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MK-677 and potential dementia link?

mk677 ibutamoren mesylate dementia gherlin mimetic

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#1 enharmonics

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Posted 22 January 2017 - 01:54 PM

Hey guys. I use MK677 for sleep/appetite stimulation (I've got pretty bad insomnia and not much of an appetite due to anxiety disorders). It works great and definitely improves sleep onset time (takes less time for me to fall asleep) and quality (I wake up feeling a bit more rested and even dream pretty frequently, a rarity for me). 


I recently came across an old copy-pasted post from a forum called Datbtrue, which was a research forum for peptides that was pretty popular until its owner shut it down, allegedly for health reasons. In the post, Dat mentions a study done on long-acting gherlin mimetics and the effect they may have on receptors in the brain. Post to follow:




-taken from Datbtrue's forum. Posted by Datbtrue

Five years ago I was very much interested in Stress and started a thread -> Stress - temporary notepad. The idea, if I remember correctly was to change the receptor expression in key regions of the body in regard to cortisol- active, cortisol - inactive. By changing the quantity of the enzymes responsible for some of this activity such as 11b-hydroxysteroid dehydrogenase type 1 (11b-HSD1) the idea was that insulin sensitivity could be increased in insulin resistant states... in specific tissues. The idea was that perhaps depression could be alleviated in the brain. The idea was to use this area to positively impact body-shape change, enhance mood, enhance health, etc.

What wasn't consider so much was the question of "what happens if you change the quantity or activity of receptors for extended durations in the brain. ...does this become permanent? Blunting the 11b-HSD1 enzymatic activity sounds great but what if you impair it?

Valsamakis et al. showed that impaired 11b-HSD1 activity in obese adults may help preserve insulin sensitivity and prevent diabetes mellitus. Failure to downregulate 11b-HSD1 activity in patients with diabetes may potentate dyslipidemia, insulin resistance, and obesity. Therefore, inhibition of 11b-HSD1 activity may represent a therapeutic strategy in patients with type 2 diabetes mellitus and obesity. - Valsamakis G, 11b-hydroxysteroid dehydrogenase type 1 activity in lean and obese males with type 2 diabetes mellitus, Journal of Clinical Endocrinology and Metabolism 2004 89 4755–4761.

I saw some good in the Valsamakis study. What I failed to understand is that impairing 11b-HSD1 activity in normal people leads to set-point changes which can become ingrained. These changes can result in receptor activity that may never come back. I paid the price for that failure to understand and through my self-experimention ...

Here's an example of loss of receptor expression in the brain.

Mood Disorders: Clinical Management and Research Issues, Eric J. L. Griez, Wiley; 1 edition (March 18, 2005),
Recent work has shown that corticosteroids regulate the genomic expression and function of a number of monoamine receptors in the brain. For example, it has been shown that corticosteroids can decrease the expression of postsynaptic 5-HT1a receptors in the hippocampus; this finding has led to the suggestion that excessive cortisol secretion may precipitate depressive states through decreasing 5-HT neurotransmission. Experimental studies of animals have also linked excessive cortisol secretion in depression to damage to neurons in the hippocampus. Subsequently it has been suggested that chronic cortisol hypersecretion could be associated with the cognitive impairment which may be a particular feature of chronic depression.

How do we lose GHSR1a (Ghrelin receptor's) in the brain? 

It appears that transient stimulation such as what one would get with GHRPs (GHRP-2, GHRP-6, Ipamorelin, Hexarelin) leads to a rapid desensitization and internalization of the receptors in the brain and this is a good thing. On the other hand administration of long acting Ghrelin-memetic (ibutamoren mesylate (MK-0677) likely leads to a habitual loss receptor status. This is a very bad thing.

Ghrelin mimetics (or agonists) do more that create growth hormone

I'm not sure most people understand that the Ghrelin mimetics do more than create GH. The Growth hormone secretagogue receptor 1a (GHSR1a) is the primary receptor for Ghrelin and the Growth Hormone Releasing Peptides as well as the non-peptide Growth Hormone Secretagogues. There are subtype receptors that both acyl-Ghrelin and the GHRPs bind to that the non-peptide GHS's do not. However the primary receptor is the GHSR1a and it is located on somatotrophs (GH-releasing cells) in the anterior pituitary. Ghrelin or a GHRP or non-peptide GHS bind to these receptors sometimes in concert with Growth Hormone Releasing Hormone (GHRH) and cause growth hormone release.

