It is theorized in the community that MK-677 can cause brain damage via chronically elevating ghrelin levels in the body.
Does this crossover to human use, and has it been observed to date?
Well, there have in fact been links established between chronic ghrelin exposure and negative mental outcomes.
I did cover this briefly in my original post.
How applicable is this in humans though?
MK-677 Enhances Fear In Rats
One study on rats evaluated if MK-677 can cause enhanced levels of fear.
There is evidence to support that one of the ways ghrelin is modulated is through exposure to stress.
What this study intended to assess specifically was if rats would have a greater likelihood of experiencing fear and posttraumatic stress disorder (PTSD) when their ghrelin levels are artificially raised 24/7 with a ghrelin receptor agonist (MK-677).
Rats were continuously administered MK-677 and frightened constantly, and their difference in response (MK-677 treated vs non treated) was assessed.
The rats with chronic ghrelin elevation were found to have enhanced fear memory compared to baseline [R].
Like I mentioned, there's evidence to support that one of the ways ghrelin is modulated is through exposure to stress, and this study was able to stir up quite a bit of controversy in the community with its results showing a blatantly negative effect on the amygdala where the fear-enhancing effects of repeated ghrelin receptor stimulation seemed to be concentrated in.
Ghrelin and growth hormone act together in the amygdala to enhance fear, at least in this rodent model.
How Does MK-677 Work?
If you don't already know, ghrelin is the hunger hormone.
As you would expect, ghrelin levels are high before meals, and low after finishing meals.
This is how your body regulates its appetite and knows when to eat and when to stop eating.
GHRP’s and GH secretagogues don't just signal GH secretion, some also have a very significant effect on ghrelin.
The most notable being GHRP-6 and MK-677.
These are both notorious as appetite stimulating compounds.
This is why peptides like GHRP-6, GHRP-2, and secretagogues like MK-677 cause such a drastic spike in hunger.
When you use them, you're basically tricking your brain into thinking you're hungry when you otherwise may not be.
Growth hormone is secreted by the somatotrophes of the anterior pituitary gland in multiple pulses each day.
Growth hormone is released into the blood stream and then stimulates the liver to produce insulin-like growth factor-1 (IGF-1), which stimulates linear growth before epiphyseal fusion and also exerts several metabolic effects throughout life.
After ingestion, MK-677 increases somatotrophe secretion of GH via signalling the pituitary gland to secrete a sufficient amount of growth hormone [R, R].
The most common cause of GH deficiency in childhood is believed to be caused by a lack of adequate stimulation of the pituitary gland by hypothalamic GHRH, which is why something like Ibutamoren which can systemically increase IGF-1 levels for 24 hours with a single oral dose is very promising for potential clinical use [R].
The likely mechanism of action following MK-677 administration is the activation of the ghrelin receptor by MK-677, with feedback by IGF-I preventing excess GH production [R].
The mechanism of action through which MK-677 promotes GH secretion is comparable to growth hormone releasing peptides like GHRP-6, GHRP-2, Ipamorelin and Hexarelin, with GHRP-6 being the most similar in regards to the amount of ghrelin secretion that occurs post-administration.
MK-677 does not stimulate a greater quantity of secretion events per day (number of GH pulsations), but rather it stimulates a greater total 24 hour GH production rate [R].
In other words, Ibutamoren can substantially increase the strength of each GH pulsation that occurs in the body.
Was This Study Flawed?
Rats chronically exposed to ghrelin were found to have enhanced fear memory compared to baseline.
There is some confusion around exactly how this test was carried out, and the reality is that the rats weren't getting MK-677 infused into their brains off the bat like many seem to think.
In this study, rats were injected with 1ml/kg (i.p.).
I.P. stands for Intraperitoneal injection, and is the injection of a substance into the peritoneum (body cavity).
The peritoneum is the serous membrane forming the lining of the abdominal cavity.
This is where MK-677 was first administered to evaluate whether increased activation of the ghrelin receptor is sufficient for enhancement of fear memory.
After they established that activation of the ghrelin receptor is indeed sufficient for enhancement of fear memory, they then proceeded to infuse MK-677 directly into the basolateral complex of the amygdala to determine whether repeated ghrelin receptor activation in the basolateral complex of the amygdala is sufficient to enhance fear memory.
Repeated intra-amygdala ghrelin infusions enhanced fear memory [R].
Now, while this all paints a pretty bad picture for MK-677 at a first glance, keep in mind that this study also showed that a single injection of a ghrelin receptor agonist was not sufficient to enhance fear, and even chronic ghrelin receptor agonism did not alter locomotion, innate anxiety, or the expression of previously acquired fear memories [R].
How Applicable Is This In Humans?
In humans, MK-677 has been found to be well tolerated for over a year straight using 25 mg per day orally.
Humans aren't injecting this compound, and they certainly aren't infusing it into their brains either.
This finding has yet to be replicated in human trials, or even in anecdotal logs to date.
With that being said, are they looking for this in the human data?
