Agmatine as an 'Anti-Depressant' Supplement

How Rodent Experiments Influence Perception of Supplements

It seems like a trend on social media, to make claims about some “miraculous supplement” and follow it up with screen shots of the study title and abstract like that paints the whole picture. Yes, it gives us insight into how these compounds work and what effect they may have, but some of the time these studies are only done in rodents (mice and rats). Given that my real life job is to conduct research with mice, I happily acknowledge there is a level of information that we gather that can translate to humans, especially around mechanism of action, but it is translational data and it needs to be acknowledged that just because something works one way in a mouse doesn’t mean it will work that was in humans. Today I am going to cover how studies can be used to influence public perception of supplements and other compounds.

What I specifically want to talk about is how rodent behavior experimental data is used to make claims such as “x supplement has anti-depressant properties”. In particular I want to focus on agmatine, a substance produced endogenously in the body, but also a supplement gaining popularity for its “anti-depressant effect”. I’m not writing this to dismiss this as a supplement because it actually may have merit, and it seems to based on rodent data and anecdotal reports (though no human studies as of now). I’m simply trying to show how behavioral tests are used to make certain claims.

When it comes to studying depression in rodents, there are a few behavioral test that are frequently used. I’ll focus on the tail-suspension test and forced swim test since they were used in the paper I’m going to use as an example and are poplar tests for depression. The paper referenced in the rest of this post is: “Antidepressant-like effect of agmatine and its possible mechanism” (Li et al, 2003) Link to full paper

This is an original study on this molecule, looking at the effects and potential mechanism of action for agmatine. Let’s look specifically at the behavioral results and see why they claim “antidepressant-like effect”.

Tail-Suspension Test

In the tail suspension test, rodents are hung from the ceiling by their tails. Instinctively they will flail about and try to get free, so this test measured 'time spent immobile' or time spent hanging passively as a measure of depression-like behavior. The more time immobile, the more 'depressed' the animal. Therefore if a substance decreases immobility time, it has anti-depressant effects.

Here we have results from the tail suspension test in mice. First column is a normal mouse given nothing, second column are mice given an anti-depressant medication injected into their abdominal region (i.p.), and the last 5 are the mice getting agmatine at varying dosages orally (p.o.).

Notice all of the groups (except the megadose) decrease mobility time compared to the control, and the 80 mg/kg group edging closely to the anti-depressant group. The third and fourth bar in the agmatine group signify an 'anti-depressant effect’ because they show a meaningful enough decrease in time spent immobile.

Forced Swim Test

Similar to the TST, this test measures immobility time, just in a different scenario. Animals are placed in a glass cylinder filled with water. The animal tries to escape with no success, and gives up at times.

"A mouse was recorded immobile when floating motionless or making only those movements necessary to keep its head above water"

Here are the results from this test in mice, same groups only the added difference in methods of administration. Top is orally (p.o.), bottom is subcutaneous injection (s.c.). There are similar results between the two graphs, and the doses of 40mg/kg p.o. and 20 mg/kg s.c. are claimed to have an antidepressant effect. Again, this is becuase they decrease immobility time during this experiment.

Immobility time in these tests is a measure of ‘depression-like behavior’, and since you can’t actually tell if a mouse has depression this is a good as it will get. Tests like these also exist for anxiety (elevated plus maze and open field for example) and it’s a good indication of whether a drug has potential effects in humans for the same use case.

It's also important to note that this study gives the animals these doses of agmatine 3 days in a row before running the test, then runs it 1 hour after the last dosage is given. The antidepressant drug is given once, 1 hour prior to the behavior being ran.

In conclusion, hopefully this gives you a little insight into how research is conducted and analyzed in this context. The reduction in 'depression-like' behavior is translated to "this substance has anti-depressant like effects”. This isn't meant to be a full review of this paper, just a closer look at a small piece of it. I suggest you check out the full study if interested, especially to read through the methods for more info on how these experiments are ran.