Scientific Guide to Somatostatin & its importance in heightmaxxing (HIGH EFFORT)

Research on this topic is lacking on this forum, and I have not seen a detailed thread specifically about this yet. This is an undervalued part of heightmaxxing that not many people know about.

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Somatostatin could be why some people respond really well to heightmaxxing and others dont, and it could be a way to get past your genetic limit.


TLDR AT BOTTOM.


oops did not see https://looksmax.org/threads/the-unknown-key-to-unlocking-hgh-igf-1-somatostatin.704036/ this thread that already exists on this topic until after I posted it luckily we dont have the exact same reccomendations and we look into a few different things, so reccomened reading both threads to get even more knowledge on the topic

btw idk how to use bbcode i use markdown in my personal notes so lmk if formatting is fucked


What is somatostatin & Introduction?

Somatostatin is a hormone that regulates the secretion of several other hormones, including growth hormone, which affects the growth of bones and tissues. It is released primarily by the hypothalamus, pituitary gland & pancreas, however other glands in the body such as the stomach and thyroid can also release it.

Acronyms used here:
  • SST, SRIF both refer to somatostatin
  • CNS refers to the central nervous system, the brain and spine
  • CSF refers to cerebro spinal fluid
  • PNS refers to peripheral nervous system
  • 'Peripheral effects of SST’ used on its own refers to effect of SST on the liver
  • Where a quotation is provided it is from the last refrenced study unless otherwise stated
  • Sourcing is done via numbers in brackets in superscript, the corresponding link to the study is provided at the bottom of this post.
Unfortunately, to measure your somatostatin levels you may need to go through a doctor, as I cant find any blood tests online that do it, additionally, plasma somatostatin levels may not be indictive of somatostatin levels in the brain

1703995801344



Relevant effects of somatostatin
  • Inhibits HGH release from the pituitary gland → Lower serum HGH levels
  • Inhibit synthesis of IGF1 in the liver → Lower serum IGF levels → Less growth
  • Inhibit insulin production in the pancreas [4] : This is desired effect, and another reason why inhibiting somatostatin is complex and dangerous. If inject HGH into our body, the IGF produced will cause blood sugar levels to drop, if somatostatin was not there, more insulin levels would also be produced which can potentially be dangerous.
  • Prevent secretion of TSH [5] → lower metabolism. This further supports the use of thryoid hormones while heightmaxxing.
  • Preserves pulsatile release of HGH, the pulsatile release of HGH is due to alternating secretion of GH releasing hormone and Somatostatin in the brain.


How can we inhibit somatostatin:
Lets explore what increases the amount of somatostatin released, and what we can do to inhibit its release:

What wont work:


1. Injecting HGH and assuming you bypassed it.
You cant just inject HGH and think you have bypassed it, because as described already it inhibits the synthesis of IGF1 [1] at the liver, and both increased HGH levels & IGF1 levels cause more somatostatin to be released:
(Source 1)
Hepatocytes were next preincubated with 100 nM SRIF14 or octreotide for one hour before stimulation with 100 or 500 ng/ml GH. Cells were incubated for 24 hours and IGF-I quantified by RPA. Both SRIF and octreotide inhibited GH-induced IGF-I transcription independent of the GH dose used to induce IGF-I (Figure [2](https://www.jci.org/articles/view/19933#F2)A). These results suggest that SRIF and its analog suppress the GH–IGF-I axis by inhibiting pituitary GH release as well as GH-induced hepatocyte IGF-I production.
1703996165309

Octreotide is a medication that stimulates somatostatin receptors, the researchers are using that to simulate somatostatin. The mechanism by which IGF1 increases synthesis of SST is not fully understood however the following is the current theory:

It is believed IGF1 crosses the blood brain barrier via IGF BP3 [2]

Blood-borne IGF-1 bound to insulin-like growth factor–binding protein (IGFBP)-3 is able to cross the brain endothelial cell after IGFBP-3 degradation by matrix metalloproteinase-9 (4).

After IGF-1’s entry to the VRS, it is unclear whether it is transported as free IGF-1 or bound to IGF-1 binding proteins present in the brain. IGFBP-2, -5, and -6 have been reported in the CSF

^ these to excerpts from the source show how IGF1 is believed to enter the brain.

Additionally, it is unknown whether peripheral (pituitary-secreted) GH and IGF-1 (from the liver) feedback to inhibit both GH and IGF-1 production in the brain.

^ This following excerpt from the source could be misinterpreted to mean that what I just isn’t true, however this is referring to GH and IGF-1 produced in the brain that remains in the brain. All 3 extracts are from source [2]


So how do we do it:

1. Increasing GABA & Reducing glutamate

GABA is a neurotransmitter in the brain, a more detailed explanation is provided in the magnesium section below. In the pancreas, GABA inhibits the release of somatostatin when glucose is high, whereas it increases secretion of somatostatin. The amount of somatostatin produced in the pancreas is at levels as high in the brain so it can have a significant effect on the peripheral action of somatostatin (inhibiting IGF synthesis at the liver).

