GHRP-2 and Memory Research




GHRP-2 (short for Growth Hormone Releasing Peptide-2) is an agonist of the ghrelin receptor. Ghrelin has wide-ranging effects that include growth hormone release and protection of cardiac (heart) muscle cells. Scientific studies based on animal test subjects suggests that both ghrelin and its receptor agonists, like GHRP-6, may also play a significant role in memory formation.


Fear Memory Encoding


One of the primary roles of memory in animals is to store associations regarding safe and dangerous encounters. Fear is one of the most potent memory stimulants known. The fear memory-encoding mechanism has been isolated to a region of the brain called the lateral amygdala and years of research have demonstrated changes in this brain region occur in response to fear conditions. It is also well-accepted that learning not to fear a previously feared condition is exceptionally difficult.


Animal studies have found that food deprivation can increase the rate at which a fear response is lost (fear extinction) [1]. In other words, not eating can actually increase the rate of learning how to not be afraid. It was thought that this effect may be related to the elevated levels of ghrelin that occur with food deprivation, a hypothesis that was confirmed when blocking of ghrelin receptors was found to impair fear extinction in rats [2].


Studies with GHRP-6 and Memory


Very recent work has found that GHRP-6 administration immediately after learning, can improve retention in rats. Additionally, rats that have no ghrelin receptor 1a take much longer to learn new tasks, even with GHRP-6 injection, suggesting that ghrelin and its analogues are highly active in memory formation [2]. Older research using GHRP-6 has also demonstrated a benefit in spatial learning (ability to navigate a maze) among rats who had GHRP-6 injected directly into their amygdalas [3].


Teasing Out Nuance


It has been known for some time that growth hormone (GH) plays a role in memory, mental alertness, and motivation [4], [5]. This is part of the reason that exercise has been linked to improvements in memory and learning because exercise itself has been shown to help increase natural growth hormone levels. At least part of the benefit of GHRP-6 and ghrelin analogues stems from their GH releasing properties, but this doesn’t account for the entirety of their benefits. There is some speculation that they may benefit memory by directly modulating the brain’s insulin-like growth factor (IGF) system. IGF levels and IGF-1 expression are known to impact neuron health and both are impacted by GH levels. The brain IGF system may be the common link that ties together the effects on memory of both GH and molecules like GHRP-6.




[1] C.-C. Huang, D. Chou, C.-M. Yeh, and K.-S. Hsu, “Acute food deprivation enhances fear extinction but inhibits long-term depression in the lateral amygdala via ghrelin signaling,” Neuropharmacology, vol. 101, pp. 36-45, Sep. 2015.

[2] S. Beheshti and S. Shahrokhi, “Blocking the ghrelin receptor type 1a in the rat brain impairs memory encoding,” Neuropeptides, vol. 52, pp. 97-102, Aug. 2015.

[3] K. Tóth, K. László, and L. Lénárd, “Role of intraamygdaloid acylated-ghrelin in spatial learning,” Brain Res. Bull., vol. 81, no. 1, pp. 33-37, Jan. 2010.

[4] L. M. Frago, C. Pañeda, S. L. Dickson, A. K. Hewson, J. Argente, and J. A. Chowen, “Growth hormone (GH) and GH-releasing peptide-6 increase brain insulin-like growth factor-I expression and activate intracellular signaling pathways involved in neuroprotection,” Endocrinology, vol. 143, no. 10, pp. 4113-4122, Oct. 2002.

[5] E. H. Quik, E. B. Conemans, G. D. Valk, J. L. Kenemans, H. P. F. Koppeschaar, and P. S. van Dam, “Cognitive performance in older males is associated with growth hormone secretion,” Neurobiol. Aging, vol. 33, no. 3, pp. 582-587, Mar. 2012.

GHRP-2 Research




GHRP-2, a synthetic agonist of the ghrelin receptor, has been found to modulate pain in animals without increasing rates of addiction via interaction with the central opioid system. This is the same system by which drugs like Oxycontin and hydrocodone ect.

Scientific studies based on animal test subjects have been able to determine that GHRP-2 has also been found to increase the effects of opioid medications, improving their potency and more importantly reducing long-term addictive effects.


Early Signs

GHRP-2 and GHRP-6 have long been associated with improved joint pain in animal test subjects with osteoarthritis. This was originally attributed to the molecule’s ability to increase growth hormone (GH) levels within the animal test subject. (GH can accelerate healing). What was interesting, however, was that GHRP-2 produced pain relief long before any healing could take place. This suggested that GHRP-2 was working to relieve pain through some other mechanism. It was eventually discovered that GHRP-2 interacts with opioid receptors.


The Opioid Receptors and Addiction


There are four major opioid receptors (DOR, KOR, MOR, and NOP) as well as several minor variants within each major category. The properties of opioid medications are determined by how strongly they bind to each of the receptors as follows.