However GHSR1a are located in all sorts of non-pituitary tissue. When Ghrelin or GHRP-2 or GHRP-6 or Ipamorelin or Hexarelin bind to these receptors in these tissues they generally have positive effects. In some instances they can increase local acting growth hormone in those tissues. Their receptor interaction is transient because peptides break down. They do not over-stimulate receptors on the heart, lung, spleen, muscle or brain.

GHS molecules that do not break down readily cause non-physiological states. They overstimulate and in regard to the brain they create chronic stresses that are potentially neurologically damaging or altering of physiology that can lead to states of unhealth.

Ghrelin in the brain is a stress hormone that acts independent of cortisol. Whether this activity is good or bad depends on how long the GHSR1a is activated

Brain GHSR1a activation is biphasic:

Acute Ghrelin or agonists (GHRP-2, Ipamorelin, GHRP-6, Hexarelin): 
- anti-depressive 
- anti-anxiety 
- protective of stress 
- potentially neurologically protective

Chronic (non-pulsed) Ghrelin agonists (ibutamoren mesylate (MK-0677) : 
- depression producing 
- anxiety producing 
- fear conditionoing producing effects of chronic stress 
- potentially neurologically damaging 

It's important to understand what follows. A tip toe through the literature often reveals the good that Ghrelin produces. However those studies used acute methodologies.

The recent study A ghrelin–growth hormone axis drives stress-induced vulnerability to enhanced fear, RM Meyer, Molecular Psychiatry (2014), 1284 – 1294 distinguishes it's results by using a low dose but longer lasting Ghrelin mimetic (ibutamoren mesylate (MK-0677)) in creating a chronic situation. I will elaborate from the study...
GH is created not only in the pituitary but also in brain regions such as basolateral complex of the amygdala (BLA) . The growth hormone secretagogue receptor 1a (GHSR1a) is found in the BLA. This is the region that regulates emotional states such as fear.

Over-expression of recombinant GH in the BLA does not alter fear acquisition but it does enhance long-term fear memory that is created by chronic Ghrelin.

Chronic Ghrelin or long-lasting agonists such as ibutamoren mesylate (MK-0677) can create the fear/stress response, in the absence of an externally stressful event (in other words the chronic Ghrelin engenders the stressful state) and the presence of GH can amplify it.

Prolonged stress "load" and neuronal dysfunction are correlated. So one would expect chronic Ghrelin to lead to neuronal dysfunction. 

Again it is important to remember that GHRPs do more than increase GH release from GH-releasing cells in the pituitary. They also do so peripherally. By peripherally I mean tissue that generally does not release factors systemically but rather uses what it makes locally within the neighboring tissue (paracrine). That tissue does not need to be all of the same type. For instance bone and muscle sometimes share locally released factors.

Not all GHRPs produce the same peripheral GH. They appear to differ somewhat in their ability to bring about GH locally via GHSR1a (growth hormone secretagogue receptor 1a).

In this RM Meyer study stimulation of the GHSR1a in BLA cells by ibutamoren mesylate (MK-0677) led to significantly elevated release of brain GH. Antagonizing the GHSR1a to prevent it's activation prevents the fear conditioning stress response.

However chronic stimulation of the GHSR1a led to the severe brain stress-enhancing effects.

How would Ghrelin or ibutamoren mesylate (MK-0677 readily crosses the blood–brain barrier and has a half-life of >6h) would be available in the amygdala (BLA): 
"Ghrelin may also be synthesized by small populations of neurons in the hypothalamus, the cerebral cortex and the brainstem, where it may act as a paracrine hormone rather than being secreted into the blood stream. However, immunoreactive ghrelin-containing fibers have never been reported in amygdala. Thus, it seems that the most likely source of bioactive ghrelin affecting fear lies in the periphery, although a role for centrally derived ghrelin cannot be fully eliminated."

Thus higher amounts or long-lasting agonists would likley supply the activation of GHSR1a in the amygdala (BLA). Peptidyl Growth Hormone Releasing Hormone are short lived and would be expected to exert positive effects (as discussed in the follow on sections) and not likely be, if used physiologically, capable of the detrimental effects.

