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Dr Edouard Mills (MBChB Honours, MRCP, MRes Distinction, PhD) is a Clinical Lecturer in Endocrinology in the Section of Endocrinology and Investigative Medicine at Imperial College London.

 He completed a prestigious 3-year MRC-funded Clinical Research Training Fellowship and PhD in 2022 (under the mentorship of Professor Alexander Comninos and Professor Waljit Dhillo), where he conducted the first-into-patient studies of kisspeptin administration in men and women with low sexual desire. As part of a 4-year NIHR-funded Clinical Lectureship, his research continues to investigate the interplay between reproductive hormones and human behaviour. 

Dr. Barrett 01:06 Introduction of Dr. Edouard Mills

Dr. Mills is an endocrinologist and researcher from the section of endocrinology and investigative medicine at the Imperial College of London. Dr. Mills is heavily invested into research about kisspeptin, which is a neuropeptide that is integral in sexual function and arousal. And as a behavioral modifier. Dr. Mills explains his research into how kisspeptin functions and how it's being studied with functional MRI.

Dr. Mills 02:26 Gives us his background

I've always been very much struck by the frequency of psychosexual symptoms, but also how wellbeing problems are often a problem with hormone related conditions. And one of the big issues that we have is that the symptoms are always alleviated when you treat the underlying cause. And so that very much inspired me to do some research looking at the brain pathways that were involved in psychosexual disorders, but then try and develop some new effective treatments for my patients.

Dr. Barrett 03:36 When was Kisspeptin first discovered?

Dr. Mills 03:44 The discovery

It's good question. So, it was probably back in about 1996. Okay, Lee and colleagues first identified the kisspeptin gene. And actually, at that time, they thought this was a anti-cancer gene, rather than a gene to do with reproduction. And the sort of story behind it's quite interesting in that it was first identified at Pennsylvania State University, which we know is near the city of Hershey. Hershey itself is probably better known for its chocolate factory, right? And its most famous product been Hershey's chocolate kisses, right? And so what Lee and colleagues did was they named what they thought was an anti- cancer gene after Hershey chocolate kisses. And really at that point, they had absolutely no idea that be so heavily involved in reproduction and so aptly named with the word kiss.

Dr. Barrett 04:35 My great affinity for Hershey, Pennsylvania

Dr. Mills 05:05 We had no idea about the peptide’s role in reproduction

Dr. Barrett 06:01 Is there a distinct difference in sexes as far as how much kisspeptin is produced?

Dr. Mills 06:12

Yeah, so to an extent, so we know that it's heavily involved in reproduction for both men and women. And the reason being is that it is the hormone which sits at the very top of the reproductive axis. So that's the pathway which controls all of your reproductive hormones.

Dr. Barrett 06:31 What about the HPG?

Dr. Mills 06:35 Explains the HPG axis.

Dr. Barrett  07:00 The HPG sounds to me like it's a very similar access as the HPA axis.

Dr. Mills 7:07

Yes, that's absolutely right. The hypothalamus being the gland, which makes certain stimulatory hormones, which make the pituitary gland then affect the target organ. So the HPA axis because it's affecting your adrenal glands, but the HPG axis because it's affecting the gonads. And so it's a similar sort of mechanism. It's that this is the target organ at the end to the gonads for the reproductive axis.

Dr. Barrett  07:33 Is it the same pathway and the HPG and the HPA Axis except the end destination, or are they distinct pathways all the way through?

Dr. Mills 07:49

They're distinct pathways all the way through in that the hypothalamus will make a hormone called gonadotropin releasing hormone, which is GnRH. That then stimulates your pituitary gland to make two hormones. One is luteinizing hormone and other is follicle stimulating hormone. And that's what controls the gonads. Whereas with the HPA axis, it's a different series of hormones, but it's same anatomical location, just different stimulatory hormones.

Dr. Barrett 08:20 Kisspeptin is endogenously made both in the hypothalamus as well as maybe in the amygdala and certain other organs like the placenta and and these types of things. Is that correct?

Dr. Mills 08:37

Yeah. And that's actually what's very fascinating about the hormone. So originally, when all this evidence came out in 2003, people thought this was purely a reproductive hormone. And that then, over the next sort of decade, we've now realized that it's made in lots of other areas of the brain. So not just the hypothalamus and limbic brain structures which are all important in behavior, and then also in lots of brain areas, or parts of the body outside. So, placenta, testes, ovary liver, so it's given us this understanding that this is not just a reproductive hormone, but it's sort of pleotropic, it's got lots of other functions, not just reproduction. So, bone biology, metabolism, and obviously behavior, which is the bit that I'm most interested in.

