disorder subjects exhibited higher palmitoylethanolamide (PEA) and N-oleoylethanolamide, while EC did not differ. Interestingly, PEA correlated significantly with PPQ “worst pain the week before” in the HC group with Spearman ρ = 0.519, P = 0.003, but not in the FGID group (ρ = 0.079, P = 0.66).
Conclusion:
Children with FGID exhibit significant pain in nongastrointestinal regions. The higher concentrations of PEA found in the FGID subjects, also occurring in other chronic pain conditions, could reflect a compensatory response due to feedback loops from a downregulated or nonresponsive PPAR system, while the absence of the expected relationship between pain intensity and PEA levels in the FGID group suggests that the PPAR system may not be functioning normally.
Article notes
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Received 2024 Mar 22; Revised 2024 Dec 17; Accepted 2025 Mar 3; Collection date 2025 Aug.
1. Background
Pain dominates many pediatric disorders of brain gut interaction (DGBI) as the most significant symptom.3,20 Among these disorders are irritable bowel syndrome (IBS), dyspepsia, and functional abdominal pain syndrome. Many theories attempt to explain the pathophysiology of DGBI, including gut hypersensitivity, altered brain gut connections, dysbiosis, genetic and epigenetic factors, and increased gut permeability.7 Although the endocannabinoid system (ECS) plays a significant role in many physiological functions, an understanding of the role of circulating ECs in DGBI-related gastrointestinal symptoms is still limited.12 The ECS regulates several dominant neurotransmitter systems, such as gamma aminobutyric acid and glutamate.
The ECS, therefore, modulates downstream bodily functions such as the inflammatory response, development, appetite, pain, and other gastrointestinal functions.6
The ECS is a lipid signaling system comprises the cannabinoid receptors CB1 and CB2, their ligands (ECs N-arachidonoylethanolamine [anandamide or AEA] and 2 arachidonoylglycerol [2-AG]23), as well as the enzymes that synthesize or break down the ECs.6,12,22,23 In the gastrointestinal tract, CB1 is located in the enteric nervous system, and in the endings of the vagal nerve and spinal neurons. These EC receptors are usually located in the presynaptic cells and modulate neurotransmission through a negative feedback loop, affecting mainly acetylcholine, glutamate, and gamma aminobutyric acid.6 Endocannabinoids are produced by the dorsal and probably the enteric nervous system and lead to tonic inhibition of gastrointestinal tract motility.23
Activation of the CB1 receptor in the enteric nervous system has been shown to reduce motility, decrease secretion, and decrease hypersensitivity in the gut.23 In addition, N-oleoylethanolamide (OEA) and palmitoylethanolamide (PEA) are also emerging as key modulators of nociceptive processing,18 where they activate peroxisome proliferator–activated receptors (PPARs). Palmitoylethanolamide has anti-inflammatory effects, and OEA has anorexigenic effects due to the interaction with PPARα.12 Recent data indicate that inhibition of peripheral catabolism of PEA opposes the transition to chronic pain in a preclinical model.8
Circulating ECs arise from many sources, including the brain, adipose tissue, muscle, and circulating cells. They are highly lipophilic and they enter the circulation by equilibrating from the different tissues and may be indirect markers of tissue EC levels.12 Little data are available regarding circulating EC in DGBI. In adults with cyclic vomiting syndrome, Venkatesan et al.26 described elevated concentrations of AEA and 2-AG during the vomiting episodes compared to the nonvomiting periods, but the difference did not reach statistical significance. Interestingly, PEA and OEA were significantly increased and correlated with the degree of distress of the patient.26 Palmitoylethanolamide has been found to positively correlate with cortisol after stress.12 In females with gastroparesis associated with diabetes, AEA and 2-AG are decreased in comparison with diabetic females without gastroparesis.
The authors postulated that perhaps this decrease in AEA and 2-AG may contribute to the development of symptoms given that EC are antiemetics.2 Anandamide is also much higher in acute and chronic pancreatitis when compared with asymptomatic controls.11
The purpose of this pilot study was to determine if ECs and related PPAR agonists play a role in pediatric patients with a DGBI. Based on the above literature, we hypothesized that OEA, PEA, AEA, and 2-AG would be the molecules to distinguish DGBI from healthy control (HC) subjects. Second, we hypothesized that findings would provide evidence on whether the ECS contributes to, or compensates for, the pathophysiology of pediatric DGBI.
