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Osie
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I believe this was the original peptide guide that Derek discovered the effectiveness of combining CJC-1295 and MK677. Despite the thread being made in 2009, it’s way ahead of its time and provides answers to many of the questions of this forum. Most of this thread will be copy and paste of the information that I’ll believe you guys will find the most important.
THIS IS A HIGHLY SUMMARIZED VERSION AS I KNOW YOU PEEPS HATE READING. I REALLY RECOMMEND READING THE WHOLE THING THOUGH.
A brief summary of dosing and administration (GHRP, GHRH)
Dosing GHRPs
The saturation dose in most studies on the GHRPs (GHRP-6, GHRP-2, Ipamorelin & Hexarelin) is defined as either 100mcg or 1mcg/kg. What that means is that 100mcg will saturate the receptors fully, but if you add another 100mcg to that dose only 50% of that portion will be effective. If you add an additional 100mcg to that dose only about 25% will be effective. Perhaps a final 100mcg might add a little something to the GH release but that is it.
So 100mcg is the saturation dose and you could add more up to 300 to 400mcg and get a little more effect.
A 500mcg dose will not be more effective than a 400mcg, perhaps not even more effective than 300mcg.
The additional problems are desensitization & cortisol/prolactin side effects:
Ipamorelin is about as efficacious as GHRP-6 in causing GH release but even at higher doses (above 100mcg) it does not create prolactin or cortisol.
GHRP-6 at the saturation dose of 100mcg does not really increase prolactin & cortisol but may do so slightly at higher doses. This rise is still within the normal
range.
GHRP-2 is a little more efficacious than GHRP-6 at causing GH release but at the saturation dose or higher may produce a slight to moderate increase in prolactin & cortisol. This rise is still within the normal range although doses of 200 - 400mcg might make it the high end of the normal range.
Hexarelin is the most efficacious of all of the GHRPs at causing an increase in GH release. However, it has the highest potential to also increase cortisol & prolactin. This rise will occur even at the 100mcg saturation dose. This rise will reach higher levels of what is defined as normal.
Desensitization
GHRP-6 can be used at saturation dose (100mcg) three or four times a day without risk of desensitization.
GHRP-2 probably at saturation dose several times a day will not result in desensitization.
Hexarelin has been shown to bring about desensitization but in a long-term study, the pituitary recovered its sensitivity so that there was no long-term loss of sensitivity at saturation dose. However, dosing Hexarelin even at 100mcg three times a day will likely lead to some down-regulation within 14 days.
If desensitization were to ever occur for any of these GHRPs simply stopping use for several days will remedy this effect. Chronic use of GHRP-6 at 100mcg dosed several times a day every day will not cause pituitary problems, significant prolactin or cortisol problems, nor desensitization.
GHRH
Now Sermorelin, GHRH (1-44), and GRF(1-29) all are basically GHRH and have a short half-life in the plasma because of quick cleavage between the 2nd & 3rd amino acids. This is no worry naturally because this hormone is secreted from the hypothalamus and travels a short distance to the underlying anterior pituitary and is not really subject to enzymatic cleavage. The release from the hypothalamus and binding to somatotrophs (pituitary cells) happens quickly. However when injected into the body it must circulate before finding its way to the pituitary and so within 3 minutes, it is already being degraded.
That is why GHRH in the above forms must be dosed high to get an effect.
GHRH analogs (CJC-1295)
All GHRH analogs swap Alanine at the 2nd position for D-Alanine which makes the peptide resistant to quick cleavage at that position. This means analogs will be more effective when injected at smaller dosing.
The analog tetra or 4 substituted GRF(1-29) sometimes called CJC w/o the DAC or referred to by me as modified GRF(1-29) has other amino acid modifications. They are glutamine (Gln or Q) at the 8-position, alanine (Ala or A) at the 15-position and leucine (Leu or L) at the 27-position.
For use in vivo, in humans, the GHRH analog known as CJC w/o the DAC or tetra (4) substituted GRF(1-29) or modified GRF(1-29) is a very effective peptide with a half-life of probably 30+ minutes. That is long enough to be completely effective. The saturation dose is also defined as 100mcg.
