Human Oxytocin Research Gets a Drubbing
brain-OT
There’s a new paper out by Gareth Leng and Mike Ludwig1 that bears the coy title “Intranasal Oxytocin: Myths and Delusions” (get the full text here before it disappears behind a pay wall) that you need to know about if you’re interested in research on the links between oxytocin and human behavior (as I am; see my previous blog entries here, here, and here). Allow me to summarize some highlights, peppered with some of my own (I hope not intemperate) inferences. Caution: There be numbers below, and some back-of-the-envelope arithmetic. If you want to avoid all that, just go to the final paragraph where I quote directly from Gareth and Mike’s summary.Fig 1. It's complicated.
In the brain, it’s the hypothalamus that makes OT, but it’s the pituitary that stores and distributes it to the periphery. I think those two facts are pretty commonly known, but here’s a fact I didn’t know: At any given point in time, the human pituitary gland contains about 14 International Units (IU) of OT (which is about 28 micrograms). So when you read that a researcher has administered 18 or 24IU of oxytocin intranasally as part of a behavioral experiment, bear in mind that they have dumped more than an entire pituitary gland’s worth of OT into the body.
To me, that seems like a lot of extra OT to be floating around out there without us knowing completely what its unintended effects might be. Most scientists who conduct behavioral work on OT with humans think and of course hope that this big payload of OT is benign, and to be clear, I know of no evidence that it is not benign. Even so, research on the use of OT for labor augmentation has found that labor can be stimulated with as little as 3.2 IU of intranasal OT during childbirth by virtue of its effects on the uterus. This is saying a lot about OT’s potential to influence the body’s peripheral tissues because that OT has to overcome the very high levels of oxytocinase (the enzyme that breaks up OT) that circulate during pregnancy. It of course bears repeating that behavioral scientists typically use 24 IU to study behavior, and 24 > 3.2.2
Three decades ago, researchers found that rats that received injections of radiolabeled OT showed some uptake of the OT into regions of the brain that did not have much of a blood brain barrier, but in regions of the brain that did have a decent blood brain barrier, the concentrations were 30 times lower. Furthermore, there was no OT penetration deeper into the brain. Other researchers who have injected rats with subcutaneous doses of OT have managed to increase the rats’ plasma concentrations of OT to 500 times their baseline levels, but they found only threefold increases in the CSF levels. On the basis of these results and others, Leng and Ludwig speculate that as little as 0.002% of the peripherally administered OT is finding its way into the central nervous system, and it has not been proven that any of it is capable of reaching deep brain areas.
The fact that very low levels of OT appear to make it into the central nervous system isn’t a problem in and of itself—if that OT reaches behaviorally interesting brain targets in concentrations that are high enough to produce behavioral effects. However, OT receptors in the brain are generally exposed to much higher levels of OT than are receptors in the periphery (where baseline levels generally range from 0 to 10 pg/ml). As a result, OT receptors in the brain need to be exposed to comparatively high amounts of OT to produce behavioral effects—sometimes as much as 5 to 100 nanograms.
Can an intranasal dose of 24 IU deliver 5 – 100 nanograms of OT to behaviorally relevant brain areas? We can do a little arithmetic to arrive at a guess. The 24 IU that researchers use in intranasal administration studies on humans is equivalent to 48 micrograms, or 48,000 nanograms. Let’s assume (given Point 3 above) that only .002 percent of those 48,000 nanograms is going to get into the brain. If that assumption is OK, then we might expect that brain areas with lots of OT receptors could—as an upper limit—end up with no more than 48,000 nanograms * .00002 = .96 (~1) nanogram of OT. But if 5 – 100 nanograms is what’s needed to produce a behavioral effect, then it seems sensible to conclude that even a 24 IU bolus of OT (which, we must remember, is more than a pituitary gland’s worth of OT) administered peripherally is likely too little to produce enough brain activity to produce a behavioral change—assuming that it's even able to get into deep brain regions.
Leng and Ludwig aren't completely closed to the idea that intranasal oxytocin affects behavior via its effects on behaviorally relevant parts of the brain that use oxytocin, but they maintain a cautious stance. I can find no better way to summarize their position clearly than by quoting from their abstract:
The wish to believe in the effectiveness of intranasal oxytocin appears to be widespread, and needs to be guarded against with scepticism and rigor. 1If you don’t know who Gareth Leng and Mike Ludwig are, by the way, and are wondering whether their judgment is backed up by real expertise, by all means have a look at their bona fides.2A little bet-hedging: I think I read somewhere that there is upregulated gene expression for oxytocin receptors late in pregnancy, so this could explain the uterus’s heightened sensitivity to OT toward the end of pregnancy. Thus, it could be that the uterus becomes so sensitive to OT not because 3.2 IU is “a lot of OT” in any absolute sense, but because the uterus is going out of its way to “sense” it. Either way, 3.2 IU is clearly a detectible amount to any tissue that really “wants”* to detect it.
*If you’re having a hard time with my use of agentic language to refer to the uterus, give
a scan.