If it contributes, the levels would be lower. If it compensates, the levels would be higher. Finally, we hypothesized that the ECs would correlate best with function (reflected in the functional disability inventory [FDI]) rather than pain, since function provides a better reflection of the pain burden.13,16
2. Methods
2.1. Subjects
This was an Institutional Review Board–approved study performed at Children's Wisconsin in Milwaukee between April 2015 and March 2018. We enrolled adolescents and children ages 12 to 18 years with a DGBI based on ROME III criteria, including functional dyspepsia, IBS, functional abdominal pain, and functional abdominal pain syndrome.
Carefully screened HC subjects were excluded if they had any chronic pain syndrome, painful functional gastrointestinal disorder, fibromyalgia assessed by history and tender point examination as described by the American College of Rheumatology,27 chronic sleep complaints, chronic fatigue, dizziness, history of >3 syncopal episodes in their life, Raynaud syndrome, or a neuropathy on examination. This was done through a detailed interview and questionnaire assessing for the symptoms of migraines, IBS, cyclic vomiting syndrome, functional dyspepsia, functional abdominal pain syndrome, fatigue lasting for more than 3 months, tender points for fibromyalgia, etc. Healthy controls also underwent a basic neurological examination consisting of assessment of gait, coordination, rapid alternating movements, prick, and vibration sensation.
2.2. Functional and pain measurements
Functional and pain measurements included FDI, measuring perceived difficulties in performing activities across home, school, recreational, and social domains due to health status4 and the Varni/Thompson Pediatric Pain Questionnaire (PPQ) assessing chronic pain intensity, location, and the sensory, evaluative, and affective qualities of pain with child- and parent-report forms.25
2.3. Measurements of endocannabinoids, proliferator-activated receptor agonists, and catecholamines
We obtained blood for measurement of ECs, PPAR agonists, and catecholamines. Blood was centrifuged, and serum and cells separated. Serum was immediately frozen and stored at −80°C until assay. Concentrations of serum using stable isotope dilution, liquid chromatography-mass spectrometry following previously published methods.5 Briefly, deuterated AEA and 2-AG were added to 300 to 500 µL of serum; lipids were separated using C-18 solid phase extraction columns with acetonitrile as the solvent following the method reported in Spagnolo et al.21 After drying, the samples were reconstituted into methanol and analyzed using liquid chromatography-mass spectrometry of the daughter ions; ECs were quantified using isotope dilution. Catecholamines were sent to Quest laboratories for high performance liquid chromatography analysis.
2.4. Statistical methods
Median and interquartile range described continuous data and number (%) categorical data. The DGBI group and HC group were compared using a 2 sample 2 sided Mann–Whitney test for continuous or ordinal variables, and a Fisher exact test for categorical variables. Spearman correlations (ρ) explored relationships of EC receptors, pain scores, and physiological factors. A 2-sided P value <0.05 (not adjusted for multiple comparisons) was reported as statistically significant. All data analyses were conducted using SAS 9.4 and SPSS 24. This was a preliminary exploratory (pilot) study with the purpose of identifying which ECs might be of interest. Hence, no adjustment for multiple comparisons was made.
3. Results
We enrolled 33 subjects with DGBI (31 females, age 16 [15-17] years) and 18HCs (13 females, age 14 [14-16] years). There were no significant differences in age and gender (P = 0.13 for age; P = 0.08 for gender; Table 1).
| HC (n = 18) | DGBI (n = 33) | P | |
|---|---|---|---|
| Age (y), median (IQR) | 14 (14-16) | 16 (15-17) | 0.13 |
| Female, n (%) | 13 (72) | 31 (94) | 0.08 |
| Pain nowhere, n (%) | 6 (33) | 3 (9) | <0.0001 |
| Pain at abdominal area only, n (%) | 1 (5) | 2 (6) | |
| Pain at other locations (non-abdominal), n (%) | 11 (61) | 3 (9) | |
| Pain at both abdominal and other locations, n (%) | 0 (0) | 25 (76) | |
| Pain at any locations, n (%) | 12 (67) | 30 (91) | 0.052 |
3.1. Endocannabinoids
Table 2 and Figure 1 show the different EC in each group. The only 2 different ECs were PEA (P = 0.019) and OEA (P = 0.03).