Dr. Barrett 09:25 This neuropeptide appears that does it upregulate, dopamine and serotonin, or did I get that wrong?

Dr. Mills 09:43 It has interplay with dopamine, serotonin, GABA, glutamate, and actually these are all very behavioral neuropeptides.

Dr. Barrett 10:07 It's probably inextricably woven together that reproduction is going to be as you point out in these articles, it's going to definitely be affected by mood and other behaviors, obviously.

Dr. Mills 10:36 That's one of the areas that we look at very pure reproduction. And then we've also looked at it in its context of using it to try and treat men and women that have got problems with sexual desire.

Dr. Barrett 11:10 Can Kisspeptin be an adjuvant drug for ED?

Dr. Mills 11:47 Explains the interplay of the neuropeptide

Dr. Mills 12:55 Discusses arousal versus ED

Dr. Barrett 13:35 How does Kisspeptin related to testosterone levels?

Dr. Mills 13:55

So actually, lots of these men and women are often sort of ignored slightly within the healthcare setting, because they go and see their doctor, they've got normal levels of their reproductive hormones, there's told they're told there's nothing wrong with them, and say, That's kind of the end of it. But actually, this is a treatable condition. And we know that that causes a lot of distress for people. So actually, people go around their lives, they've had often lots of relationship breakdowns because of problems with their desire, their partners think that they're not interested in them. Right. And so actually, this is a treatable condition. And I think often it's looked down on within the medical community, but there's, that has often been because there's been no effective treatments. But within the last year, there's been a lot more interest in it, because we've shown for example, with kisspeptin, that there are potentially interventions that these patients can receive.

Dr. Barrett 14:46 Is there a biomarker for Kisspeptin?

Dr. Mills 14:59 Explains how to look for it in the systemic circulation

Dr. Barrett 15:32 What about the CSF to get really what's going on in the brain?

Dr. Mills 15:41 Discusses fMRI

Dr. Barrett 16:05 Is it really just a clinical diagnosis then?

Dr. Mills 16:51

So, it's exactly as you say. So, at the moment, this is what we call a clinical diagnosis, meaning that you can only get the diagnosis from taking a very good history with the patient. And there's certain behavioral questionnaires where the scores give you an idea. But really, the defining feature is someone complaining of low sexual desire is persistent for more than six months. They're very distressed by it. You do lots of investigations, often from blood tests, and they don't have any other hormonal calls. They've got normal reproductive hormones. So really, this is what we call a diagnosis of exclusion. Say there is no there's nothing abnormal in the in the sort of assessment other than the symptoms that they've got some and actually, we don't really do the MRIs in a normal clinical setting. This is all from a research perspective that we're doing it.

Dr. Barrett 17:45 I understand the reluctance of one to do a lumbar puncture on everybody to look at their CSF. But you know, I mean, the research and clinical are two different arenas. But let's let's go into the research just a second, because that's really fascinating to see these functional MRIs and, and how things differentiate. And I think one of your studies, well explain how you do that and how you image it what you're looking for, because I think that's really interesting.

Dr. Mills 18:15

Yeah, so the imaging technique that we use is something called functional MRI. And essentially, what that is, is a type of scan that allows you to look at brain activation patterns. And it relies on fluctuations in blood oxygen levels, when certain areas of the brain are activated or deactivated during a task. C for this particular study, what we did was we administered kisspeptin to participants. But the task that they were doing was that in the MRI scanner, they needed something that was going to trigger their underlying sexual brain activity, right? And say, for the purpose of our studies looking at reproductive behavior, they were actually watching pornographic videos on a screen that was in the MRI scanner. And when they were then given kisspeptin, it gave you an idea of which brain areas kisspeptin was able to stimulate, but also which, which areas kisspeptin was able to deactivate during the context of a sexual stimuli essentially.

Dr. Barrett 19:19

So, you would think the activation is empirical makes a lot of sense that deactivation makes sense. I think if you think about it a little longer, because, you know, you talked about some of the things like fear. Fear is definitely let's call it a buzzkill for lack of the better way, right, of putting it, but there are certain areas of the brain that up that increase their activity, and then what is it maybe a suppression of other things that can be more negative thoughts about it? Exactly.

