Metabolomics reveals reasons for the efficacy of acupuncture in migraine patients: The role of anaerobic glycolysis and mitochondrial citrate in migraine relief

Acupuncture is used worldwide to treat migraine, but its scientific mechanism remains unclear. Here, we report a 1H NMR metabolomics study involving 40 migraine patients and 10 healthy people randomly receiving acupuncture or sham acupuncture, followed by machine learning techniques and functional analysis. We found that acupuncture at acupoints particularly enhanced anaerobic glycolysis and modified mitochondrial function by adjusting the levels of plasma pyruvic acid (P = 0.012), lactic acid (P = 0.031) and citrate (P = 0.00079) at a Bonferroni-corrected level of significance compared to the pre-treatment level of these three metabolites in migraine patients. Therefore, acupuncture supplies energy to migraine patients and relieves migraine attacks. In contrast, we observed that sham acupuncture may partially supply energy to migraine patients through lipid metabolism by changing the levels of plasma lipid (P = 0.0012), glycerine (P = 0.021), and pyruvic acid (P = 0.047) at a Bonferroni-corrected level of significance. The functional network analysis further indicates this different way of supplying energy contributes to the different effects of acupuncture and sham acupuncture. Our findings reveal novel metabolic evidence for the specific effect of acupuncture in relation to sham acupuncture. This metabolic evidence could enlighten a brand new direction into acupuncture analgesia mechanism, which in turn would pose fresh challenges for future acupuncture research. ### Competing Interest Statement The authors have declared no competing interest. ### Clinical Trial NCT00599586 ### Funding Statement This study was funded by grants from the National Basic Research Program of China (973 Program, nos. 2012CB518501 and 2006CB504501), National Natural Science Foundation of China (no. 81973941, no. 81202741), State Scholarship Fund (no. 201608320044). ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: The clinical trial protocol was approved by the Ethics Review Committee of the 1st Teaching Hospital of Chengdu University of TCM and had been published \[2007KL-002\] ([Li et al., 2008][1]). I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines and uploaded the relevant EQUATOR Network research reporting checklist(s) and other pertinent material as supplementary files, if applicable. Yes All data, models, or code used during the study are available from the corresponding author by request. [1]: #ref-29