Elsevier

Biological Psychiatry

Volume 79, Issue 3, 1 February 2016, Pages 243-250
Biological Psychiatry

Review
Intranasal Oxytocin: Myths and Delusions

https://doi.org/10.1016/j.biopsych.2015.05.003Get rights and content

Abstract

Despite widespread reports that intranasal application of oxytocin has a variety of behavioral effects, very little of the huge amounts applied intranasally appears to reach the cerebrospinal fluid. However, peripheral concentrations are increased to supraphysiologic levels, with likely effects on diverse targets including the gastrointestinal tract, heart, and reproductive tract. The wish to believe in the effectiveness of intranasal oxytocin appears to be widespread and needs to be guarded against with scepticism and rigor. Preregistering trials, declaring primary and secondary outcomes in advance, specifying the statistical methods to be applied, and making all data openly available should minimize problems of publication bias and questionable post hoc analyses. Effects of intranasal oxytocin also need proper dose-response studies, and such studies need to include control subjects for peripheral effects, by administering oxytocin peripherally and by blocking peripheral actions with antagonists. Reports in the literature of oxytocin measurements include many that have been made with discredited methodology. Claims that peripheral measurements of oxytocin reflect central release are questionable at best.

Section snippets

Oxytocin and The Blood-Brain Barrier

Most of the oxytocin in the body is stored in the posterior pituitary, which, in the adult rat, contains .5–1 µg oxytocin and similar amounts of vasopressin. This gland contains the nerve endings of magnocellular neurons whose cell bodies lie in the hypothalamus, but it lies outside the blood-brain barrier, so peptide released from these endings readily enters the blood. The rat pituitary contains enough vasopressin to maintain the normal plasma concentration of 1 pg/mL for 30 days and a

Oxytocin Penetration of The Brain After Intranasal Administration

Two routes have been proposed for the passage of peptides from nose to brain. The first postulates internalization of peptide into olfactory or trigeminal neurons, followed by axonal transport and exocytosis. There is doubt about whether peptides survive internalization, and Born et al. (17) dismissed this as requiring hours for substances to reach the brain by axonal transport. Oxytocin might pass through intercellular clefts into the subarachnoid space, but transport across the arachnoid

How Much Oxytocin Must Enter The Brain for A Behavioral Effect?

Although intranasal application seems inefficient, doses of oxytocin that have become conventional in human studies all exceed the pituitary content of oxytocin. Given that enormous amounts are given, the tiny rate of penetration might still allow biologically relevant amounts of peptide to enter the brain. If 24 IU oxytocin were delivered as a bolus intravenously, the peak plasma concentration would exceed 1400 pg/mL, which is three orders of magnitude higher than physiologic concentrations.

Peripheral Consequences of Intranasal Oxytocin

Although intranasal applications deliver only modest increases in CSF concentrations, they produce large and prolonged increases in circulating oxytocin to levels far above the levels needed for physiologic effects. Oxytocin receptors are widely distributed in the periphery: Their presence in mammary tissue and uterus is well known, but there are many other sites of expression (30). Intranasal oxytocin was commonly used to augment labor 50 years ago, using doses much lower than used more

Peripheral Targets for Oxytocin

Oxytocin regulates feeding and metabolism at multiple sites (34, 35). Its receptors are expressed throughout the gastrointestinal tract and on gastric vagal nerve endings (36). Intranasal application in dogs increases glucagon and insulin secretion (37), and this is probably mediated peripherally, as intravenous oxytocin has a similar effect in goats (38) and dogs (39). In rats, oxytocin receptors are expressed by glucagon-secreting and insulin-secreting cells in the pancreas (40), and direct

Measuring Oxytocin and Vasopressin

Many studies have drawn conclusions from highly questionable measurements of plasma oxytocin, and others mistakenly claim that plasma measurements reliably reflect oxytocin release in the brain. Validated radioimmunoassays have long converged on the conclusion that basal circulating levels of oxytocin and vasopressin in humans are in the range 1–10 pg/mL, confirmed by combined liquid chromatography/mass spectrometry (57). However, assays of unextracted plasma mainly measure immunoreactivity

Central and Peripheral Release of Oxytocin

The lack of access to central measures of oxytocin led some investigators to turn to peripheral measures of oxytocin in the belief that these are convergent. Central oxytocin derives from at least three separate systems. Some magnocellular neurons project sparsely to some other brain areas, including the amygdala and septum, but it seems likely that most of the central innervations derive from non-neuroendocrine neurons of the paraventricular nucleus (76) that do not project to the pituitary.

Publication Bias

Much of the interest in intranasal oxytocin followed a report that it enhanced trust (96); extravagant data interpretations and unorthodox uses of statistics in some of these studies have been criticized (97), and such defects appear to be widespread. The unreliability of small clinical trials is recognized and attributed to a combination of publication bias, questionable statistical analysis, and methodologic weaknesses, and there are similar concerns about basic biological research (98).

Acknowledgments and Disclosures

This work was supported by the Biotechnology and Biological Sciences Research Council (Grant No. BB/J004723), the Edinburgh Patrick Wild Centre, and the European Union’s Seventh Framework Programme for research, technological development and demonstration (Grant No. 245009; NeuroFAST) and (Grant No. 607310; Nudge-it).

We thank Professor Rainer Landgraf (Munich, Germany) for his helpful comments regarding measuring of oxytocin and vasopressin.

The authors report no biomedical financial interests

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