Dr. Mills 19:54

Yeah. See, so we knew that in this condition hypoactive sexual desire disorder You tend to get an imbalance in brain activity. You tend to get hyperactivity in certain brain areas. So, they're very cortical brain areas that are involved in things like self-monitoring, self-judgment, self-control. And what that does that over activity then suppresses the more emotional limbic brain areas, which are your sexual desire and arousal centers. And so really, what we wanted to see is whether kisspeptin was able to restore that by dampening the areas which are hyperactive, and then stimulating the areas which are your sexual arousal and desire centers. And actually, that's what we were able to show was that you were getting this restoration of brain activity.

Dr. Barrett 20:40

So, it knocks out the negative and accentuates the positive. Yes, absolutely. Interesting. All right. So in one of your articles that I read, you talk about how kisspeptin affects things like audition, or fear, but it's really interesting, because if you think about it, from a neurological standpoint, you have this substance that circulating or not circulating around in your system, and it could make all the difference between your olfactory perception of a person versus when you're when you have a high level of kisspeptin, or when you don't, and you touch on pheromones and where you're talking about this, I think, and I know nothing about pheromones, except, you know, kind of the concept of it. And I know that I think animals are more dialed in because they have superior olfaction systems compared to humans. Olfaction probably is one of the most primitive senses that there is.

Dr. Mills 25:41

we can't really necessarily say that, but what we can say is that it amplified all of the brain areas, which are involved in olfaction, rewards sexual processing…

Dr. Barrett 25:50 we might need to come up with a perfume that has kisspeptin in it.

Dr. Mills 25:55

Well, that would be very interesting.

Dr. Mills 26:32

Mood and emotions are obviously required for optimal reproductive health. See, when your mood is off, when your emotions are off, you're less likely to want to have sexual intercourse. And actually, there's been plenty of animal studies mainly shown in mice, where they showed that kisspeptin can actually have antidepressant effects. And what was very interesting was a study that our group did a number of years ago, where they showed that in healthy men kisspeptin administration was able to reduce negative mood. And that's obviously how antidepressants work. Alright, so what would be a really exciting feature area would be to see where the kisspeptin is positive effects can also be seen in, in people with mood disorders. And certainly there is a real link between mood disorders and reproductive behavior. And they all kind of work together in the same sorts of succession of events, really.

Dr. Barrett 27:28

Dr. Mills, has anybody looked at kisspeptin in the role of pain.

Dr. Mills 27:34

So there's been some work, and we know that there are kisspeptin receptors, so the receptor, what kisspeptin binds to, in some of the nerves in the skin. And so there's been a bit of data on that they've looked at, for example, seeing if it can be used in the context of migraine treatments. But actually, lots of that work is quite at an early stage. And I don't think it's really been pursued that far

Dr. Barrett 28:04

We know for sure that it takes a very short period of time when somebody develops a peripheral nerve injury to affect their neurotransmission. And it's almost impossible in severe pain to have a patient that does not have some component of anxiety or depression. So, if something up regulates mood to a better state, you would think that might have a role. Although it may not be a direct receptor on a nociceptor. But it could be if I elevate this patient's mood, maybe they're able to tolerate this pain just a little bit more.

Dr. Mills 28:43

Potentially, yeah.

Dr. Barrett  28:51 Let's talk about what are the adverse effects of kisspeptin.

Dr. Mills 28:57

So actually, I think what's fascinating is that there are no adverse effects. And the reason being is that it's a naturally occurring hormone. In fact, in our group at Imperial College London, we've probably given it to, in excess of 500 men, women and children now across our different portfolio of studies, and we've never detected the significant effects. And for example, there's no effect on blood pressure on heart rate. And the reason being is that when we administer kisspeptin, we're obviously causing supra physiological levels, right, but levels that we get are still certainly a lot lower than you get in other situations. For example, during pregnancy, the levels of kisspeptin go to about 7000 pico moles per liter, that's very high levels. Okay. The levels that we'd use are 5000. They're still elevated, but there are a lot less than you'd see normal physiology. Say, the fact it's a naturally occurring hormone is is what offers the fact that there are no side effects with kisspeptin There's no safety concerns at all.

Dr. Barrett 30:03 So has this been clinically utilized throughout the UK and throughout the US now for sexual dysfunction as well as helping with infertility?