Problem w/ Using any GHRH alone
The problem with using a GHRH even the stronger analogs is that they are only highly effective when somatostatin is low (the GH-inhibiting hormone). So if you unluckily administer in a trough (or when a GH pulse is not naturally occurring) you will add very little GH release. If however you luckily administer during a rising wave or GH pulse (somatostatin will not be active at this point) you will add to GH release.
Solution is GHRP + GHRH analog (CJC + GHRP6 OR GHRP2)
The solution is simple and highly effective. You administer a GHRH analog with a GHRP. The GHRP creates a pulse of GH. It does this through several mechanisms. One mechanism is the reduction of somatostatin release from the hypothalamus, another is a reduction of somatostatin influence at the pituitary, still, another is increased release of GHRH from the brain and finally GHRPs act on the same pituitary cells (somatotrophs) as do GHRHs but use a different mechanism to increase cAMP formation which will further cause GH release from somatotroph stores.
GHRH also has a way of reciprocally reinforcing GHRPs' actions.
The result is a synergistic GH release. The GH is not additive it is synergistic. By that I mean:
If GHRH by itself will cause a GH release valued at 2
and GHRP itself will cause a GH release valued at 5
Together the GH is not 7 (5+2) it turns out to say 16!
A solid protocol
A solid protocol would be to use a GHRP + a GHRH analog pre-bed (to support the night-time pulse) once or twice throughout the day. For anti-aging, deep restful restorative sleep, the once-at-night dosing is all you need. For an adult aged 40+, it is enough to restore GH to youthful levels.
However, for bodybuilding or fat loss, or injury repair multiple dosings can be effective:
The GHRH analog can be used at 100mcg and as high as you want without problems.
The GHRP-6 can always be used at 100mcg w/o problems but a dose of 200mcg will probably be fine as well.
Again desensitization is something to keep an eye on particularly with the highest doses of GHRP-2 and all doses of Hexarelin.
So 100 - 200mcg of GHRP-6 + 100 - 500mcg+ of a GHRH analog taken together will be effective.
This may be dosed several times a day to be highly effective.
A solid approach is a bit more conservative at 100mcg of GHRP-6 + 100mcg of a GHRH analog dosed either once, twice, three or four times a day.
When dosing multiple times a day at least 3 hours should separate the administrations.
The difference is that a once-a-day dosing pre-bed will give a youthful restorative amount of GH while multiple dosing and or higher levels will give higher GH & IGF-1 levels when coupled with diet & exercise will lead to muscle gain & fat loss.
Dose w/o food
The administration should ideally be done on either an empty stomach or with only protein in the stomach. Fats & carbs blunt GH release. Administer the peptides and wait about 20 minutes (no more than 30 but no less than 15 minutes) to eat. At that point, the GH pulse has about hit the peak and you can eat what you want.
How does CJC-1295 work?
CJC-1295 "decays" at about 10% every 24 hours so you will get a build-up of levels:
______Dose #1_(200mcg)
Day 0 - 100% (.2mg)
Day 1 - 90% (.18mg remaining)
Day 2 - 81% (.16mg remaining)
Day 3 - 73% (.14mg remaining)
Day 4 - 65% (.12mg remaining)
Day 5 - 59% (.1mg remaining)
Day 6 - 53% (.09mg remaining)
Day 7 - 47% (.08mg remaining)
Day 8 - 43% (.06mg remaining)
So by day 5 your CJC-1295 level will be (.2 + .18 + .16 + .14 + .12) = 800mcgs
The following no-dose 6th day will result in (0 + .18 + .16 + .14 + .12 + .1) = 700mcgs
The following no dose 7th day will result in (0 + 0 + .16 + .14 + .12 + .1 + .09) = 610mcg
Then you will start dosing again on the 8th day which will result in (.2 + .14 +.12 +.1 + .09 +.08) = 730mcgs
The level will build all week and by the following 2 days off the levels will be a little higher than the first couple of no-dose days.
In addition to pulsation, overall growth is better accomplished when total levels of GH are elevated without hindering pulsation. Elevated GH levels appear to be a necessary component of growth generation as well. One of the reasons for this so appears to be that chronically elevated GH levels result in more pronounced sustained levels of IGF-1 than that achieved through intermittent GH elevations. Persistent levels of GHRH do not result in desensitization. Elevated levels of GHRH result in sustained GH release.