It has been shown increased plasma GABA levels lead to decreased plasma SST levels, the study which showed this gave a patient sodium valproate, something that increases the synthesis of GABA and found lower plasma somatostatin levels [9] . This also shows that the majority of the time, GABA will inhibit the release of SST and you do not need to follow a specific diet to keep the glucose levels high, as the patient in the study was on no such instructions. The practicality of sodium valproate for Heightmaxxing will be discussed further in this post.

However, there is slightly conflicting evidence, while plasma somatostatin may be reduced with increased GABA (due to inhibition of somatostatin in the pancreas), some evidence suggests that somatostatin release is upregulated in the brain. Somatostatin acts as a co-neurotransmitter to GABA. Both somatostatin and GABA are released in SST(somatostatin)+ GABAergic cells [10]. Additionally, it has been shown that increases GABA signalling increase somatostatin secretion in those cells. [11]

suggesting that sustained increases in GABAergic transmission produce antidepressant-like behavior by disinhibiting somatostatin-positive GABAergic interneurons

It has also been shown that a low SST level decreases GABA levels, it is unclear if this holds true for the opposite (i.e low GABA = low SST) or if this relationship is one way. If this relationship is one way, then increasing GABA levels in the brain would be beneficial as it would offset the decrease due to us artifically lowering SST.

Mice deficient in somatostatin exhibits high behavioral emotionality, increased basal plasma corticosterone, and decreased GABA-synthesizing enzyme GAD67 gene expression [43], indicating that somatostatin influences the GABA signal and stress response.

Both extracts are from source 11.

However, the sodium valproate study shows us that increased gaba = reduced SST overall, and the evidence that low SST = low GABA is proven, whereas the reverse statement low gaba = low SST is an assumption. Therefore it is my recommendation to include the suggestion that increasing GABA levels in both the brain and blood is beneficial for inhibiting the release of SST(Somatostatin). The evidence in this field is highly recent & changing and different sources may contradict each other, I have attempted to use the strongest evidence base for each claim. Some sources also claim that SST released from GABAergic neurones mainly acts locally (without having an effect on HGH levels) and what diffuses out of the synapse stays in the CSF and will not affect synthesis of IGF1 in the liver [12]



Once released in the synaptic cleft, somatostatin acts locally, or it diffuses in the extracellular space through “volume diffusion”, a mechanism(s) of distribution which mainly operates in the cerebrospinal fluid and that assures the progression of neuronal signalling from signal-secreting sender structures towards receptor-expressing targeted neurons located extrasynaptically, in a non-synaptic, inter-neuronal form of communication.

Additionally, GABA supplementation has been shown to increase HGH levels in the blood [14], this evidence agrees with my conclusion that more GABA = good. It was thought that oral GABA could not cross the blood brain barrier, however recent research contests that.[15]. This supports the idea that more GABA in brain = good for heightmaxxing.

Now moving onto glutamate. Glutamate is the prominent excitatory neurotransmitter in the brain, essentially the opposite of GABA. It has been shown that glutamate triggers the secretion of somatostatin under low-glucose conditions in the pancreas [16]. Glutamate does not appear to inhibit the release of somatostatin at high glucose conditions, so we should aim to decrease it.

In the CNS, as is with GABA, it is alot more complex.
Starting from these first observations, further evidence was published demonstrating that somatostatin inhibits presynaptic glutamate release in different brain regions

Somatostatin inhibits glutamate, and unfortunately the evidence relating to this is too complicated to understand fully, however the research paper (source 13) is linked if you would like to read it. Going off an assumption that lowering glutamate means our brains homeostatic mechanisms will reduce the amount of somatostatin to compensate for this, it follows that reduced glutamate = somatostatin.


How do we reduce glutamate and increase GABA?

Magnesium:
Magnesium is a true panacea, EVERYONE should be taking it, its beneficial to almost everything you want to try and do (except if you are taking Adderall it might reduce its effectiveness.). I will introduce the effects of magnesium first and then describe why those are good at inhibiting somatostatin, it will be copy pasted from my nootropics guide so some of the links may be broken (cba to fix it rn, but i have provided the source list below). I have not posted my nootropic guide as there are alot of posts about this already but if people want it then I can post it.

Magnesium is an essential mineral that plays a vital role in many biological processes, including ATP production, DNA synthesis, neuromuscular function, homeostasis, and more. [6] It regulates several neurotransmitters that are involved in learning, memory and mood.[7][17].