Dr. Mills 30:16

At the moment, it's very much still in a research setting. So, lots of the work that's happening, particularly in humans is coming out of our group at Imperial. And we're looking at it in terms of Kennett stimulate the reproductive axis, and people with fertility problems, can use it in an IVF setting. But really, it's still very much a research setting. And there's been a bit of work within the last few years looking at whether you can use analogs of these kisspeptin. So, what we administer is the natural hormone, but you can sort of chemically modify it to make its effects last longer. There's been a bit of studies in that situation, but it's not something that you can go to a doctor and have prescribed No, not at the moment.

Dr. Barrett 31:00 And what about the administration? I would have imagined because this is a pretty long chain peptide, you have to either be sub q or IM with it?

Dr. Mills 31:07

At the moment it is parenteral, say intravenous, subcutaneous administration. So, you can't give it orally. And as you say, it's a large peptide. So, it's about 54 amino acids is the is the longest of the peptides. And over the last sort of couple of years, we've got some really exciting data that we've been doing, where we've shown that you don't necessarily just need to give it parentally. So, it doesn't just need to be injectable that we've been shown that you can also give it by into nasal spray. So directly, same way as you'd use a nasal spray for hay fever allergies, ran, we've shown that it can very robustly and increase reproductive hormone secretions that's potentially another avenue, in terms of its development long term that it doesn't just need to be injections, it could also potentially be a nasal spray.

Dr. Barrett 31:59 Are there any studies that are, you know, looking at the interplay between oxytocin and kisspeptin? Because, you know, everybody talks about it, oxytocin being the love molecule, I'm feeling great, let's call it The Empathic hormone for lack of a better way to put it, is there any Interplay directly between oxytocin and kisspeptin.

Dr. Mills 32:21

We think there is, say, a number of years ago, a group in Edinburgh, in the UK did a study and they were looking at the effects of kisspeptin, at the level of the amygdala. And what they were showing in that particular study was that there seemed to be some interplay between oxytocin but also a number of other hormones. So, for example, these are pressing dopamine, so all hormones that are having behavioral effects. But I think in a human setting, it's never been looked at, apart from in one study that we did a number of years ago, where we gave kisspeptin. And we showed that the levels of oxytocin didn't change. And but as I mentioned before, these are often these are peripheral levels that we're checking, but we don't know really what's going on at the level of the brain.

Dr. Barrett 33:08

Were you able to discern some clinical benefits, even though you couldn't see any changes in the, in the blood level?

Dr. Mills 33:14

Oh, yeah. So, in that particular study, but the effects that we saw probably were more direct from kisspeptin, rather than from the oxytocin. Anyway, so we showed that kisspeptin was influencing brain activity. And it was also causing a reduction in sexual aversion. So, these were healthy men. And that's actually what allowed us to catapult this forward and take it forward into this patient group of men with low desire.

Dr. Barrett 33:39

And in that patient group, how long have you followed them up? And did it did it?

Dr. Mills 34:14

We don't really know, the reason being is that the levels are so low in the blood anyway. So, we don't essentially, we don't know the answer to that. And I guess what's interesting, more about the patient cohort that we look at is that these are men that are distressed. So, it's fairly normal as people get older that their sexual desire will change. Often it drops. I guess the defining feature for this patient cohort is that they are distressed by it. And so that's what allows us to make the diagnosis of hypoactive sexual desire disorder rather than just medicalizing the normal phenomenon, which may be happening anyway to certain people.

Dr. Barrett 34:54

This is going to be a wild a wild conjecture, but is there any known antagonists to Kisspeptin?

Dr. Mills 35:04

There is. So, there's a kisspeptin receptor antagonist, which has been used only in animals, say in a rodent setting. And actually, one of the things that people often talk to us about is, could you use that in, for example, people who've got problems with hypersexuality, therefore dumping their kisspeptin system. Now, it's obviously very plausible that that would happen. If you were to give it I guess the problem with that is if you knock off the entire kisspeptin system, then you're effectively chemically castrating somebody. So, you suppress all of their reproductive access, but it's it's plausible that it would also I mean, it would certainly affect their reproductive behavior as well.

Dr. Barrett  35:47

Yeah, I was just thinking for, you know, patients that have sexual addictions or you know, Nymphomaniac or something like that.

