Problems with measuring peripheral oxytocin: can the data on oxytocin and human behavior be trusted?

McCullough, Michael E.; Churchland, Patricia Smith; Mendez, Armando J.

doi:10.1016/j.neubiorev.2013.04.018

Cited by 416Neuroendocrine regulation and behaviorNeuropeptides and Animal PhysiologyStress Responses and Cortisol

Problems with measuring peripheral oxytocin: can the data on oxytocin and human behavior be trusted?

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McCullough, Michael E., Churchland, Patricia Smith, Mendez, Armando J.·2013·Neuroscience & Biobehavioral Reviews

DOI 10.1016/j.neubiorev.2013.04.018

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Abstract

Research on the neurobiological and behavioral effects of oxytocin (OT), as well as on its possible therapeutic applications, has intensified in the past decade. Accurate determination of peripheral OT levels is essential to reach meaningful conclusions and to motivate, support and inform clinical interventions. Different, but concordant, methods for measuring plasma OT have been developed over the past four decades, but since 2004 several commercially available methods have been favored in research with humans. Evaluation of these methods reveals that they lack reliability when used on unextracted samples of human fluids, and that they tag molecules in addition to OT, yielding estimates that are wildly discrepant with an extensive body of earlier findings that were obtained using methods that are well validated, but more laborious. An accurate, specific, and readily available method for measuring OT that can be adopted as the standard in the field is urgently needed for advances in our understanding of OT's roles in cognition and behavior.

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In recent evaluations, the RIA method was shown to have low sensitivity in the majority of samples tested.
“in recent evaluations the RIA method was shown to have low sensitivity in the majority of samples tested (McCullough et al., 2013)”
From Peripheral oxytocin and vasopressin: Biomarkers of psychiatric disorders? A comprehensive systematic review and preliminary meta-analysis (2016) · cites this paper as McCullough et al., 2013
Both the commercially available immunoassays (RIA and EIA) have high heterogeneity and questionable validity.
“Both the commercially available immunoassays (RIA and EIA) have high heterogeneity and questionable validity (McCullough et al., 2013).”
From Peripheral oxytocin and vasopressin: Biomarkers of psychiatric disorders? A comprehensive systematic review and preliminary meta-analysis (2016) · cites this paper as McCullough et al., 2013
Even in extracted samples, non-OT immunoreactive products of uncertain nature account for most of the measured immunoreactivity.
“even in extracted samples the non-OT immunoreactive products of uncertain nature account for most of the measured immunoreactivity (McCullough et al., 2013).”
From Peripheral oxytocin and vasopressin: Biomarkers of psychiatric disorders? A comprehensive systematic review and preliminary meta-analysis (2016) · cites this paper as McCullough et al., 2013
For saliva and urine, estimated levels are highly discrepant and weakly correlated to plasmatic levels.
“With respect to other bodily fluids, such as saliva and urine, it has been demonstrated that the estimated levels are highly discrepant and weakly correlated to plasmatic levels (McCullough et al., 2013).”
From Peripheral oxytocin and vasopressin: Biomarkers of psychiatric disorders? A comprehensive systematic review and preliminary meta-analysis (2016) · cites this paper as McCullough et al., 2013
The manufacturer's advice to extract plasma has been largely ignored; many studies have used the Enzo assay on unextracted human plasma, reporting mean concentrations of oxytocin and vasopressin typically 100-500 pg/ml, and those that diluted samples did so by less than the manufacturer's recommendations without confirming that their dilution was adequate.
“This advice has been largely ignored. Many studies have used this assay on unextracted human plasma, reporting mean concentrations of oxytocin and vasopressin of typically 100–500 pg/ml 3, 4, 5, 6, 114. Those that have diluted samples have done so by less than the manufacturer's recommendations, without confirming that their dilution is adequate.”
From Measuring Oxytocin and Vasopressin: Bioassays, Immunoassays and Random Numbers (2016) · cites this paper as [114]

