How does intranasal oxytocin change how we perceive the world around us?
New research illuminates the nasal cavity’s role in delivering neuropeptides to the brain
A paper recently came out in Biological Psychiatry provocatively titled, “Intranasal oxytocin: myths and delusions”. In this review, Gareth Leng and Mike Ludwig summarise their skepticism around intranasal oxytocin administration and its ability to influence behavior and cognition.
While I disagree with some of their conclusions, they raise some important points on what’s missing from intranasal oxytocin research, summed up here:
“Effects of intranasal oxytocin need proper dose-response studies, and need to include controls for peripheral effects, by administering oxytocin peripherally…”
Now it’s clear that intranasal oxytocin can influence social cognition and behavior (look at meta-analyses here and here) but it’s not completely understood how it actually does this. We’ve taken some educated guesses in past work but there’s still a lot of work to do.
Current thinking on how intranasal oxytocin exerts its effects
A key assumption of intranasal administration is that it provides direct access to the brain as it bypasses the blood brain barrier, which prevents transport of larger-sized molecules (like oxytocin) circulating in blood from crossing this barrier. When you administer oxytocin intranasally it’s purported to travel to the brain via two sets of nerve fibre pathways, the olfactory and trigeminal, after navigating the narrow nasal valve (see below). Much of this understanding has come from animal work but it’s less clear how this process operates in humans.
The role of peripherally circulating oxytocin is not well understood as it’s uncertain if intranasal oxytocin gets to the brain via these ‘direct’ pathways or indirectly through systemic circulation and across the BBB. This peripheral route is plausible given that some of the earliest work on oxytocin used intravenous administration but curiously no other work has tried looking at these effects, let alone compared intranasal with intravenous administration.
A second assumption relates to the most appropriate dosage of oxytocin to administer. While most studies have used something between 24 and 40 international units (IU), there is little justification for the selection of this dose beyond the precedent of prior work. Sure, 24IU worked ‘last time’, but what if we could get stronger effects with another dose? Dose dependent studies, whereby the response to different dosages are compared, would help clear up which dose is the most effective.
Our new study
In an effort to address these two unsettled assumptions around intranasal oxytocin administration we recently completed a trial that compared different doses of intranasal oxytocin and compared this with peripheral oxytocin and placebo, with the first results just published in Translational Psychiatry.
For this study we recruited 16 young men and administered a single administration of four treatments in a random order over successive weeks; a low dose of intranasal oxytocin (8IU), a higher (but more commonly used dose) intranasally (24IU), intravenous oxytocin (1IU — i’ll get back to why we used this dose soon) and placebo.
We also used a novel intranasal administration device that’s designed to deliver the nasal spray beyond the nasal valve barrier and deeper into the nose to nose-to-brain targets.
After administration, participants completed an emotion perception task, where they had to rate the level of anger or happiness in a set of faces on a scale of 1–5. We chose a task like this as previous work has shown that intranasal oxytocin administration can modulate how people respond to such tasks, namely, people tend to rate negative stimuli as less negative after oxytocin.
Oxytocin reseach is rife with placebo effects (thanks, internet). In fact, a recent study in children with autism found that the strongest predictor of response to intranasal oxytocin was actually the caregiver’s belief of whether oxytocin was administered instead of placebo.
Given the role of placebo effects not only were both participants and study team blind to what treatment was being administrated but we also did what’s known as “double-dummy” administration to blind how the treatment was administered.
This meant for every treatment session participants recieved an intranasal solution as well as an intravenous solution. The contents of these solutions depended on the treatment schedule they happened to be randomised to for that session. This admittedly made things a bit more complicated but it was worth the effort.
The intravenous oxytocin solution (1IU infused over the course of 20 minutes) was chosen as this matched the levels of OT in blood after intranasal administration.
Now this is a really important point — by matching blood levels of intravenous and intranasal oxytocin we can control for potential peripheral effects of oxytocin and also test if oxytocin effects are due to nose-to-brain transport or simply via blood transport across the BBB.
Any observed effects with intranasal oxytocin, but not intravenous, would be consistent with nose-to-brain transport and that peripheral effects of oxytocin have no appreciable effects on social behavrior and cognition.
What we discovered
We did some pilot testing before the trial but you can also see the results for trial below confirming that blood oxytocin levels were equivalent between all three treatment conditions during the social cognitive task 40 minutes after treatment administration.
We also used acoustic rhinometry (think of it like radar for inside your nose) to measure the dimensions of everyone’s nasal cavity at each visit. This was done to first confirm there was no significant nasal congestion but second, we wanted to look at the impact of nasal dimensions on response to oxytocin. We were especially interested in nasal valve dimensions as this is the narrowest section of the nasal cavity and can act as a barrier for drug delivery to the brain.
If intranasal oxytocin worked as we expected, we also wanted to see if the nasal environment plays any role in this response.
In regards to the social cognitive task, we found that the lower intranasal dose reduced the anger ratings of emotionally ambiguous faces compared to both placebo and higher dose intranasal treatment (see left).
Even though intravenous oxytocin produced similar peripheral concentrations after treatment, there was no effect on anger ratings compared to placebo (or any other) treatment.
In what we understand to be a first, we also found that nasal anatomy influenced the response to intranasal oxytocin. Specifically, there was a relationship between nasal valve width and our observed response (see below).
In other words, people with wider the nasal valve dimensions rated faces as the less angry after the low dose intranasal oxytocin treatment. There was no relationship between these ratings and nasal valve dimensions after the other three treatments.
So what does this tell us?
First, we now have evidence that intranasally administered oxytocin reaches the brain via nose-to-brain pathways rather than through systemic transport. This has long been assumed but never experimentally evaluated in humans.
Second, the data also points to the possibility that a lower intranasal oxytocin dose may be more effective than than the more traditionally used dose. There’s some animal research that suggests lower may be better but this is the first experimental comparison in humans.
Finally, it looks like nasal anatomy plays an important part in the response to intranasal oxytocin treatment. Most research that has been done in the past has not considered the impact of the nasal environment so this may help explain response to intranasal oxytocin in future work.
The next step for research is to replicate this finding in people with psychiatric illness. This new form of intranasal administration using lower dose shows promise but data is needed in populations that this treatment will eventually be targeted to.
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