| HC (n = 18), median (IQR) | DGBI (n = 33), median (IQR) | P | |
|---|---|---|---|
| FDI | 0 (0-2) | 22 (7-26) | <0.0001 |
| PPQ-worst pain this week (mm) | 13 (5-42) | 62 (37-72) | <0.0001 |
| PPQ-how do you feel now (mm) | 5 (0-18) | 22 (11-38) | 0.032 |
| 2-AG (pmol/mL) | 13.6 (9.1-38.2) | 11.6 (6.2-40.8) | 0.58 |
| AEA (pmol/mL) | 1.5 (1.4-1.7) | 1.4 (0.9-2.0) | 0.24 |
| 2-OG (pmol/mL) | 298.1 (126.6-463.8) | 202.8 (106.8-552.2) | 0.62 |
| PEA (pmol/mL) | 2.1 (1.7-8.7) | 6.7 (3.7-9.2) | 0.019 |
| OEA (pmol/mL) | 2.4 (1.8-4.8) | 3.5 (2.4-83) | 0.030 |
3.2. Pain and disability
The PPQ questionnaire includes questions about “how you feel now” and how severe was the “worse pain the week before.” As expected, the DGBI group reported feeling worse at the time of the study and having worse pain the week before the study (Table 2).
Twelve of the healthy subjects had pain located in diverse areas including the chest (1), lower abdomen (1), in the upper extremities (front = 9, back = 5), in the hands (3), lower extremities (2), feet (1), lower back (1). The presence of pain and its location is also listed in Table 1.
Furthermore, the DGBI group reported worse FDI when compared to HCs (Table 2), as expected. Nonetheless, HC did experience a significant amount of acute “day to day” pain.
Compared to HC, the DGBI group was more likely to use the following words to describe pain: tiring (48.5% vs 11.1%, P = 0.013), deep (33.3% vs 5.6%, P = 0.037), stabbing (57.6% vs 22.2%, P = 0.020), sharp (63.6% vs 33.3%, P = 0.038), and significantly less likely to use pricking (3.0% vs 22.2%, P = 0.047) and scraping (0% vs 16.7%, P = 0.039).
Interestingly, PEA and PPQ “worst pain the week before” were significantly correlated in the HC group with ρ = 0.52 and P = 0.003, but not in the DGBI group (ρ = 0.08 and P = 0.66). Along these same lines, PEA correlated with the FDI in the HC group (ρ = 0.57 and P = 0.014) but not in the DGBI group (ρ = 0.18 and P = 0.32).
3.3. Catecholamines
Norepinephrine and total catecholamine levels were not different between HC and DGBI and showed no significant correlations with any of the lipids.
4. Discussion
This study, assessing circulating concentrations of the ECs (AEA and 2-AG) and PPAR agonists (OEA and PEA) in adolescents with DGBI, demonstrated several findings. (1) Most of the DGBI subjects (83% of the painful DGBI group) reported pain outside the abdominal area and were more likely to use terms reflecting suffering pain for example, “tiring,” “deep,” than nociceptive pain, for example, “pricking.” (2) About two-third of the HC group reported pain. (3) The PPAR agonists (OEA and PEA), but not the ECs, were different between HCs and DGBI group, with higher levels of PEA and OEA in the DGBI groups. (4) Self-reported pain (PPQ “worst pain the week before”) correlated positively with circulating concentrations of PEA in HC but not in DGBI. (5) Lower function (higher FDI score) correlated with higher PEA levels, again in HC but not in DGBI. (6) There were no differences in the catecholamine concentrations between DGBI and HC. The presence of pain outside the abdominal region in DGBI subjects parallels the findings of the NIH-Multidisciplinary Assessment of Pelvic Pain (MAPP) who separated 2 phenotypes based on the absence (“pelvic pain [PP] alone”) or presence (“PP and beyond”) of pain outside the pelvic region.17 The PP and beyond group accounted for 81% of the MAPP cohort and demonstrated more evidence of central hyperalgesia, worse sleep, worse quality of life, and more depression.17 Interestingly, the proportion of subjects with “abdominal pain and beyond” at 83% almost exactly matched the MAPP report. Numbers were insufficient to meaningfully compare these particular group characteristics in our study. Nonetheless, the greater use of suffering pain adjectives (compared to sensory pain) in the DGBI group is consistent with more “centralized” pain with its associated characteristics such as catastrophizing and fear-avoidance.