Combined administration of CJC-1295 and GHRP-6 is a very effective, well-studied method of increasing the total amount of GH secreted within the body. By adjusting the dosing of these compounds and accounting for such factors as age one may choose to achieve a "youthful" restoration, an above-normal elevation, or a substantially above-normal elevation of both GH levels and pulsatile release.
I'm not a big fan of ac-inhibitors. I just answered this in a message though so I'll repost it here. Just keep in mind that you don't want to "kill" Somatostatin. It plays a significant role in creating important pulsation and helps provide breaks from constant GHRH stimulation which is a good thing.
The Growth Hormone Releasing Peptides have several modes of action which all contribute to growth hormone release. One of their modes of action is that they INDIRECTLY increase GH secretion by reducing the release of somatostatin (the GH-inhibiting hormone) from the hypothalamus and DIRECTLY by reducing the magnitude of somatostatin's inhibiting action once it binds to the pituitary cells.
So I'm not sure if using cholinesterase inhibitors along with GHRPs would add anything. The GHRPs of course affect the release directly via the GHS-Receptor and indirectly by inducing GHRH at the hypothalamus so GHRPs are more beneficial. Now young people (let's say below 30) don't seem to benefit as much from inhibiting somatostatin & its mode of action as older people. As we age the signaling becomes less favorable to GH release.
From the studies:
GHRH + cholinesterase inhibitor = GH release
GHRH + GHRP = larger GH release
GHRH + GHRP + cholinesterase inhibitors = even greater GH release.
Evidence:
Intranasal administration of neostigmine potentiates both intravenous and intranasal growth hormone (GH)-releasing hormone-induced GH release in short children
E Ghigo, M Procopio, J Bellone, E Mazza, M Mucci, MF Boghen, EE Muller and F Camanni
Administration of cholinergic agonists increases both basal and GH-releasing hormone (GHRH)-induced GH secretion, probably acting via inhibition of endogenous somatostatin release.
The aim of our study was to verify in two groups of children with idiopathic short stature the effect of intranasal administration of neostigmine (inNS; 3 mg), a cholinesterase inhibitor, on basal GH levels as well as on the somatotroph response to GHRH when the peptide was administered either iv (ivGHRH; 1 microgram/kg) or intranasally (inGHRH; 10 micrograms/kg).
In group A (n = 6; age, 10.6-16.0 yr) inNS induced a significant GH increase [inNS vs. saline, area under the curve (AUC; mean +/- SEM), 263.7 +/- 60.2 vs. 73.8 +/- 3.1 micrograms/L.h; P less than 0.03] and potentiated the somatotroph response to ivGHRH (inNS with ivGHRH vs. ivGHRH, 1316 +/- 183.0 vs. 644.9 +/- 154.5 micrograms/L.h; P less than 0.03). In group B (n = 6; age, 11.5-15.9 yr) ivGHRH induced a GH rise clearly higher than that induced by inGHRH (604.2 +/- 154.3 vs. 137.1 +/- 28.2 micrograms/L.h; P less than 0.03). Administration of inNS induced a GH rise similar to that occurring after inGHRH (AUC, 239.2 +/- 69.5 micrograms/L.h) and markedly increased the inGHRH-induced GH response (482.4 +/- 103.6 micrograms/L.h; P less than 0.05 and 0.03 vs. inNS and inGHRH, respectively), so that it overlapped with that induced by ivGHRH alone.
In conclusion, cholinergic agonists such as neostigmine are able to increase both basal and GHRH-induced GH secretion in short children even when given intranasally. Combined intranasal administration of neostigmine and GHRH (10 micrograms/kg) is able to induce a GH rise similar to that induced by ivGHRH alone (1 microgram/kg), suggesting the potential usefulness of this combination cocktail and route of administration for the treatment of short stature.
THIS IS A HIGHLY SUMMARIZED VERSION AS I KNOW YOU PEEPS HATE READING. I REALLY RECOMMEND READING THE WHOLE THING THOUGH.
