Anandamide Is Related to Clinical and Cardiorespiratory Benefits of Aerobic Exercise Training in Migraine Patients: A Randomized Controlled Clinical Trial
Restricted accessResearch articleFirst published online December, 2019
Anandamide Is Related to Clinical and Cardiorespiratory Benefits of Aerobic Exercise Training in Migraine Patients: A Randomized Controlled Clinical Trial
Since endocannabinoids have been implicated in migraine pathophysiology, we conducted a randomized, controlled clinical trial to test the effects of a 12-week aerobic exercise intervention on plasma anandamide (AEA) and its relation with clinical, psychological, and cardiorespiratory outcomes.
Materials and Methods:
Episodic migraine patients taking no preventive drugs and nonheadache individuals were recruited from Hospital São Paulo and a tertiary headache clinic between March 2012 and March 2015. Participants were randomly assigned to receive aerobic exercise or enter the waitlist. Primary outcome was changes in plasma AEA; secondary outcome was number of days with migraine/month; and other clinical variables, mood scores, and cardiorespiratory fitness were chosen as tertiary outcomes. Measurements were taken on headache-free days. Data were analyzed by generalized linear models.
Discussion:
Fifty participants concluded the study (mean±SD age=36.2±10.9, and BMI=26.5±4.5). The plasma AEA reduced in migraine exercise (p<0.05) and control exercise groups (p<0.01). The number of days with migraine (p<0.01), migraine attacks (p<0.05), and abortive medication used (p<0.05) reduced in the migraine exercise group, whereas cardiorespiratory fitness increased in migraine exercise and control exercise groups (both p<0.05). Anxiety, depression, anger, and fatigue scores improved in the migraine exercise group (p<0.05 for all). Significant correlations between reduction in abortive medication used and cardiorespiratory fitness (r=−0.81 p<0.001), and reduced AEA (r=0.68 p<0.05) were found.
Conclusions:
This study suggests that peripheral AEA metabolism may be partly linked to the clinical and cardiorespiratory benefits of regular aerobic exercise in migraine patients. Trials registration: #NCT01972607.
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References
1.
WoldeamanuelY, CowanR. Migraine affects 1 in 10 people worldwide featuring recent rise: a systematic review and meta-analysis of community-based studies involving 6 million participants. J Neurol Sci. 2017; 372:307–315.
2.
GBD 2015 Neurological Disorders Collaborator Group. Global Health Metrics Global, regional, and national burden of neurological disorders during 1990–2015: a systematic analysis for the Global Burden of Disease Study 2015. Lancet Neurol. 2017; 11:877–897.
3.
SantiagoMDS, Carvalho D deS, GabbaiAA, et al.Amitriptyline and aerobic exercise or amitriptyline alone in the treatment of chronic migraine: a randomized comparative study. Arq Neuropsiquiatr. 2014; 72:851–855.
4.
VarkeyE, CiderA, CarlssonJ, et al.Exercise as migraine prophylaxis: a randomized study using relaxation and topiramate as controls. Cephalalgia. 2011; 31:1428–1438.
5.
DarabaneanuS, OverathCH, RubinD, et al.Aerobic exercise as a therapy option for migraine: a pilot study. Int J Sports Med. 2011; 32:455–460.
6.
OverathCH, DarabaneanuS, EversMC, et al.Does an aerobic endurance programme have an influence on information processing in migraineurs?. J Headache Pain. 2014; 15:1–10.
7.
WoldeamanuelY, CowanR. The impact of regular lifestyle behavior in migraine: a prevalence case-referent study. J Neurol. 2016; 263:669–676.
8.
VarkeyE, CiderA, CarlssonJ, et al.A study to evaluate the feasibility of an aerobic exercise program in patients with migraine. Headache. 2009; 49:563–570.
9.
HagenK, WisløffU, Ellingsen Ø, et al. Headache and peak oxygen uptake: the HUNT3 study. Cephalalgia. 2016; 36:437–444.
PiscitelliF, Di MarzoV. “Redundancy” of endocannabinoid inactivation: new challenges and opportunities for pain control. ACS Chem Neurosci. 2012; 3:356–363.
12.
MicaleV, Di MarzoV, SulcovaA, et al.Endocannabinoid system and mood disorders: priming a target for new therapies. Pharmacol Ther. 2013; 138:18–37.
13.
SilvestriC, Di MarzoV. The endocannabinoid system in energy homeostasis and the etiopathology of metabolic disorders. Cell Metab. 2013; 17:475–490.
14.
RaichlenDA, FosterA, GerdemanG, et al.Wired to run: exercise-induced endocannabinoid signaling in humans and cursorial mammals with implications for the “runner's high.”. J Exp Biol. 2012; 215:1331–1336.
15.
HeymanE, GameliF-X, GoekintM, et al.Intense exercise increases circulating endocannabinoid and BDNF levels in humans-Possible implications for reward and depression. Psychoneuroendocrinology. 2011; 37:844–851.
16.
GaldinoG, RomeroTRL, SilvaJFP, et al.The endocannabinoid system mediates aerobic exercise-induced antinociception in rats. Neuropharmacology. 2014; 77:313–324.
17.
GrecoR, MangioneAS, SandriniGet al.Effects of anandamide in migraine: data from an animal model. J Headache Pain. 2011; 12:177–183.
18.
Di MarzoV, CôtéM, MatiasI, et al.Changes in plasma endocannabinoid levels in viscerally obese men following a 1 year lifestyle modification programme and waist circumference reduction: associations with changes in metabolic risk factors. Diabetologia. 2009; 52:213–217.
19.
