Acupuncture Eases Migraines but Leaves Key Biomarker CGRP Unchanged

Migraine is one of the most common and disabling neurological disorders worldwide, affecting more than one billion people and ranking among the leading causes of years lived with disability, particularly in individuals under 50 years of age. While acute medications can relieve individual attacks, patients with frequent or disabling migraines often require preventive therapies. Pharmacological prophylaxis, however, is frequently limited by adverse effects and poor adherence, which has driven interest in non-pharmacological alternatives. Manual acupuncture has emerged as one such option, with randomized controlled trials and meta-analyses suggesting efficacy at least comparable to conventional oral prophylactic drugs, along with a favorable safety profile. Yet the biological mechanisms underlying acupuncture’s effects in migraine remain incompletely understood, and researchers have long sought measurable biomarkers that could explain or predict treatment response.

Calcitonin gene-related peptide, commonly abbreviated CGRP, is a key neurotransmitter in the trigeminovascular system and plays a central role in migraine pathophysiology. Plasma levels of CGRP are elevated during migraine attacks, and the development of CGRP-targeting therapies, including monoclonal antibodies and gepants, has further underscored the peptide’s importance. Despite its established therapeutic relevance, the clinical significance of circulating peripheral CGRP concentrations as a biomarker of migraine activity or treatment response remains uncertain. A recent large-scale registry using a validated high-affinity radioimmunoassay found no significant adjusted differences in plasma CGRP concentrations among individuals with episodic migraine, chronic migraine, and healthy controls. Whether circulating CGRP changes longitudinally following therapeutic interventions, particularly non-pharmacological ones, has remained unclear.

To address this gap, a team of Italian researchers conducted a single-center, prospective, longitudinal pilot study, the first to investigate changes in plasma CGRP levels following acupuncture in patients with episodic migraine. The study, published in Frontiers in Neurology, enrolled 52 patients diagnosed with episodic migraine according to the International Classification of Headache Disorders, third edition, who were referred to the tertiary Headache Center of IRCCS Institute of Neurological Sciences of Bologna. Recruitment took place between March 2021 and May 2024. Participants received a total of 10 sessions of standardized manual acupuncture, administered once weekly over 10 weeks by trained medical acupuncturists, each with at least 10 years of clinical experience, in collaboration with the Bologna Association of Medical Acupuncturists.

The acupuncture intervention followed the STRICTA guidelines for reporting interventions in clinical trials of acupuncture. The core prescription consisted of bilateral LR3, GB34, SP6, LI4, and TE5, together with GV20, with additional points selected individually according to Traditional Chinese Medicine principles based on each patient’s diagnosis and headache localization. Sterile, single-use, disposable stainless-steel needles of varying diameters and lengths were inserted to depths generally ranging from approximately 5 to 35 mm, with superficial or oblique insertion used for cranial and facial points and deeper insertion for limb and muscular points. Manual stimulation combining rotation and lifting-and-thrusting techniques was performed to elicit the characteristic de qi sensation, assessed by the patient’s subjective report of soreness, heaviness, and distension. Needles were retained for approximately 30 minutes per session.

The primary endpoint was the change in plasma CGRP levels before and after the 10-session acupuncture cycle. Venous blood samples were collected at baseline and again one week after treatment completion, always during the interictal period, at the same time of day between 8:00 and 10:00 am, with no participant having taken acute triptans within the 48 hours preceding either sampling. EDTA plasma samples were collected from the antecubital vein, aliquoted, and stored at −80 °C. CGRP plasma concentrations were measured using enzyme-linked immunosorbent assay kits according to the manufacturer’s specifications. Secondary outcomes included changes in migraine frequency, pain intensity, acute medication intake, and migraine-related disability assessed with the Headache Impact Test, a validated six-item questionnaire known as HIT-6.

The results revealed a striking dissociation between the biological marker and the clinical picture. Median plasma CGRP levels were 60.9 pg/ml at baseline and 62.4 pg/ml after treatment, with a Wilcoxon signed-rank test showing no statistically significant difference between the two time points (p = 0.841). The median individual percentage change in CGRP levels from baseline was just 0.28 percent. Moreover, no significant association was identified between CGRP concentrations and the time elapsed since the most recent migraine attack at either baseline or follow-up. In other words, the peptide widely regarded as central to migraine biology remained essentially flat throughout the study period, even as patients reported meaningful improvements across every clinical outcome measured.