A brief summary of dosing and administration (GHRP, GHRH)
Dosing GHRPs
The saturation dose in most studies on the GHRPs (GHRP-6, GHRP-2, Ipamorelin & Hexarelin) is defined as either 100mcg or 1mcg/kg. What that means is that 100mcg will saturate the receptors fully, but if you add another 100mcg to that dose only 50% of that portion will be effective. If you add an additional 100mcg to that dose only about 25% will be effective. Perhaps a final 100mcg might add a little something to the GH release but that is it.
So 100mcg is the saturation dose and you could add more up to 300 to 400mcg and get a little more effect.
A 500mcg dose will not be more effective than a 400mcg, perhaps not even more effective than 300mcg.
The additional problems are desensitization & cortisol/prolactin side effects:
Ipamorelin is about as efficacious as GHRP-6 in causing GH release but even at higher doses (above 100mcg) it does not create prolactin or cortisol.
GHRP-6 at the saturation dose of 100mcg does not really increase prolactin & cortisol but may do so slightly at higher doses. This rise is still within the normal
range.
GHRP-2 is a little more efficacious than GHRP-6 at causing GH release but at the saturation dose or higher may produce a slight to moderate increase in prolactin & cortisol. This rise is still within the normal range although doses of 200 - 400mcg might make it the high end of the normal range.
Hexarelin is the most efficacious of all of the GHRPs at causing an increase in GH release. However, it has the highest potential to also increase cortisol & prolactin. This rise will occur even at the 100mcg saturation dose. This rise will reach higher levels of what is defined as normal.
Desensitization
GHRP-6 can be used at saturation dose (100mcg) three or four times a day without risk of desensitization.
GHRP-2 probably at saturation dose several times a day will not result in desensitization.
Hexarelin has been shown to bring about desensitization but in a long-term study, the pituitary recovered its sensitivity so that there was no long-term loss of sensitivity at saturation dose. However, dosing Hexarelin even at 100mcg three times a day will likely lead to some down-regulation within 14 days.
If desensitization were to ever occur for any of these GHRPs simply stopping use for several days will remedy this effect. Chronic use of GHRP-6 at 100mcg dosed several times a day every day will not cause pituitary problems, significant prolactin or cortisol problems, nor desensitization.
GHRH
Now Sermorelin, GHRH (1-44), and GRF(1-29) all are basically GHRH and have a short half-life in the plasma because of quick cleavage between the 2nd & 3rd amino acids. This is no worry naturally because this hormone is secreted from the hypothalamus and travels a short distance to the underlying anterior pituitary and is not really subject to enzymatic cleavage. The release from the hypothalamus and binding to somatotrophs (pituitary cells) happens quickly. However when injected into the body it must circulate before finding its way to the pituitary and so within 3 minutes, it is already being degraded.
That is why GHRH in the above forms must be dosed high to get an effect.
GHRH analogs (CJC-1295)
All GHRH analogs swap Alanine at the 2nd position for D-Alanine which makes the peptide resistant to quick cleavage at that position. This means analogs will be more effective when injected at smaller dosing.
The analog tetra or 4 substituted GRF(1-29) sometimes called CJC w/o the DAC or referred to by me as modified GRF(1-29) has other amino acid modifications. They are glutamine (Gln or Q) at the 8-position, alanine (Ala or A) at the 15-position and leucine (Leu or L) at the 27-position.
For use in vivo, in humans, the GHRH analog known as CJC w/o the DAC or tetra (4) substituted GRF(1-29) or modified GRF(1-29) is a very effective peptide with a half-life of probably 30+ minutes. That is long enough to be completely effective. The saturation dose is also defined as 100mcg.
Problem w/ Using any GHRH alone
The problem with using a GHRH even the stronger analogs is that they are only highly effective when somatostatin is low (the GH-inhibiting hormone). So if you unluckily administer in a trough (or when a GH pulse is not naturally occurring) you will add very little GH release. If however you luckily administer during a rising wave or GH pulse (somatostatin will not be active at this point) you will add to GH release.