Whereas non-peptidyl longer lived agonists would be expected to exert negative effects and as the RM Meyer study demonstrates are capable of the detrimental effects.

Most of the Discussion from A ghrelin–growth hormone axis drives stress-induced vulnerability to enhanced fear, RM Meyer, Molecular Psychiatry (2014), 1284 – 1294

They found that the
...effects of stress are not simply downstream from glucocorticoids or adrenal catecholamines. We also show that increased ghrelin receptor activity is sufficient and necessary for stress-enhanced fear and is dissociable from HPA activity. Repeated activation of ghrelin receptors in nonstressed animals significantly enhances fear learning without elevating HPA stress hormones, whereas systemic blockade of the ghrelin receptor during chronic stress prevents stress-related enhancement of fear, even in the presence of elevated adrenal stress hormones We demonstrate that the amygdala, a brain region that displays enhanced function in chronically stressed animals and in patients with trauma-related disorders, is likely the locus of the fear enhancing effects of repeated ghrelin receptor stimulation. Finally, we show that GH, a downstream effector of ghrelin receptor activation, is increased in the BLA by chronic stress, is sufficient to enhance fear learning and plays a necessary role in the fear potentiating effects of ghrelin. Thus, ghrelin and growth hormone act together in the amygdala to enhance fear.

Our study is the first to explicitly examine the effects of protracted exposure to elevated ghrelin, as observed following chronic stress. We show that there are profound differences in the behavioral consequences of ghrelin exposure following different exposure durations, similar to the cumulative nature of stress. We also provide the first evidence to link prolonged exposure to elevated ghrelin with a specific, detrimental consequence of stress, enhanced fear memory, which typifies trauma-induced anxiety disorders such as PTSD. Because PTSD is a multifaceted disorder producing many symptoms, including those related to avoidance and hyperarousal, it will be interesting to determine whether chronically elevated ghrelin contributes to these sequelae of PTSD in addition to promoting changes in fear learning and memory.

Our study is also the first to show that GH is a critical downstream mediator of the effects of ghrelin in amygdala. Such a relationship between ghrelin and GH has not been described outside of the pituitary.51 We also provide the first evidence to link elevated amygdala GH with chronic stress and enhanced fear memory. Taken together, our data reveal that the amygdala may be especially sensitive to ghrelin-mediated effects of stress because chronic stress amplifies both ghrelin and GH.

In contrast to our findings that link ghrelin to a pathological condition, prior studies have argued that ghrelin promotes adaptive changes during stress, including antidepressant effects ( Lutter M, The orexigenic hormone ghrelin defends against depressive symptoms of chronic stress. Nat Neurosci 2008; 11: 752–753) and reduction in anxiety.(Spencer SJ, Ghrelin regulates the hypothalamic-pituitary-adrenal axis and restricts anxiety after acute stress. Biol Psychiatry 2012; 72: 457–465) However, these studies are problematic because they either focused exclusively on acute ghrelin manipulations, which we show can have profoundly different effects from repeated ghrelin manipulations or used short- and long-term ghrelin manipulations interchangeably. In addition, the alterations in ghrelin levels were achieved through artificial states: heightened ghrelin levels were attained by extreme food deprivation or a single bolus injection of the short-lived peptide. The antidepressant effect of ghrelin requires extremely high levels of ghrelin, as found in food-restricted rodents after 10–15% weight loss.13 We find that this level of food deprivation leads to increased exploratory motor activity (Supplementary Figure 10; F(1, 13)¼7.51, Po0.05). A recent study has also reported similar motor effects following acute ghrelin manipulations.57 These motor effects can be a significant confound for measures that require locomotor activity, such as social interaction or exploration. Thus, the ghrelin may alleviate the psychomotor effects of depression in a manner similar to amphetamine.58 It is also important to note that the antidepressant effect of ghrelin reported following a single injection of exogenous ghrelin was only a mild improvement of a stressmrelated impairment in social interaction;13 enhanced ghrelin signaling did not promote ‘normal’ function following stress. Indeed, our results reported here are consistent with limited human data showing that patients with treatment-resistant major depressive disorder have higher ghrelin levels than control patients.59