Earlier ELISAs had a high rate of non-specific binding, leading to artificially elevated oxytocin concentrations.
“These improvements have sought to address the main concern raised by McCullough et al. [7], namely that earlier ELISAs had a high rate of non-specific binding (when non-OT compounds bind to ‘OT-specific’ antibodies), leading to artificially elevated concentrations of OT.”
From Salivary oxytocin concentrations in males following intranasal administration of oxytocin: a double-blind, cross-over study (2015) · cites this paper as [7]
Lyophilization has been found to significantly increase the validity of measuring oxytocin via ELISA, so lyophilisation was used instead of the chemical concentration process.
“Lyophilization has also been found to significantly increase the validity of measuring OT via ELISA [7, 21, 22]. Therefore, we used the lyophilisation process instead of the chemical process outlined in the manual.”
From Salivary oxytocin concentrations in males following intranasal administration of oxytocin: a double-blind, cross-over study (2015) · cites this paper as [7]
An increasing number of studies demonstrate the same effects of behavior, social context, and social relationships on both central and peripheral oxytocin measures.
“Furthermore, an increasing number of studies demonstrate the same effects of behavior, social context, and social relationships on both central and peripheral oxytocin measures (35–37).”
From Oxytocin reactivity during intergroup conflict in wild chimpanzees (2017) · cites this paper as [35]
The biological validity of peripheral oxytocin measurements with respect to central oxytocin patterns is debated.
“The biological validity of peripheral oxytocin measurements with respect to central oxytocin patterns nonetheless is debated (33–35).”
From Oxytocin reactivity during intergroup conflict in wild chimpanzees (2017) · cites this paper as [35]
Oxytocin pathways can involve coordinated central and peripheral oxytocin release, indicating that high peripheral measures reflect the release of central oxytocin.
“However, an increasing body of evidence shows that oxytocin pathways can involve coordinated central and peripheral oxytocin release, indicating that high peripheral measures reflect the release of central oxytocin.”
From Oxytocin reactivity during intergroup conflict in wild chimpanzees (2017) · cites this paper as [35]
The interpretation of peripheral oxytocin measurements is hampered by methodological issues and the absence of a strong linear relationship between peripheral and central oxytocin concentrations.
“Of note, the interpretation of peripheral OXT measurements is hampered by methodological issues (76) and the absence of a strong linear relationship between peripheral and central OXT concentrations (77).”
From Dissecting the Role of Oxytocin in the Formation and Loss of Social Relationships (2016) · cites this paper as [76]
Studies examining CSF levels of oxytocin after intranasal administration have shown small CSF increases in animal models at around 40 minutes to 1 hour post-administration.
“Studies that have examined CSF levels of oxytocin after intranasal administration have shown small CSF increases in animal models at around 40 minutes to 1 hour post-administration, 78,79”
From Beyond the hype and hope: critical considerations for intranasal oxytocin research in autism spectrum disorder (2017) · cites this paper as [79]
Non-extracted approaches may not have been appropriate as a methodology.
“Non-extracted approaches may not have been appropriate as a methodology.48, 59”
From Oxytocin efficacy is modulated by dosage and oxytocin receptor genotype in young adults with high-functioning autism: a 24-week randomized clinical trial (2016) · cites this paper as [59]

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Authors: McCullough, M. E., Churchland, P. S., & Mendez, A. J.
Affiliations: University of Miami (US)
University of California San Diego (US)
Corresponding author: Mendez, Armando J.
ORCID: McCullough, Michael E.
Churchland, Patricia Smith
Mendez, Armando J.
Venue: Neuroscience & Biobehavioral Reviews
Publisher: Elsevier BV
Published: 2013-09
Volume: 37
Issue: 8
Pages: 1485-1492
ISSN: 0149-7634 (ISSN-L)
DOI: 10.1016/j.neubiorev.2013.04.018
OpenAlex: W2124961114
Cited by: 416
References: 108
Citations by year: 2026: 17 · 2025: 14 · 2024: 24 · 2023: 17 · 2022: 21 · 2021: 42 · 2020: 32 · 2019: 36 · 2018: 40 · 2017: 46 · 2016: 50 · 2015: 42 · 2014: 26 · 2013: 9
FWCI: 5.61
Type: journal article
Language: en
Open access: green
escholarship.org
Licence: www.elsevier.com/tdm/userlicense/1.0/ (tdm)
Locations: Neuroscience & Biobehavioral Reviews (publishedVersion)
PubMed (publishedVersion)
eScholarship (California Digital Library) (submittedVersion)
Topics: Social Sciences › Psychology › Social Psychology › Neuroendocrine regulation and behavior
Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuropeptides and Animal Physiology
Life Sciences › Neuroscience › Behavioral Neuroscience › Stress Responses and Cortisol
Keywords: oxytocin, assay validation, method reliability, cross-reactivity
MeSH terms: Humans, Immunoenzyme Techniques, Oxytocin, Radioimmunoassay, Reproducibility of Results

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Problems with measuring peripheral oxytocin: can the data on oxytocin and human behavior be trusted?

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