.   DOR – pain relief (analgesia) and addiction.

.   KOR – analgesia and sedation, but not addiction.

.   MOR – analgesia, addiction, and respiratory depression (decrease in breathing).

.   NOP – appetite loss and changes in tolerance to opioids.


Most opioid medications are non-discriminate binders, meaning they tend to bind to all four receptors and thus produce a wide range of effects. This is why all opioid medications have a potential for addiction. GHRP-2, however, appears to be different. GHRP-2 has strong proclivity for the DOR and KOR receptors and almost no affinity for the MOR receptor [1].


Given that the MOR receptor is the one most strongly associated with the negative side effects of opioids (addiction, respiratory depression, constipation), GHRP-2 may be able to offer pain relief without many of the risks of other opioid drugs. Though the DOR receptor is associated with addiction, animal studies suggest that low-level DOR binding may actually counteract some of the effects associated with MOR binding and thus combat addictive potential [2].


Future Research


While GHRP-2 is known to increase the effects of opioid medications, GHRP-6 has been found to decrease their effects [3]. This indicates that the role of ghrelin and its synthetic analogues in pain relief is likely modulated by more complex receptor interactions than are currently understood. Whatever the case may be, ongoing research is continuing to demonstrate unique benefits of synthetic peptide secretagogues like GHRP-2.




[1] P. Zeng, S. Li, Y. Zheng, F.-Y. Liu, J. Wang, D. Zhang, and J. Wei, “Ghrelin receptor agonist, GHRP-2, produces antinociceptive effects at the supraspinal level via the opioid receptor in mice,” Peptides, vol. 55, pp. 103-109, May 2014.

[2] Y. F. Su, R. W. McNutt, and K. J. Chang, “Delta-opioid ligands reverse alfentanil-induced respiratory depression but not antinociception,” J. Pharmacol. Exp. Ther., vol. 287, no. 3, pp. 815-823, Dec. 1998.

[3] P. Zeng, J.-X. Chen, B. Yang, X. Zhi, F.-X. Guo, M.-L. Sun, J.-L. Wang, and J. Wei, “Attenuation of systemic morphine-induced analgesia by central administration of ghrelin and related peptides in mice,” Peptides, vol. 50, pp. 42-49, Dec. 2013.

Epithalon (Epitalon) Research



Epithalon (a.k.a. epitalon) is a short peptide, just four amino acids long, that has received a great deal of attention through scientific animal test studies for its ability to fend off the effects of aging. Derived from the naturally occurring epithalamin, epithalon has been found to regulate brain function, control various hormone levels, mitigate stress, and even act as an antioxidant. Epithalon was discovered in the 1980s, but it wasn’t until recently that its exact mechanism of action was elucidated. How epithalon really works is startling.


Epithalon Crosses the Cell Membrane


Cells are protected by fatty coatings called cell membranes (lipid bilayers). For the most part, anything that enters or exits the cell has to go through special protein channels in the cell membrane because passing directly through the bilayer is impossible. The lipid bilayer is a highly effective way to protect a cell and allow it to regulate its internal environment, but it is also a major impediment to the delivery of medication.


A particular issue with the lipid bilayer has been the delivery of gene therapy. Molecules designed to regulated DNA and change its function are notoriously difficult to deliver, intact, to DNA, which sits not just inside the cell membrane, but inside a second lipid bilayer called the nuclear membrane. Epithalon, it turns out, easily cross both membranes to directly affect DNA activity.


Epithalon and DNA

Scientific studies based on animal test subjects has been able to determine that Epithalon is a promoter peptide, which means it binds to very specific sections of DNA and turns on certain genes. In particular, epithalon interacts with CD5, IL-2, MMP2, and Tram1 signaling molecules [1]. CD5 is found on the surface of cells in the immune system, particularly T-cells. It plays a role in protecting the body against autoimmune diseases. IL-2 is also associated with the immune system and works to regulate white blood cells, again mostly T-cells, by preventing autoimmune responses and by promoting T-cell development.


Though the effects of epithalon appear both diverse and complicated, they explain one of the reasons that the peptide is so effective at warding off aging. By activating CD5 and IL-2 genes, epithalon both reduces the risk of autoimmune dysfunction and increases the ability of the immune system to respond to disease. This means better immune responses to everything from cancer to bacterial infections, but it also means less tissue damage from aberrant immune cells attacking the very body they should protect.




[1] V. K. Khavinson, S. I. Tarnovskaya, N. S. Linkova, V. E. Pronyaeva, L. K. Shataeva, and P. P. Yakutseni, “Short cell-penetrating peptides: a model of interactions with gene promoter sites,” Bull. Exp. Biol. Med., vol. 154, no. 3, pp. 403-410, Jan. 2013.