Probably not, and obviously those using MK-677 recreationally aren't getting brain scans before and after their use.
You probably shouldn't be chronically exposing yourself to ghrelin in the first place for years on end if you can avoid it.
There are auto-regulating mechanisms in your body for a reason.
It would be wise to err on the side of caution and cycle MK-677 if you are going to use it anyways, regardless of what the data may or may not imply.
Even if there was no neurological risk, I would still advise cycling MK-677 if you are going to take it because of its effect on insulin sensitivity, which I think is a more immediate concern than any extrapolated claims about its effects on brain health.
What I'd Be More Concerned With – Insulin Sensitivity
We already know that MK-677 and exogenous GH can negatively impact blood glucose control, and we already know that poor blood glucose control is one of the main issues that cascades into the majority of health problems we see widespread nowadays.
Chronically elevating your blood sugar with MK-677 is going to have a negative impact on your insulin sensitivity to some extent.
Although several clinical studies found no change in blood glucose levels, there were a couple studies where MK-677 caused an elevation of fasted blood glucose levels and decreased insulin sensitivity [R, R].
GH causes blood sugar levels to rise, which in turn requires the pancreas to work harder to compensate and release insulin to bring blood sugar levels back down to homeostasis.
Chronic GH elevation can create chronic pancreatic stress in certain scenarios, which eventually can result in pancreatic beta cell degeneration, and insulin resistance.
Chronic blood glucose elevation and pancreatic cell degeneration is what eventually leads to Type 2 Diabetes.
Individuals with other lifestyle factors that contribute to insulin resistance as is (excessive carbohydrate intake, holding too much body fat, lack of exercise, etc.), or have genetic predispositions that increase their likelihood of Diabetes, could potentially end up pushing themselves over the brink and become Type 2 Diabetic with MK-677 or synthetic growth hormone usage.
MK-677 can also cause reverse hypoglycemia in insulin resistant individuals.
When MK-677 or GH raises blood glucose levels, this is autocorrected and regulated by the pancreas in healthy individuals.
In insulin resistant individuals, MK-677 can cause reactive hypoglycemia, whereby sharp spikes in blood sugar can cause an exaggerated level of insulin secretion and glucose uptake into the cells, consequently crashing blood sugar and causing hypoglycemia [R].
This poor endogenous regulation of blood glucose levels is typically indicative of some degree of insulin resistance in an individual.
Signs and symptoms of reactive hypoglycemia may include hunger, weakness, shakiness, sleepiness, sweating, lightheadedness and anxiety.
I believe that long-term MK-677 use will probably force you to to implement blood sugar control strategies that you wouldn't have needed to otherwise.
If you're a borderline type II diabetic to begin with, and you throw MK into the mix long-term, that could easily push you over the border.
For somebody completely healthy, you could potentially take yourself from completely healthy to like mildly insulin resistant if you deploy MK for years straight without breaks.
Much like the same occurrence if you used a high dose of growth hormone for a long span of time, it would impede your blood glucose control to some degree.
This doesn't mean that you can't use MK-677 or exogenous GH without developing insulin resistance, I'm simply asserting that you will likely have to keep a closer eye on your blood sugar, and may have to start incorporating certain strategies into your lifestyle that you may have not needed to otherwise to remain as healthy as possible while using it.
Getting back to the effect MK-677 has on stress and fear, I don't think it's going to cause any notable mental degradation, and all of the clinical data and anecdotal logs seem to reinforce that.
With that being said, throwing a wrench into your stress feedback loop may have deleterious outcomes that we are simply not evaluating with accurate metrics, and with that in mind, it would be wise to cycle MK-677, especially if it is being used for performance enhancement and not to treat a GH deficiency.
If it is being used therapeutically for GH deficiency, obviously that is a different story.
Monitor Your Glucose Control And Insulin Sensitivity
I think the more immediate concern when it comes to MK-677 is insulin resistance rather than the speculated neurological degradation that doesn't seem to occur with its use in practical application at commonly used dosages in humans.
We do know MK-677 has a notable impact on blood sugar not just in the long-term, but immediately following its first administration.
In addition, the excessive amounts of ghrelin MK-677 causes the body to secrete will cause overeating in many individuals.
The population is fatter than ever, and has already shown that they have horrible self-control when it comes to refraining from overeating.
Add a ghrelin receptor agonist on top of that that literally tricks their brain into thinking that they are even hungrier and you can just imagine what the outcome of that would be for the average guy.
In my opinion, this is the main concern with MK-677, not fear memory enhancement.
If you are going to use MK-677 or exogenous GH, keep a blood sugar monitor on hand and keep a close eye on your fasting blood glucose levels, your blood glucose control post-meals, and incorporate lifestyle, diet, or supplement protocols that will prevent the excessive amounts of ghrelin and spike in GH/IGF-1 from impairing your health status.
MK-677 has a lot of therapeutic promise, and can even enhance a performance enhancing protocol significantly if used correctly.
Knowing how to minimize your risk profile while you use it though is critical and should be well thought out before you haphazardly start taking it without any prior research.