Elevated cerebrospinal fluid and blood concentrations of oxytocin following its intranasal administration in humans
Open accessAbstract
There has been an unprecedented interest in the modulatory effects of intranasal oxytocin on human social cognition and behaviour, however as yet no study has actually demonstrated that this modality of administration increases concentrations of the peptide in the brain as well as blood in humans. Here using combined blood and cerebrospinal fluid (CSF) sampling in subjects receiving either 24 IU of oxytocin (n = 11) or placebo (n = 4) we have shown that oxytocin levels significantly increased in both plasma and CSF. However, whereas oxytocin plasma concentrations peaked at 15 min after intranasal administration and decreased after 75 min, CSF concentrations took up to 75 min to reach a significant level. Moreover, there was no correlation (r = <0.10) between oxytocin plasma and CSF concentrations. Together, these data provide crucial insights into the plasma and CSF kinetics of intranasally administered oxytocin.
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Only one study has studied the exact pharmacokinetics of intranasal oxytocin; it showed an elevation of CSF oxytocin 75 minutes after intranasal administration.
“only one study [23] has studied its exact pharmacokinetics. This study showed an elevation of CSF OT occurs 75 minutes after intranasal administration (whereas most of the behavioral tasks in the literature take place 45 minutes post-administration).”
From Failed Replication of Oxytocin Effects on Trust: The Envelope Task Case (2015) · cites this paper as [23]
The Results report significantly elevated CSF oxytocin 75 minutes after intranasal administration, and the Discussion describes this as the first study to show increased human CSF concentrations. The broader claim that only one study had examined the exact pharmacokinetics is not supported: the paper cites earlier studies of plasma concentrations and says the precise duration of elevated CSF concentrations remains unknown. (LLM, conf=0.87)
Experimental — accuracy not yet measuredFour studies raised oxytocin concentrations above 20 pg/ml from basal levels below 5 pg/ml; Dal Monte et al. reported a rise to 80 pg/ml after nasal spray but no significant rise with a nebuliser, and Modi et al. reported a 100-fold plasma increase in macaques to more than 300 pg/ml and a rise to about 60 pg/ml after nebuliser application.
“Of the above-mentioned studies, four (20,22,24,25) achieved oxytocin concentrations in excess of 20pg/ml from basal levels of <5pg/ml, while Dal Monte et al. reported a rise to 80pg/ml after nasal spray, but no significant rise with a nebulariser (23).Modi et al. reported a 100-fold increase in plasma in the macaque (to >300pg/ml), and a rise to ~60pg/ml (from 10pg/ml) after nebulariser”
From Intranasal Oxytocin: Myths and Delusions (2016) · cites this paper as [20]
Split into 2 atoms — 0 confirmed, 1 partially supported, 0 disputed, 0 misattributed, 1 unverifiable. Expand the claim to see per-atom verdicts.
Experimental — accuracy not yet measuredA study by Heinrichs and colleagues suggested that oxytocin may have anxiolytic properties in humans.
“As a study by Heinrichs and colleagues suggested that OT may also have anxiolytic proprieties in humans (25)”
From Is there a Publication Bias in Behavioural Intranasal Oxytocin Research on Humans? Opening the File Drawer of One Laboratory (2016) · cites this paper as [25]
The Abstract (page unavailable) discusses potential benefits of intranasal oxytocin for conditions including social anxiety, which is consistent with a tentative anxiolytic effect in humans. But the paper reports changes in cerebrospinal fluid and blood oxytocin concentrations, not anxiety outcomes, and our copy does not identify a Heinrichs-led study making this finding. (LLM, conf=0.76)
Experimental — accuracy not yet measuredIn 11 patients given 24 IU intranasal oxytocin, Striepens et al. observed no CSF increase at 45 or 60 minutes, although three patients sampled at 75 minutes had CSF oxytocin 64% above controls.