We do not know which of these characteristics may be key to the association with our molecular findings.
Our study also pointed to a significant amount of “acute pain” in the control group. This is particularly interesting given that the careful and detailed screening of the control group for any chronic pain condition. While surprising at first glance, these results parallel studies done in the general population.
Data from the Health Behavior in School-aged Children: WHO Collaborative Cross-National survey reports frequent headache, stomach pain, or back pain happening at least once per month for the last 6 months in 37% to 54% of the subjects with about 75% having had at least one of the 3 pain types.24
Another study in the United States found that adolescent girls reported headaches, abdominal pain, back pain, and morning fatigue more than once a week at a rate of 20% to 30%.10 This pain prevalence is similar to current findings of about 60% to 70% reporting some pain in the body.
The circulatory concentrations of the PPARα agonists PEA and OEA were higher in the DGBI group than in HC. Since PPAR activation is associated with reduced pain and decreased neuropathic inflammation,18 inflammatory joint pain, back pain, and postoperative pain,1,9,14 the higher levels in the DGBI group may suggest a counter-regulatory attempt by the nervous system to reduce pain through the formation of these lipids or a compensatory increase in their production due to downregulated PPAR responsiveness. The fact that PEA correlated with both lower function and higher pain in the last week in the HC group but not in the DGBI group suggests an abnormal relationship between pain, function, and PEA levels in the DGBI group, which might provide important insights into the pathophysiology of DGBI when further explored. Perhaps the higher PEA levels create a ceiling effect preventing any further rise.
A similar finding of increased PEA was found in cerebrospinal fluid of individuals with chronic migraine and probable analgesic-overuse headache. In particular, cerebrospinal fluid concentrations of PEA were increased and AEA slightly reduced in individuals with both disorders compared to nonheadache subjects.19 Given that the increase PEA and lower AEA was present in 2 differing headache disorders, the authors postulated that this finding might occur in other chronic pain disorders, and that increased PEA concentration may counteract faster catabolism of AEA in chronic pain syndromes.19 A metanalysis of the role of EC in fibromyalgia and chronic widespread pain also found no difference in plasma levels of 2-AG and AEA, while there was increased plasma levels of OEA and stearoylethanolamide in patients with fibromyalgia compared with those in controls and increased plasma levels of PEA in patients with chronic widespread pain compared to controls.15 Although our subjects had gastrointestinal pain as their chief complaint, the majority also complained of more generalized pain. We did not analyze stearoylethaolamide, but the findings of higher PEA and OEA are similar to the findings in chronic widespread pain. Further studies will elaborate on the significance of these findings.
This study has several limitations. Due to the small sample size and exploratory nature of the study, to avoid type II errors, we did not adjust for multiple comparisons. We have given the unadjusted P values should a reader want to adjust.
The 2 groups were overall quite similar, yet there was clearly a trend for more males in the HC group compared to the DGBI group, which could have affected the comparison. Numbers are moderate (33 DGBI and 18 HC). We did not account for diet, exercise, body mass index, medications, or other factors that may affect the ECS.15 Types of DGBI were varied, and certain types may be more prone to demonstrating these findings than others.
In conclusion, pediatric DGBI in a tertiary care center is not limited to the gastrointestinal tract but associated with pain in other regions of the body. Further studies are needed to examine the hypothesis that PEA increases above normal values and loses its usual responsiveness to pain and function in patients with DGBI. In addition, it is possible that this pattern might even constitute a biomarker for DGBI.
Disclosures
T. Chelimsky and G. Chelimsky are co-owners of PainSTakers LLC. T. Chelimsky was a consultant at Proctor & Gamble. C. Hillard has equity in Formulate Biosciences. The other authors have no conflicts of interest to declare.