Here we demonstrate changes in endogenous ghrelin following stress and also use a low-dose, long-acting agonist to replicate the naturally occurring ghrelin state. We also provide clear evidence that acute and chronic ghrelin receptor manipulations have profoundly different effects. It is important to note that the changes in fear reported here occurred following small, but persistent, changes in ghrelin signaling, and all were in the absence of any locomotor effects. We suggest that the utility of ghrelin in the stress response may be similar to glucocorticoids: under ‘normal’ conditions, there is an optimal level of the hormone,60 and too little61,62 or too much hormonal signaling16 can lead to dysfunction in neuronal circuits. Repeated activation of ghrelin and glucocorticoid pathways together contributes to stress-induced ‘load’ on the body. In this regard, heightened ghrelin signaling may have both advantageous and undesirable consequences, but these must be carefully considered with respect to the length and level of elevated ghrelin exposure.

It is not clear why acute and repeated ghrelin receptor stimulation have opposite effects on fear learning. Although GHSR1a activation engages excitatory Gq-dependent molecular cascades, GHSR1 also exhibits an extremely high level of constitutive activity in the absence of bound ligand.77 Accordingly, transient stimulation of GHSR1a leads to rapid desensitization and internalization of the receptor that is slow to recover.78 Such a change is consistent with the decreased fear learning we observed 24 h after a single injection of ghrelin receptor agonist. It is also consistent with the observation that transient bath application of ghrelin to lateral amygdala slices leads to decreased excitatory neurotransmission.15 The electrophysiological changes elicited by chronic ghrelin receptor stimulation in amygdala are completely unexplored, but our work suggests that the change must be opposite to that seen after acute ghrelin receptor stimulation. We suggest that the internalization of the ghrelin receptor may habituate63 following either chronic administration of ghrelin receptor agonist or chronic stress exposure. The differences in receptor kinetics following acute versus chronic ghrelin receptor stimulation represent an especially promising area for future research.

Practical notation...

Although the study highlights conditioned fear (term used to describe a cluster of behavioral effects produced when an initially neutral stimulus is paired with an aversive stimulus. A stressfull condition becomes married to the ordinary which in turn evokes a chonic stress response). - The Role of the Amygdala in Fear and Anxiety Annual Review of Neuroscience Vol. 15: 353-375 (Volume publication date March 1992)) it has much wider implications. Those wider implications may not be felt but may increase vulnerability to future disease states.

Pulsed GHRPs or spaced GHRPs give their receptors in the brain time off. Activation of those receptors does not become chronic. This is a good thing especially in the presence of growth hormone. GHRPs or any Ghrelin mimietc such as long-lasting analog have functions independent of growth hormone release. If made available physiologically they can reduce Vascular Stress (reducing insulin resistance) - Ghrelin has novel vascular actions that mimic PI 3-kinase-dependent actions of insulin to stimulate production of NO from endothelial cells, M. Iantorno, American Journal of Physiology, vol. 292, no. 3, pp. E756–E764, 2007; act in muscle repair similiar to muscle IGFs - Ghrelin and Des-Acyl Ghrelin Promote Differentiation and Fusion of C2C12 Skeletal Muscle Cells, Nicoletta Filigheddu, MBoC Vol. 18, Issue 3, 986-994, March 2007; acts as an anti-inflammatory - GH-releasing peptide-2 administration prevents liver inflammatory response in endotoxemia, Miriam Granado, AJP - Endo January 2008 vol. 294 no. 1 E131-E141, exhibit some anti-cancer effects - The antiproliferative effect of synthetic peptidyl GH secretagogues in human CALU-1 lung carcinoma cells, Ghe C, Cassoni P, Catapano F, Marrocco T, Deghenghi R, Ghigo E, Muccioli G, Papotti M, Endocrinology 2002, 143, 484–491

However when allowed to activate their receptors beyond their pulsed nature (aside from situations such as drastic calorie deprivation) Ghrelin-mimetics can bring ill effects that may only manifest themselves many years later as a result of increase stress responses that create degeneration.






Dat later conjectures that there might be a link between the use of a chronic gherlin mimetic like MK677 and dementia:




GHRP long-lasting analogs

Ghrelin is a very interesting compound. Perhaps the least interesting aspect is it's ability to cause the release of and the remaking of GH. One of the areas under study at the moment (mid-2015) is it's role in psychiatric disorders. On the one hand, Ghrelin has proven to exert neuroprotective and memory-enhancing effects. On the other hand it was also shown to play a crucial role in the pathophysiology of addictive disorders, promoting drug reward, enhancing drug seeking behavior and increasing craving in both animals and humans as it alters neurons. 