“Striepens et al. (20) measured CSF oxytocin in 11 patients given 24IU oxytocin intranasally.Whereas Born et al. saw an increase after 10min (albeit with vasopressin, at a larger dose) (17), Striepens et al. saw no increase at 45 or 60min.However, three patients sampled at 75min had CSF levels 64% higher than controls (at ~30pg/ml).”
From Intranasal Oxytocin: Myths and Delusions (2016) · cites this paper as [20]
Recent findings have demonstrated that intranasal oxytocin increases oxytocin concentration in cerebrospinal fluid in both humans and animals.
“Recent findings have demonstrated that IN-OT increases OT concentration in CSF in both human (25) and animal (38,39).”
From Is there a Publication Bias in Behavioural Intranasal Oxytocin Research on Humans? Opening the File Drawer of One Laboratory (2016) · cites this paper as [25]
The only study to date found that intranasal oxytocin does not yield elevated cerebrospinal fluid oxytocin levels 45 minutes after administration.
“the only study conducted to date (with a very small sample size) found that IN-OT does not yield elevated cerebrospinal fluid (CSF) OT levels 45 minutes after administration”
From Is there a Publication Bias in Behavioural Intranasal Oxytocin Research on Humans? Opening the File Drawer of One Laboratory (2016) · cites this paper as [25]
Intranasal oxytocin pharmacokinetics are not fully understood.
“IN-OT pharmacokinetics are not fully understood”
From Is there a Publication Bias in Behavioural Intranasal Oxytocin Research on Humans? Opening the File Drawer of One Laboratory (2016) · cites this paper as [25]
It is doubtful how far intranasal oxytocin crosses the blood-brain barrier.
“doubt has been cast on the extent to which intranasal OXT crosses the blood-brain barrier (Neumann et al., 2013;Paloyelis et al., 2014;Striepens et al., 2013).”
From Oxytocin increases attention to the eyes and selectively enhances self-reported affective empathy for fear (2017) · cites this paper as Striepens et al., 2013
The intranasal dose administered in the present study has been associated with changes in central function in humans, and similar or smaller doses of oxytocin or vasopressin have been associated with elevations in peptide levels in the cerebrospinal fluid in humans or macaques of no more than approximately 55 pg/ml or up to 0.005% of the administered dose.
“The intranasal dose administered in the present study has been associated with changes in central function in humans 58, and similar or smaller doses of oxytocin or vasopressin (24–48 IU for oxytocin; 40–80 IU for vasopressin) have been associated with elevations in peptide levels in the cerebrospinnal fluid in humans or macaques of no more than approximately 55 pg/ml in actual levels 70, 71, 72,”
From The Analgesic Effect of Oxytocin in Humans: A Double‐Blind, Placebo‐Controlled Cross‐Over Study Using Laser‐Evoked Potentials (2016) · cites this paper as [71]
Plasma oxytocin is significantly elevated 15 minutes after intranasal oxytocin administration.
“A recent study [15] investigating the relationship between IN-OT and its impact on OT concentrations in plasma and cerebrospinal fluid found that plasma OT was significantly elevated 15 minutes post-administration.”
From Salivary oxytocin concentrations in males following intranasal administration of oxytocin: a double-blind, cross-over study (2015) · cites this paper as [15]
Intranasal delivery of synthetic oxytocin causes an increase in cerebrospinal fluid levels of oxytocin.
“OXT IN causes an increase in CSF levels of OXT (45), although we note that the exact transnasal route the peptide takes to reach the brain is still unclear and even a peripheral feedback mechanism enhancing endogenous release cannot be excluded.”
From Dissecting the Role of Oxytocin in the Formation and Loss of Social Relationships (2016) · cites this paper as [45]
Intranasal administration of oxytocin increases oxytocin concentration in the cerebrospinal fluid.
“The intranasal administration of OXT has been shown to increase OXT concentration in the CSF (Striepens et al, 2013).”