Dr. Mills 36:16

The way that we administered kisspeptin, in that particular study was as a 75 minute intravenous infusion. And the reason we gave it as an intravenous infusion is that allowed us to control the kisspeptin levels very well. But it also means that as soon as you stop the kisspeptin infusion that within typically about a couple of hours, the levels go back to completely normal. So, what we were not what we were studying was more what the acute effects were on behavior on brain activity. So, there were there was no long-lasting effects. And that was just because it was given as intravenous infusion. Now, obviously, what we need to be doing in the next steps now is looking what the effects is, if you were to give repeated administration, would you continuously stimulate their sexual desire. But the work that we've done so far has mainly been in an acute, short setting. So, although we were able to increase their sexual desire and arousal, that was only within the study period, chances are within a couple of hours, it had gone back to normal, but future studies now need to look at chronic administration base.

Dr. Barrett  37:22

IV is not a good modality for chronic administration, but obviously, subcutaneous, or IM would be pretty easy for folks to do.

Dr. Mills 37:33

Yeah, and certainly, we can give kisspeptin by subcutaneous injection, and there is a precedence in fact for using subcutaneous injections for sexual desire, but also potentially via this intranasal delivery, which we're developing as well.

Dr. Barrett  38:15 Is kisspeptin available?

Dr. Mills 38:46

It's not a commercially available, and lots of the peptides that you can buy are often labeled not for human use, because they are designed for animal studies, rather than somebody administering it at home. And I guess part of the problem is that lots of the work that's been done has been looking at the acute effects, rather than we don't know what or the long-term effects are now, clearly, it will have long term effects and long term beneficial effects. But there's been no studies looking at what repeated administration does, particularly for sexual desire, say, really, over the next 5 to 10 years that the big interest will be looking at bigger patient groups looking at broader populations, different sexual identities orientations. So, for example, postmenopausal women, these are all things that we need to be looking at. So broader cohorts, essentially, I think is where we're going.

Dr. Barrett 39:46 Is kisspeptin on the endocrinology map now is it on the radar where every endocrinologist is aware of this and they're diving into it, or is there still only the early adopters?

Dr. Mills 39:59

I think is probably still only early adopters. And I guess the reason why the average endocrinologist may not know about kisspeptin is that the, for example, checking the levels is only something that can be done in a research settings. There's only a few labs like our lab at Imperial where we can measure levels for people, right. And so, people are very familiar with, you know, hormones like testosterone, luteinizing, hormone follicle stimulating hormone, all the other reproductive hormones, but they're less aware of kisspeptin. But we hope that over the last 10 years, lots of the work that we've been doing has made people a lot more aware of it. And particularly, as you know, new treatments are developed based. I'm sure it'll become even more parts of the armory of what an endocrinologist is going to be using in prescribing.

Dr. Barrett 40:51

And same thing probably for infertility as well, that's a that's a pretty big market and the medical place.

Dr. Mills 40:58

very much, say. A group a number of years ago did a study where they looked at women that were at high risk of complications from IVF. So, what are the big complications that women can get us and that we call ovarian hyperstimulation syndrome, where you over stimulate the ovaries produces too many eggs. And sometimes that can be detrimental to women. And so, we looked at using kisspeptin as a sort of more natural stimulus of egg maturation, and say, it shows very promising results, particularly in the women that are at high risk of this complication. And so there needs to be now studies looking at it in a bit more detail in terms of IVF settings, but there's lots of promising initial results anyway.

Dr. Barrett 41:44

So, what you're saying there, if I, if I understand it, is that in lieu of what they're traditionally using to increase the egg count, they may just be able to substitute kisspeptin? Or would it be an adjuvant?

Dr. Mills 41:57

It would be probably an adjuvant.

Dr. Barrett 42:07

Interesting. And so which do you think is going to come on the clinical horizon? First, the hypoactive, or the infertility space?

Dr. Mills 42:18

Difficult question, I guess for pharmaceutical companies, which often lots of the original work is done in a university setting. And then it's these big pharma companies, which pick up drugs and show that they often go for the ones which are going to be more lucrative, and I suspect the hypersexuality conditions are going to be the thing that they may go for.