Those clinical improvements were substantial and statistically robust. Median migraine frequency decreased by 1.5 days per month, from 8 days at baseline to 7 days after treatment (p < 0.001). Median headache intensity on a 10-point numerical rating scale fell by one point, from 7 to 6.2 (p < 0.001). Median monthly acute medication use dropped by 2 units, from 10 to 7 (p < 0.001), representing a 16.7 percent reduction. HIT-6 scores, which quantify headache-related disability, decreased by a median of 6 points, from 65 to 60 (p < 0.001), a relative reduction of 8.7 percent. Only mild, transient side effects, namely needle stick pain, were reported by five individuals, and no serious adverse events occurred.

The dissociation between unchanged CGRP levels and significant clinical gains raises important questions about how acupuncture might exert its effects in migraine. The authors suggest that acupuncture may act through alternative mechanisms, such as modulation of pain processing pathways, autonomic nervous system regulation, and neuroimmune interactions. Changes in serotonin levels following acupuncture have been reported both in migraine and in other pain conditions, pointing to serotonergic pathway modulation as a potential mechanism. It is also possible that peripheral plasma CGRP concentrations simply do not reliably reflect the central neurochemical changes where acupuncture is more likely to act. Methodological factors may have contributed as well, including the substantial heterogeneity among commercially available CGRP assay kits, the absence of standardized measurement guidelines, and the biological variability of CGRP, which fluctuates with migraine phase, medication use, and time since the last attack. Blood samples in this study were collected a mean of 2.5 days after the last attack at baseline and 3.5 days at follow-up, intervals that may have introduced variability.

The study has notable strengths, including stringent inclusion criteria that yielded a relatively homogeneous patient sample, the combination of clinical assessments with a biological marker within the same cohort, and the standardized, STRICTA-compliant acupuncture protocol delivered by experienced practitioners. However, the single-arm design represents a major limitation. Without a control group, the observed improvements cannot be specifically attributed to acupuncture, as placebo and nonspecific effects, regression to the mean, and natural fluctuations in migraine symptoms cannot be excluded. The relatively small sample size of 52 patients may also have limited the statistical power to detect subtle changes in CGRP levels. The authors emphasize that the findings should be considered exploratory and hypothesis-generating rather than evidence of clinical effectiveness, and they call for controlled trials, ideally including a sham-acupuncture comparator and standardized methods for blood sampling and CGRP measurement.

Despite these caveats, the study delivers a provocative message for the migraine field: peripheral plasma CGRP may not be a straightforward biomarker of the clinical changes observed following acupuncture. As the role of CGRP as a therapeutic target continues to expand with monoclonal antibodies and gepants, understanding which patients respond to which treatments, and why, remains a central challenge. This pilot investigation, the first of its kind to track plasma CGRP longitudinally after acupuncture in episodic migraine, suggests that the peptide’s story in migraine biology is more nuanced than a simple blood test can capture. Future studies could assess CGRP in plasma alongside other biological fluids such as saliva or tears, explore the potential role of electroacupuncture, and investigate whether specific subgroups of patients respond differently. For now, the clinical improvements observed in this cohort, whatever their precise mechanism, offer a reminder that meaningful patient benefit and measurable biomarker change do not always travel together.

Subject of Research: Changes in plasma CGRP levels and clinical outcomes following acupuncture in episodic migraine

Article Title: Changes in plasma CGRP levels and clinical outcomes following acupuncture in episodic migraine: a prospective pilot study (the AcuCGRP study)

Article References: Favoni, V., Giusti, L., Bartiromo, F., Poini, A., Calabrò, C., Merli, E., Polischi, B., Baccari, F., Zenesini, C., Mascarella, D., Pierangeli, G., Giovanardi, C. M., & Cevoli, S. (2026). Changes in plasma CGRP levels and clinical outcomes following acupuncture in episodic migraine: a prospective pilot study (the AcuCGRP study). Frontiers in Neurology, 17, Article 1946490. https://doi.org/10.3389/fneur.2026.1946490

Image Credits: AI Generated

DOI: 10.3389/fneur.2026.1946490

Keywords: acupuncture, CGRP, episodic migraine, biomarker, migraine prophylaxis, HIT-6, pilot study, trigeminovascular system, non-pharmacological treatment, Frontiers in Neurology, Changes, plasma