From An oxytocin-induced facilitation of neural and emotional responses to social touch correlates inversely with autism traits (2014) · cites this paper as Striepens et al, 2013
Intranasal oxytocin at 24 IU enhances oxytocin concentration in cerebrospinal fluid by 60 percent 75 minutes after intake.
“Not only does IN-AVP increase AVP CSF levels, IN-OT (24 IU) also enhances OT concentration in the CSF (60% increase) 75 min after intake (Striepens et al. 2013).”
From A precision medicine approach to oxytocin trials (2017) · cites this paper as Striepens et al. 2013
Levels of oxytocin in the periphery are lower than those in the CSF in humans, providing a concentration gradient for transport.
“Levels of oxytocin in the periphery are lower than those in the CSF, in humans16,61,62, providing a concentration gradient for what appears to be a transport mechanism: this point of view depends on the methods of oxytocin measurements in blood, because a recent report has shown much higher blood OT levels than previously thought using a robust nanoLC-MS platform63.”
From Vascular RAGE transports oxytocin into the brain to elicit its maternal bonding behaviour in mice (2019) · cites this paper as [16]
The acute effects of intranasal oxytocin persist until 60-80 min post-administration.
“The acute effects of intranasal oxytocin are reported to persist until 60–80 min post-administration.33, 34”
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 [34]
Single-dose intranasal administration of 24 IU oxytocin increases the cerebrospinal fluid oxytocin level 1.5-fold in volunteers without ASD.
“a recent study showed that single-dose intranasal administration of 24 IU oxytocin increases the cerebrospinal fluid oxytocin level 1.5-fold in volunteers without ASD.34”
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 [34]
Only a small amount of intranasally administered oxytocin reaches the brain.
“It is estimated that only a small amount of intranasally administered oxytocin reaches the brain.33, 34, 46, 47”
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 [34]
The exact transnasal-CNS route remains unknown, and the proportion of OXT that actually reaches the CNS is exceptionally small relative to the given dose.
“the exact transnasal-CNS route remains unknown, and the proportion of OXT that actually reaches the CNS is exceptionally small relative to the given dose (Born et al., 2002; Chang et al., 2012; Striepens et al., 2013; Dal Monte et al., 2014; Modi et al., 2014).”
From Marmosets treated with oxytocin are more socially attractive to their long-term mate (2015) · cites this paper as Striepens et al., 2013
Intranasal administration rapidly upregulates OT levels in the brain and plasma during the timeframe of behavioral testing, and OT clears the system several hours after testing.
“These results suggest that intranasal administration rapidly upregulates OT levels in the brain and plasma during the timeframe of behavioral testing, and that OT clears the system several hours after testing.”
From Oxytocin facilitates fidelity in well-established marmoset pairs by reducing sociosexual behavior toward opposite-sex strangers (2014) · cites this paper as Striepens et al., 2013
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“A recent study [15] investigating the relationship between IN-OT and its impact on OT concentrations in plasma and cerebrospinal fluid found that plasma OT was significantly elevated 15 minutes post-administration.”