Solution is GHRP + GHRH analog (CJC + GHRP6 OR GHRP2)
The solution is simple and highly effective. You administer a GHRH analog with a GHRP. The GHRP creates a pulse of GH. It does this through several mechanisms. One mechanism is the reduction of somatostatin release from the hypothalamus, another is a reduction of somatostatin influence at the pituitary, still, another is increased release of GHRH from the brain and finally GHRPs act on the same pituitary cells (somatotrophs) as do GHRHs but use a different mechanism to increase cAMP formation which will further cause GH release from somatotroph stores.
GHRH also has a way of reciprocally reinforcing GHRPs' actions.
The result is a synergistic GH release. The GH is not additive it is synergistic. By that I mean:
If GHRH by itself will cause a GH release valued at 2
and GHRP itself will cause a GH release valued at 5
Together the GH is not 7 (5+2) it turns out to say 16!
A solid protocol
A solid protocol would be to use a GHRP + a GHRH analog pre-bed (to support the night-time pulse) once or twice throughout the day. For anti-aging, deep restful restorative sleep, the once-at-night dosing is all you need. For an adult aged 40+, it is enough to restore GH to youthful levels.
However, for bodybuilding or fat loss, or injury repair multiple dosings can be effective:
The GHRH analog can be used at 100mcg and as high as you want without problems.
The GHRP-6 can always be used at 100mcg w/o problems but a dose of 200mcg will probably be fine as well.
Again desensitization is something to keep an eye on particularly with the highest doses of GHRP-2 and all doses of Hexarelin.
So 100 - 200mcg of GHRP-6 + 100 - 500mcg+ of a GHRH analog taken together will be effective.
This may be dosed several times a day to be highly effective.
A solid approach is a bit more conservative at 100mcg of GHRP-6 + 100mcg of a GHRH analog dosed either once, twice, three or four times a day.
When dosing multiple times a day at least 3 hours should separate the administrations.
The difference is that a once-a-day dosing pre-bed will give a youthful restorative amount of GH while multiple dosing and or higher levels will give higher GH & IGF-1 levels when coupled with diet & exercise will lead to muscle gain & fat loss.
Dose w/o food
The administration should ideally be done on either an empty stomach or with only protein in the stomach. Fats & carbs blunt GH release. Administer the peptides and wait about 20 minutes (no more than 30 but no less than 15 minutes) to eat. At that point, the GH pulse has about hit the peak and you can eat what you want.
How does CJC-1295 work?
CJC-1295 "decays" at about 10% every 24 hours so you will get a build-up of levels:
______Dose #1_(200mcg)
Day 0 - 100% (.2mg)
Day 1 - 90% (.18mg remaining)
Day 2 - 81% (.16mg remaining)
Day 3 - 73% (.14mg remaining)
Day 4 - 65% (.12mg remaining)
Day 5 - 59% (.1mg remaining)
Day 6 - 53% (.09mg remaining)
Day 7 - 47% (.08mg remaining)
Day 8 - 43% (.06mg remaining)
So by day 5 your CJC-1295 level will be (.2 + .18 + .16 + .14 + .12) = 800mcgs
The following no-dose 6th day will result in (0 + .18 + .16 + .14 + .12 + .1) = 700mcgs
The following no dose 7th day will result in (0 + 0 + .16 + .14 + .12 + .1 + .09) = 610mcg
Then you will start dosing again on the 8th day which will result in (.2 + .14 +.12 +.1 + .09 +.08) = 730mcgs
The level will build all week and by the following 2 days off the levels will be a little higher than the first couple of no-dose days.
Lesson on Growth Hormone Secretagogues
Growth Hormone (GH) is regulated by a trinity composed of Growth Hormone Releasing Hormone (GHRH), Growth Hormone Secretagogues (GHS), and Somatostatin. GHRH and GHSs individually have a positive impact on GH secretion. These two compounds operate through distinct modes of action which complement each other and when administered together result in synergistic GH secretion. Growth Hormone Releasing Peptides (GHRPs), a subclass of GHSs are effective across all age groups in amplifying GH pulses. Pulsation is a necessary component of growth generation in mammals. GHRH when co-administered with GHRPs has the effect of further increasing the amplitude and "area under the curve" of a GH pulse. The result is a GH pulse many multiples more effective than that achieved by an unaided GH pulse.In addition to pulsation, overall growth is better accomplished when total levels of GH are elevated without hindering pulsation. Elevated GH levels appear to be a necessary component of growth generation as well. One of the reasons for this so appears to be that chronically elevated GH levels result in more pronounced sustained levels of IGF-1 than that achieved through intermittent GH elevations. Persistent levels of GHRH do not result in desensitization. Elevated levels of GHRH result in sustained GH release.