It's role in depression and anxiety or the long term consequences are not so accurately defined because few studies used long-lasting Ghrelin agonists. It appears that pulsed Ghrelin bound to receptors in certain locations in the brain has beneficial anti-anxiety effects whereas prolonged Ghrelin bound to receptors in certain locations of the brain can have detrimental effects. Studies like the RM Meyer study always make me pay attention... I am personally on guard when I see the potential seeds for dementia or future brain disorders. Perhaps I'm overly cautious. I had a business associate who developed dementia over the course of 15 years and no one ever recognized until it was full blown. He felt fine... although retrospectively there were signs... potentially destructive behavior such as being charged with a felony for chasing a man, who was initially a guest, off his property with a fully loaded gun... 

My worry extends beyond the RM Meyer study into other sorts of potential brain disorders that could come from messing about with the expression or repression of GHS-1a receptors in the brain.

Beyond that I'm not able to say. I have been told that ibutamoren mesylate will not become an approved pharmaceutical in the US or Europe (if anywhere) and that long-lasting analogs of Ghrelin are not being actively studied with the idea of making a drug for human usage. 





If anyone is interested, the relevant (RM Meyer 2014) study is here:


http://www (dot) nature (dot) com/mp/journal/v19/n12/full/mp2013135a (dot) html


Just replace the (dot)s by actual dots (can't post links yet since I'm still new).


MK677 is the one and only thing that's been able to help with my sleep and appetite so this whole thing has me really worried, even though it really doesn't seem like anything more than conjecture (no concrete evidence of any long-term psychiatric disorders caused by MK677 in any of the long-term studies). I don't know. I was hoping maybe some more experienced posters here could help assuage my fears a bit.

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#2 Madman

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Posted 22 January 2017 - 02:59 PM

Very interesting and informative, good post !


Have you tried Ipamorelin as an alternative ? - 500mcg before bed really helps my sleep.

Edited by Madman, 22 January 2017 - 03:01 PM.

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#3 Adamzski

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Posted 07 May 2017 - 01:06 PM

Maybe some slightly human terms? I will read it and digest it later. 


How do you feel about it? Is it making you consider stopping it?


Have ordered some and will do it full time at 15mg before bed with a maybe unneeded loading does of 20mg for a week.


Whats your dose? Along with hopeful gym results I will be taking it for much the same reasons as you better sleep, I use a few beers and a few OTC sleeping pills most nights so this could be healthier. Any water retention for you?

#4 adamh

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Posted 08 May 2017 - 01:13 AM

All I see in the OP is theorizing, possible this possible that and then maybe it encourages dementia. Nice sounding theories and bits of good information but to link it together I see nothing. Where are the studies showing elevated dementia or the studies showing chronic stress resulting from using mk 677 in humans? The mouse studies are not convincing. Mouse studies typically use huge doses and maybe too frequent dosing to see if they can produce negative side effects. Many side effects are dose and frequency dependent.


MK 677 has been used for quite a few years now as has hgh. The results on hgh are mixed, and tend to be troubling. On the contrary we have not seen similar reports on mk 677 probably because it is not exogenous but instead encourages the body to produce more of its own. Until I see studies and reports, not just an anecdote here and there, showing the bad results predicted, then its just another theory. I don't mean that its nothing to watch for and consider but I need evidence rather than conjecture. So far the evidence that has come along does not support the stress and dementia spoken of. In fact it seems to help with sleep, not what you would get if stress levels were elevated.

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#5 sagafemina

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Posted 30 October 2019 - 04:30 PM

You will be unlikely to see any studies on this drug as it is not FDA approved and not particularly expensive, so there is no inducement for further study.  Mouse studies may be all that you will get.  


I wish we COULD have some human studies, of course.  Having said that, I have read that some may be considering its potential usefulness for frailty and cancer cachexia. 


I took this very briefly last year for appetite stimulation, and then developed a very strange case of localized lipoatrophy, that is not otherwise explained.  I DID see a bump in my already somewhat elevated IGF-1, so it does seem to do what it is purported to do.  But I'm shy of it now. 



Also tagged with one or more of these keywords: mk677, ibutamoren mesylate, dementia, gherlin mimetic

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