BackgroundAlvares, G. A., Quintana, D. S., & Whitehouse, A. J. O. (2017) · Autism Research · doi:10.1002/aur.1692 · Cited by 91 · see citing works
Kuypers, K. P. C., de la Torre, R., Farre, M., Yubero-Lahoz, S., Dziobek, I., Van den Bos, W., & Ramaekers, J. G. (2014) · PLoS ONE · doi:10.1371/journal.pone.0100719 · Cited by 88 · see citing works
Mitchell, J. M., Arcuni, P. A., Weinstein, D., & Woolley, J. D. (2016) · Journal of Addiction Medicine · doi:10.1097/adm.0000000000000213 · Cited by 82 · see citing works
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Inhaled oxytocin increases positive social behaviors in newborn macaques
Simpson, E. A., Sclafani, V., Paukner, A., Hamel, A. F., Novak, M. A., Meyer, J. S., Suomi, S. J., & Ferrari, P. F. (2014) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1402471111 · Cited by 82 · see citing works
Chen, X., Hackett, P. D., DeMarco, A. C., Feng, C., Stair, S., Haroon, E., Ditzen, B., Pagnoni, G., & Rilling, J. K. (2016) · Brain Imaging and Behavior · doi:10.1007/s11682-015-9411-7 · Cited by 81 · see citing works
Kruppa, J. A., Gossen, A., Oberwelland Weiß, E., Kohls, G., Großheinrich, N., Cholemkery, H., Freitag, C. M., Karges, W., Wölfle, E., Sinzig, J., et al. (2019) · Neuropsychopharmacology · doi:10.1038/s41386-018-0258-7 · Cited by 69 · see citing works
Antisocial oxytocin: Complex effects on social behavior
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Oxytocin makes females, but not males, less forgiving following betrayal of trust
Yao, S., Zhao, W., Cheng, R., Geng, Y., Luo, L., & Kendrick, K. M. (2014) · The International Journal of Neuropsychopharmacology · doi:10.1017/s146114571400090x · Cited by 74 · see citing works
Self-citationOxytocin and vasopressin: signalling, behavioural modulation and potential therapeutic effects
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Oxytocin modulates behavioral and physiological responses to a stressor in marmoset monkeys
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Failed Replication of Oxytocin Effects on Trust: The Envelope Task Case
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“Especially as, although intranasal OT is likely to cross the bloodbrain barrier, only one study [23] has studied its exact pharmacokinetics.”
BackgroundThe neuropeptide oxytocin induces a social altruism bias
Marsh, N., Scheele, D., Gerhardt, H., Strang, S., Enax, L., Weber, B., Maier, W., & Hurlemann, R. (2015) · The Journal of Neuroscience · doi:10.1523/jneurosci.3199-15.2015 · Cited by 59 · see citing works
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Do marmosets care to share? Oxytocin treatment reduces prosocial behavior toward strangers
Mustoe, A. C., Cavanaugh, J., Harnisch, A. M., Thompson, B. E., & French, J. A. (2015) · Hormones and Behavior · doi:10.1016/j.yhbeh.2015.04.015 · Cited by 59 · see citing works
Greene, R. K., Spanos, M., Alderman, C., Walsh, E., Bizzell, J., Mosner, M. G., Kinard, J. L., Stuber, G. D., Chandrasekhar, T., Politte, L. C., et al. (2018) · Journal of Neurodevelopmental Disorders · doi:10.1186/s11689-018-9228-y · Cited by 55 · see citing works
Sniff and mimic–Intranasal oxytocin increases facial mimicry in a sample of men
Korb, S., Malsert, J., Strathearn, L., Vuilleumier, P., & Niedenthal, P. (2016) · Hormones and Behavior · doi:10.1016/j.yhbeh.2016.06.003 · Cited by 54 · see citing works
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A precision medicine approach to oxytocin trials
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Self-citationMarmosets treated with oxytocin are more socially attractive to their long-term mate
Cavanaugh, J., Huffman, M. C., Harnisch, A. M., & French, J. A. (2015) · Frontiers in Behavioral Neuroscience · doi:10.3389/fnbeh.2015.00251 · Cited by 36 · see citing works
The Potential of Nasal Oxytocin Administration for Remediation of Autism Spectrum Disorders
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Oxytocin reduces food sharing in capuchin monkeys by modulating social distance
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Bridging the gap between rodents and humans: The role of non‐human primates in oxytocin research
Putnam, P. T., Young, L. J., & Gothard, K. M. (2018) · American Journal of Primatology · doi:10.1002/ajp.22756 · Cited by 28 · see citing works
“Taken together with similar results from studies performed in humans (Gossen et al., 2012; Striepens et al., 2013), these results clearly suggest that OT enters the CSF of primates and elevates OT levels in the brain when peripherally administered at appropriate doses.”