Acknowledgements
This work was supported by a Digestive Disease Center (DDC) grant from the Medical College of Wisconsin and Advancing a Healthier Wisconsin (AHW) Grant 5520298. This sponsor had no role in the study design, data collection or analysis, or decision to publish. The first draft of the manuscript was written by G. Chelimsky. No payment was received other than salary support through the AHW and DDC grant mechanism.
Footnotes
Footnote Group
Contributor Information
Lisa Conant, Email: LConant@mcw.edu.
Pippa Simpson, Email: psimpson@mcw.edu.
Liyun Zhang, Email: liyzhang@mcw.edu.
Serge Marchand, Email: serge.marchand@usherbrooke.ca.
Cecilia Hillard, Email: chillard@mcw.edu.
Thomas Chelimsky, Email: thomas.chelimsky@vcuhealth.org.
References
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References
- [1]Aldossary SA, Alsalem M, Kalbouneh H, Haddad M, Azab B, Al-Shboul O, Mustafa AG, Obiedat S, El-Salem K. The role of transient receptor potential vanilloid receptor 1 and peroxisome proliferator-activated receptors-α in mediating the antinociceptive effects of palmitoylethanolamine in rats. NeuroReport 2019;30:32–7.
- [2]Bashashati M, Leishman E, Bradshaw H, Sigaroodi S, Tatro E, Bright T, McCallum R, Sarosiek I. Plasma endocannabinoids and cannabimimetic fatty acid derivatives are altered in gastroparesis: a sex- and subtype-dependent observation. Neurogastroenterol Motil 2021;33:e13961.
- [3]Burton-Murray H, Guadagnoli L, Vanzhula IA, Brown TA, Sperber AD, Palsson O, Bangdiwala SI, Van Oudenhove L, Staller K. Pain is a cardinal symptom cutting across Rome IV anatomical categories in disorders of gut-brain interaction: a network-based approach. Neurogastroenterol Motil 2024;36:e14877.
- [4]Claar RL, Walker LS. Functional assessment of pediatric pain patients: psychometric properties of the Functional Disability Inventory. PAIN 2006;121:77–84.
- [5]Crombie KM, Brellenthin AG, Hillard CJ, Koltyn KF. Psychobiological responses to aerobic exercise in individuals with posttraumatic stress disorder. J Trauma Stress 2018;31:134–45.
- [6]Crowley K, Kiraga Ł, Miszczuk E, Skiba S, Banach J, Latek U, Mendel M, Chłopecka M. Effects of cannabinoids on intestinal motility, barrier permeability, and therapeutic potential in gastrointestinal diseases. Int J Mol Sci 2024;25:6682.
- [7]Enck P, Aziz Q, Barbara G, Farmer AD, Fukudo S, Mayer EA, Niesler B, Quigley EMM, Rajilić-Stojanović M, Schemann M, Schwille-Kiuntke J, Simren M, Zipfel S, Spiller RC. Irritable bowel syndrome. Nat Rev Dis Primers 2016;2:16014.
- [8]Fotio Y, Jung KM, Palese F, Obenaus A, Tagne AM, Lin L, Rashid TI, Pacheco R, Jullienne A, Ramirez J, Mor M, Spadoni G, Jang C, Hohmann AG, Piomelli D. NAAA-regulated lipid signaling governs the transition from acute to chronic pain. Sci Adv 2021;7:eabi8834.
- [9]Gabrielsson L, Mattsson S, Fowler CJ. Palmitoylethanolamide for the treatment of pain: pharmacokinetics, safety and efficacy. Br J Clin Pharmacol 2016;82:932–42.
- [10]Ghandour RM, Overpeck MD, Huang ZJ, Kogan MD, Scheidt PC. Headache, stomachache, backache, and morning fatigue among adolescent girls in the United States: associations with behavioral, sociodemographic, and environmental factors. Arch Pediatr Adolesc Med 2004;158:797–803.