Dr. Barrett 42:44

Interesting. And it's very expensive to get an NDA through and all of that. So, the likelihood is they would pick their most promising market, I would think and go with that, rather than trying to get multiple indications all at once. So, this is fascinating stuff. I mean, I asked a few of my colleagues within the last couple of weeks, since I know that we were going to be talking just off the cuff. Hey, have you ever heard of kisspeptin? It's like, they look like, what are you talking about? You know. So, I think it's really interesting. And I think once this becomes more known, especially within in the endocrinology space, if it's got very little adverse effects, like most natural things to do, I would see that once the knowledge is is conveyed, that there'd be a pretty big, you know, people would pick up this technology and start to implement it more clinically, I don't think there would be a big hurdle with it.

Dr. Mills 43:45

Hmm. No, we completely agree. And we, you know, it's obviously what's fascinating is that it's not just a hormone, which affects reproduction. But it's all these other domains, as well as behavior and metabolism. And there's lots of data coming out about its effects on bone, say, you know, it's, it's a fascinating hormone, and that it affects so many different important things. And if it's a very clean and safe drug, then it's excellent, really,

Dr. Barrett 44:12 Let's talk about bone a second, since you brought it up. I mean that, you know, osteopenia is one of the big, big things, especially for females. How does kisspeptin relate to bone?

Dr. Mills 44:24

So, we've shown over the last couple of years, that the kisspeptin receptor is on a number of different types of bone cells of bone cells that are involved in a building bone. And we did a study a few years ago, where we showed that if you gave kisspeptin to men that have a normal testosterone level, they're young men that can actually increase bone turnover markers that are a sign of bone formation, but also it may also suppress the bone resorption. So, potentially this could also be a treatment for, as you say, low bone mineral density.

Dr. Barrett 45:07

Right. It could even play a role and, you know, Charcot neuroarthropathy, where you have this incredible wasting of the bone. And they're still trying to figure out the physiology of that. But again, I would think that if it plays a role, and maybe obviating osteopenia, that and with its really low side effect profile, that could be a good fit for a lot of people.

Dr. Mills 45:35

I mean, lots of the drugs that we use for osteoporosis have very effective, but they also come with side effects. So, if we're offered a thing, which doesn't have the side effects profile, then that would be very promising.

Dr. Barrett 45:47

Yeah, and one of the things I just recently discovered, and I have to do a little bit more research before I would pontificate on it a lot, is that some of the bisphosphonates actually yeah, they do show an increase in calcium deposition, but they do nothing as far as cortical bone strength or even trabecular bone strength. So, it's like, Alright, we made this bone look better on X ray, but did we do anything for the patient?

Dr. Mills 46:13

Difficult to know, right? We know, lots of these. Lots of drugs, obviously, they're very effective in reducing the fracture rates, which I guess is the endpoint that you're always trying to prevent. When somebody's got osteoporosis is, you know, pharmaceutic, right, hip fractures, vertebral fractures, because these are all right, they cause significant morbidity and mortality to patients say. So the  bisphosphonates in that sense do work very well.

Dr. Barrett 46:39

Right. Well, what else about kisspeptin? Does the audience need to know what do they need to look out for on the horizon? Because I think this is going to become more of a commonplace term, and, and discussions among colleagues in the future.

Dr. Mills 46:56

I guess we've sort of broadened people's horizons, people have always just thought of it as this reproductive hormone, you can use it to stimulate the reproductive axis, you can cause increases in these reproductive hormones, you can use it in, you know, IVF. But I guess the big interest that people really have now is all the behavior stuff. So, it's we've shown in men and women now that it can enhance sexual desire and arousal. And I guess the next bit that potentially people need to be thinking about is, what's its effects on mood. So, as I said earlier, it seems to be causing an antidepressant like effect in rodents in Healthy People. So, I guess the next thing is, is what happens when you use it in people with mood disorders? I guess it's all the behavior thing that I may be slightly biased, because that's my research area. But I think it's the mood, mood and behavior stuff, which is going to really take off.

Dr. Barrett 47:51

No, I think there's a, a bigger marketplace for depression than probably any other condition that I can think of. I mean, it's, it's, this is very, very interesting. And I like the fact that you can intervene without a lot of side effects. That's really that's what I mean, everything we do as physicians, it's risk versus benefit. And how much benefit will they get versus how much risk do they have to take. And if you have something that has a very low profile of a risk, and a high profile of benefit, people can jump on board with that pretty quickly. And yeah, so I agree with that. 100%. But, anyhow, thank you for this wonderful introduction to this, this peptide that really not many people know about, and hopefully we can get more people knowing about it and following your research. So, thanks so much for coming on.

Dr. Mills 48:50

Thank you for inviting me.