ResultNeural effects of oxytocin and mimicry in frontotemporal dementia: A randomized crossover study
Oliver, L. D., Stewart, C., Coleman, K., Kryklywy, J. H., Bartha, R., Mitchell, D. G. V., & Finger, E. C. (2020) · Neurology · doi:10.1212/wnl.0000000000010933 · Cited by 26 · see citing works
Intranasal oxytocin enhances socially-reinforced learning in rhesus monkeys
Parr, L. A. (2014) · Frontiers in Behavioral Neuroscience · doi:10.3389/fnbeh.2014.00278 · Cited by 23 · see citing works
Effects of chronic oxytocin on attention to dynamic facial expressions in infant macaques
Parr, L. A., Brooks, J. M., Jonesteller, T., Moss, S., Jordano, J. O., & Heitz, T. R. (2016) · Psychoneuroendocrinology · doi:10.1016/j.psyneuen.2016.08.028 · Cited by 23 · see citing works
Plasma pharmacokinetics of intravenous and intranasal oxytocin in nonpregnant adults
Shafer, S. L., Ririe, D. G., Miller, S., Curry, R. S., Hsu, D. T., Sullivan, G. M., & Eisenach, J. C. (2025) · British Journal of Anaesthesia · doi:10.1016/j.bja.2024.12.046 · Cited by 5 · see citing works
Sippel, L. M., Wachsman, T. R., Kelley, M. E., Knopp, K. C., Khalifian, C. E., Maglione, J. E., Glynn, S. M., Macdonald, A., Monson, C. M., Flanagan, J. C., et al. (2024) · Contemporary Clinical Trials · doi:10.1016/j.cct.2024.107534 · Cited by 3 · see citing works
- Authors
- Striepens, N., Kendrick, K. M., Hanking, V., Landgraf, R., Wüllner, U., Maier, W., & Hurlemann, R.
- Affiliations
- University of Bonn (DE)
- University of Electronic Science and Technology of China (CN)
- Max Planck Institute of Psychiatry (DE)
- Corresponding author
- Hurlemann, René
- Venue
- Scientific Reports
- Published
- 2013-12-06
- Volume
- 3
- Issue
- 1
- Pages
- 3440-3440
- ISSN
- 2045-2322 (ISSN-L)
- PMC
- PMC3853684
- OpenAlex
- W2115046242
- Cited by
- 452
- References
- 28
- Citations by year
- 2026: 8 · 2025: 13 · 2024: 20 · 2023: 21 · 2022: 24 · 2021: 42 · 2020: 42 · 2019: 47 · 2018: 50 · 2017: 58 · 2016: 53 · 2015: 37 · 2014: 34
- FWCI
- 61.86
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- Scientific Reports (publishedVersion, cc-by-nc-nd)
- Europe PMC (PubMed Central) (publishedVersion, cc-by-nc-nd)
- PubMed Central (publishedVersion, cc-by-nc-nd)
- PubMed (publishedVersion)
- Max Planck Digital Library (submittedVersion, other-oa)
- DZNE Pub (submittedVersion, other-oa)
- MPG.PuRe (Max Planck Society) (submittedVersion, other-oa)
- Funders
- National Natural Science Foundation of China (91132720)
- Rheinische Friedrich-Wilhelms-Universität Bonn
- Topics
- Social Sciences › Psychology › Social Psychology › Neuroendocrine regulation and behavior
- Life Sciences › Neuroscience › Sensory Systems › Olfactory and Sensory Function Studies
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuropeptides and Animal Physiology
- Keywords
- oxytocin, intranasal administration, cerebrospinal fluid, plasma concentration, social cognition
- MeSH terms
- Administration, Intranasal, Adult, Humans, Male, Middle Aged, Neuropsychological Tests, Oxytocin, Radioimmunoassay, Time Factors, Drug Monitoring, Young Adult, Healthy Volunteers
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