McPartlandJM, GuyGW, Di MarzoV. Care and feeding of the endocannabinoid system: a systematic review of potential clinical interventions that upregulate the endocannabinoid system. PLoS One. 2014; 9:e89566.
20.
CupiniL, BariM, BattistaN, et al.Biochemical changes in endocannabinoid system are expressed in platelets of female but not male migraineurs. Cephalalgia. 2006; 26:277–281.
21.
RossiC, PiniLA, CupiniML, et al.Endocannabinoids in platelets of chronic migraine patients and medication-overuse headache patients: relation with serotonin levels. Eur J Clin Pharmacol. 2008; 64:1–8.
22.
SarchielliP, PiniLA, CoppolaF, et al.Endocannabinoids in chronic migraine: CSF findings suggest a system failure. Neuropsychopharmacology. 2007; 32:1384–1390.
23.
CupiniLM, CostaC, SarchielliP, et al.Degradation of endocannabinoids in chronic migraine and medication overuse headache. Neurobiol Dis. 2008; 30:186–189.
24.
HeymanE, GameliF-X, AucouturierJ, et al.The role of the endocannabinoid system in skeletal muscle and metabolic adaptations to exercise: potential implications for the treatment of obesity. Obes Rev. 2012; 13:1110–1124.
25.
Headache Classification Subcommittee of the International Headache Society. The international classification of headache disorders: 2nd edition. Cephalalgia. 2004; 24(Suppl 1):9–160.
26.
BoutronI, MoherD, AltmanDG et al. Extending the CONSORT statement to randomized trials of nonpharmacologic treatment: explanation and elaboration. Ann Intern Med. 2008; 148:295–309.
27.
Di TomasoE, BeltramoM, PiomelliD. Brain cannabinoids in chocolate. Nature. 1996; 382:677–678.
28.
PelusoM. Alterações de humor associadas à atividade física intensa. [Thesis]. São Paulo: Universidade de São Paulo, 2003.
29.
ZoernerA, GutzkiF, BatkaiS, et al.Quantification of endocannabinoids in biological systems by chromatography and mass spectrometry: a comprehensive review from an analytical and biological perspective. Biochim Biophys Acta. 2011; 1811:706–723.
30.
OliveiraAB, BachiALL, RibeiroRT, et al.Unbalanced plasma TNF-α and IL-12/IL-10 profile in women with migraine is associated with psychological and physiological outcomes. J Neuroimmunol. 2017; 313:138–144.
31.
BaladyGJ, ArenaR, SietsemaK, et al.Clinician's guide to cardiopulmonary exercise testing in adults: a scientific statement from the American heart association. Circulation. 2010; 122:191–225.
32.
LiuY, ConnoleyI, WilsonC, et al.Effects of the cannabinoid CB1 receptor antagonist SR141716 on oxygen consumption and soleus muscle glucose uptake in Lep ob/Lep ob mice. Int J Obes (Lond). 2005; 29:183–187.
33.
AddyC, WrightH, Laere KVan, et al.The acyclic CB1R inverse agonist taranabant mediates weight loss by increasing energy expenditure and decreasing caloric intake. Cell Metab. 2008; 7:68–78.
34.
SparacoM, FeleppaM, LiptonR, et al.Mitochondrial dysfunction and migraine: evidence and hypotheses. Cephalalgia. 2006; 26:361–372.
35.
GuoS, EsserlindAL, AnderssonZ, et al.Prevalence of migraine in persons with the 3243A>G mutation in mitochondrial DNA. Eur J Neurol. 2016; 23:175–181.
36.
PeresM, MercanteJ, ToboP, et al.Anxiety and depression symptoms and migraine: a symptom-based approach research. J Headache Pain. 2017; 18:1–8.
RadatF, Lanteri-MinetM. What is the role of dependence-related behavior in medication-overuse headache?. Headache. 2010; 50:1597–1611.
39.
LeH, Tfelt-hansenP, SkyttheAet al.Association between migraine, lifestyle and socioeconomic factors: a population-based cross-sectional study. J Headache Pain. 2011; 12:157–172.
40.
VargaA, JenesA, MarczyloTH, et al.Anandamide produced by Ca(2+)-insensitive enzymes induces excitation in primary sensory neurons. Pflugers Arch. 2014; 466:1421–1435.
41.
Sousa-ValenteJ, VargaA, AnanthanK, et al.Anandamide in primary sensory neurons: too much of a good thing?. Eur J Neurosci. 2014; 39:409–418.
42.
IyengarS, OssipovMH, JohnsonKW. The role of calcitonin gene-related peptide in peripheral and central pain mechanisms including migraine. Pain. 2017; 158:543–559.
43.
MoreiraFA, AguiarDC, TerzianALB et al. Cannabinoid type 1 receptors and transient receptor potential vanilloid type 1 channels in fear and anxiety—two sides of one coin?. Neuroscience. 2012; 204:186–192.
44.
Gouveia-FigueiraS, GoldinK, HashemianS, et al.Plasma levels of the endocannabinoid anandamide, related N-acylethanolamines and linoleic acid-derived oxylipins in patients with migraine. Prostaglandins Leukot Essent Fat Acids. 2017; 120:15–24.
45.
RouzerCA, MarnettLJ. Endocannabinoid oxygenation by cyclooxygenases, lipoxygenases, and cytochromes P450: cross-talk between the eicosanoid and endocannabinoid signaling pathways. Chem Rev. 2011; 111:5899–5921.
46.
KarasuT, MarczyloTH, MaccarroneMet al.The role of sex steroid hormones, cytokines and the endocannabinoid system in female fertility. Hum Reprod Update. 2011; 17:347–361.