Combined administration of CJC-1295 and GHRP-6 is a very effective, well-studied method of increasing the total amount of GH secreted within the body. By adjusting the dosing of these compounds and accounting for such factors as age one may choose to achieve a "youthful" restoration, an above-normal elevation, or a substantially above-normal elevation of both GH levels and pulsatile release.
His opinion on somatostatin inhibitors (Alpha GPC, Huperzine A, Choline-CDP)
I'm not a big fan of ac-inhibitors. I just answered this in a message though so I'll repost it here. Just keep in mind that you don't want to "kill" Somatostatin. It plays a significant role in creating important pulsation and helps provide breaks from constant GHRH stimulation which is a good thing.
The Growth Hormone Releasing Peptides have several modes of action which all contribute to growth hormone release. One of their modes of action is that they INDIRECTLY increase GH secretion by reducing the release of somatostatin (the GH-inhibiting hormone) from the hypothalamus and DIRECTLY by reducing the magnitude of somatostatin's inhibiting action once it binds to the pituitary cells.
So I'm not sure if using cholinesterase inhibitors along with GHRPs would add anything. The GHRPs of course affect the release directly via the GHS-Receptor and indirectly by inducing GHRH at the hypothalamus so GHRPs are more beneficial. Now young people (let's say below 30) don't seem to benefit as much from inhibiting somatostatin & its mode of action as older people. As we age the signaling becomes less favorable to GH release.
From the studies:
GHRH + cholinesterase inhibitor = GH release
GHRH + GHRP = larger GH release
GHRH + GHRP + cholinesterase inhibitors = even greater GH release.
Evidence:
Intranasal administration of neostigmine potentiates both intravenous and intranasal growth hormone (GH)-releasing hormone-induced GH release in short children
E Ghigo, M Procopio, J Bellone, E Mazza, M Mucci, MF Boghen, EE Muller and F Camanni
Administration of cholinergic agonists increases both basal and GH-releasing hormone (GHRH)-induced GH secretion, probably acting via inhibition of endogenous somatostatin release.
The aim of our study was to verify in two groups of children with idiopathic short stature the effect of intranasal administration of neostigmine (inNS; 3 mg), a cholinesterase inhibitor, on basal GH levels as well as on the somatotroph response to GHRH when the peptide was administered either iv (ivGHRH; 1 microgram/kg) or intranasally (inGHRH; 10 micrograms/kg).
In group A (n = 6; age, 10.6-16.0 yr) inNS induced a significant GH increase [inNS vs. saline, area under the curve (AUC; mean +/- SEM), 263.7 +/- 60.2 vs. 73.8 +/- 3.1 micrograms/L.h; P less than 0.03] and potentiated the somatotroph response to ivGHRH (inNS with ivGHRH vs. ivGHRH, 1316 +/- 183.0 vs. 644.9 +/- 154.5 micrograms/L.h; P less than 0.03). In group B (n = 6; age, 11.5-15.9 yr) ivGHRH induced a GH rise clearly higher than that induced by inGHRH (604.2 +/- 154.3 vs. 137.1 +/- 28.2 micrograms/L.h; P less than 0.03). Administration of inNS induced a GH rise similar to that occurring after inGHRH (AUC, 239.2 +/- 69.5 micrograms/L.h) and markedly increased the inGHRH-induced GH response (482.4 +/- 103.6 micrograms/L.h; P less than 0.05 and 0.03 vs. inNS and inGHRH, respectively), so that it overlapped with that induced by ivGHRH alone.
In conclusion, cholinergic agonists such as neostigmine are able to increase both basal and GHRH-induced GH secretion in short children even when given intranasally. Combined intranasal administration of neostigmine and GHRH (10 micrograms/kg) is able to induce a GH rise similar to that induced by ivGHRH alone (1 microgram/kg), suggesting the potential usefulness of this combination cocktail and route of administration for the treatment of short stature.