- [11]Goodman MT, Lombardi C, Torrens A, Bresee C, Saloman JL, Li L, Yang Y, Fisher WE, Fogel EL, Forsmark CE, Conwell DL, Hart PA, Park WG, Topazian M, Vege SS, Van Den Eeden SK, Bellin MD, Andersen DK, Serrano J, Yadav D, Pandol SJ, Piomelli D; Consortium for the Study of Chronic Pancreatitis, Diabetes, and Pancreatic Cancer CPDPC. Association of serum endocannabinoid levels with pancreatitis and pancreatitis-related pain. Cannabis Cannabinoid Res 2025;10:60–70.
- [12]Hillard CJ. Circulating endocannabinoids: from whence do they come and where are they going? Neuropsychopharmacology 2018;43:155–72.
- [13]Jensen MP, Tomé-Pires C, de la Vega R, Galán S, Solé E, Miró J. What determines whether a pain is rated as mild, moderate, or severe? The importance of pain beliefs and pain interference. Clin J Pain 2017;33:414–21.
- [14]Hesselink JMK, Hekker TA. Therapeutic utility of palmitoylethanolamide in the treatment of neuropathic pain associated with various pathological conditions: a case series. J Pain Res 2012;5:437–42.
- [15]Kurlyandchik I, Lauche R, Tiralongo E, Warne LN, Schloss J. Plasma and interstitial levels of endocannabinoids and N-acylethanolamines in patients with chronic widespread pain and fibromyalgia: a systematic review and meta-analysis. PAIN Rep 2022;7:e1045.
- [16]Miettinen T, Kautiainen H, Mäntyselkä P, Linton SJ, Kalso E. Pain interference type and level guide the assessment process in chronic pain: categorizing pain patients entering tertiary pain treatment with the Brief Pain Inventory. PLoS One 2019;14:e0221437. 10.1371/journal.pone.0221437
- [17]Nickel JC, Tripp DA; International Interstitial Cystitis Study Group. Clinical and psychological parameters associated with pain pattern phenotypes in women with interstitial cystitis/bladder pain syndrome. J Urol 2015;193:138–44.
- [18]Okine BN, Gaspar JC, Finn DP. PPARs and pain. Br J Pharmacol 2019;176:1421–42.
- [19]Sarchielli P, Pini LA, Coppola F, Rossi C, Baldi A, Mancini ML, Calabresi P. Endocannabinoids in chronic migraine: CSF findings suggest a system failure. Neuropsychopharmacology 2007;32:1384–90.
- [20]Singh R, Zogg H, Ghoshal UC, Ro S. Current treatment options and therapeutic insights for gastrointestinal dysmotility and functional gastrointestinal disorders. Front Pharmacol 2022;13:808195.
- [21]Spagnolo PA, Ramchandani VA, Schwandt ML, Kwako LE, George DT, Mayo LM, Hillard CJ, Heilig M. FAAH gene variation moderates stress response and symptom severity in patients with posttraumatic stress disorder and comorbid alcohol dependence. Alcohol Clin Exp Res 2016;40:2426–34.
- [22]Starowicz K, Finn DP. Cannabinoids and pain: sites and mechanisms of action. Adv Pharmacol 2017;80:437–75.
- [23]Storr MA, Yüce B, Andrews CN, Sharkey KA. The role of the endocannabinoid system in the pathophysiology and treatment of irritable bowel syndrome. Neurogastroenterol Motil 2008;20:857–68.
- [24]Swain MS, Henschke N, Kamper SJ, Gobina I, Ottová-Jordan V, Maher CG. An international survey of pain in adolescents. BMC Public Health 2014;14:447.
- [25]Varni JW, Thompson KL, Hanson V. The Varni/Thompson Pediatric Pain Questionnaire. I. Chronic musculoskeletal pain in juvenile rheumatoid arthritis. PAIN 1987;28:27–38.
- [26]Venkatesan T, Zadvornova Y, Raff H, Hillard CJ. Endocannabinoid-related lipids are increased during an episode of cyclic vomiting syndrome. Neurogastroenterol Motil 2016;28:1409–18.
- [27]Wolfe F, Smythe HA, Yunus MB, Bennett RM, Bombardier C, Goldenberg DL, Tugwell P, Campbell SM, Abeles M, Clark P. The American College of Rheumatology 1990 Criteria for the Classification of Fibromyalgia. Report of the Multicenter Criteria Committee. Arthritis Rheum 1990;33:160–72.