One of the ways that magnesium supports brain function is by blocking NMDA receptors[8], which are activated by glutamate, the prominent neurotransmitter in the brain. Excessive glutamate stimulation can cause neuronal damage and dysfunction leading to cognitive impairment and neurodegenerative diseases[9]. Magnesium acts as a natural antagonist of NMDA receptors[10], preventing excessive glutamate activity and protecting neurons from excitotoxicity.

Magnesium also benefits the brain by supporting GABA activity. GABA is the prominent inhibitory neurotransmitter in the brain, which counteracts glutamate and promotes relaxation, calmness and sleep.[11][12][13] Magnesium enhances GABA synthesis and release. By increasing GABA levels in the brain, magnesium helps to reduce anxiety, stress and insomnia[14].

Magnesium interacts with another glutamate receptor, mGluR, which impacts synaptic plasticity and memory. Magnesium is able to activate mGluR2/3 subtypes, which inhibit glutamate release and prevent overstimulation of NMDA receptors. Magnesium also inhibits mGluR5 subtype, which enhances long term potentiation, a process of strengthening synaptic connections[7][16].

Source list for the above: (i tried usign a spoiler but the formatting killed itself so i made it small text)
[6] de Baaij JH, Hoenderop JG, Bindels RJ. Magnesium in man: implications for health and Lasike . Physiol Rev. 2015 Jan;95(1):1-46. doi: 10.1152/physrev.00012.2014. PMID: 25540137.
[7] Slutsky I, Abumaria N, Wu LJ, Huang C, Zhang L, Li B, Zhao X, Govindarajan A, Zhao MG, Zhuo M, Tonegawa S, Liu G. Enhancement of learning and memory by elevating brain magnesium. Neuron. 2010 Jan 28;65(2):165-77. doi: 10.1016/j.neuron.2009.12.026. PMID: 20152124.
[8]Hou H, Wang L, Fu T, Papasergi M, Yule DI, Xia H. Magnesium Acts as a Second Messenger in the Regulation of NMDA Receptor-Mediated CREB Signaling in Neurons. Mol Neurobiol. 2020 Jun;57(6):2539-2550. doi: 10.1007/s12035-020-01871-z. Epub 2020 Mar 25. PMID: 32215817; PMCID: PMC8202957.
[9] Lewerenz J, Maher P. Chronic Glutamate Toxicity in Neurodegenerative Diseases-What is the Evidence? Front Neurosci. 2015 Dec 16;9:469. doi: 10.3389/fnins.2015.00469. PMID: 26733784; PMCID: PMC4679930.
[10] : Chahal H et al., Modulation by magnesium of N-methyl-D-aspartate receptors in developing human brain.Arch Dis Child Fetal Neonatal Ed. 1998 Mar;78(2):F116-20.doi: 10.1136/fn.78.f116.
[11] Pedrón VT, Varani AP, Bettler B, Balerio GN. GABAB receptors modulate morphine antinociception: Pharmacological and genetic approaches. Pharmacol Biochem Behav. 2019 May;180:11-21.
[12] Kondziella D. The Top 5 Neurotransmitters from a Clinical Neurologist's Perspective. Neurochem Res. 2017 Jun;42(6):1767-1771. [[PubMed](https://pubmed.ncbi.nlm.nih.gov/27822666)] [[Reference list](https://www.ncbi.nlm.nih.gov/books/NBK513311/#article-22012.r2)]
[13] Olsen RW. GABAA receptor: Positive and negative allosteric modulators. Neuropharmacology. 2018 Jul 01;136(Pt A):10-22.
[14] Boyle NB, Lawton C, Dye L. The Effects of Magnesium Supplementation on Subjective Anxiety and Stress-A Systematic Review. Nutrients. 2017 Apr 26;9(5):429. doi: 10.3390/nu9050429. PMID: 28445426; PMCID: PMC5452159.


So to summarise, magnesium increases GABA levels in the brain, and inhibit release of glutamate. Additionally, magnesium supports calcium absorption into bones, so it is important in Heightmaxxing for that purpose too.

Oral GABA supplementation:
These can be purchased at nootropic websites, the dose used in the study described previously used a dose of 3g orally once per day.

2. Increased parasympathetic activity via inhibition of cholinesterase
WARNING: DO NOT USE IF YOU HAVE ASTHMA OR COPD !!

Cholinesterase & acetylcholinesterase is very important, it effectively reduces the parasympathetic response of the body (really its more accurate to say it prevents it from going out of hand..). Nerve agents, the most deadly compounds ever created by us, irrevsibly inhibit them (non-competitive inhibition, technically reversible by treatment with oxime within a certain time period dependant on exact agent used) which causes death by severe refractory bradycardia (extreme slowing of heart rate), paralysis and respiratory arrest.

I am saying this to give you an idea of the dangerous of pyridostigmine overdose and the role of the parasympathetic neverous system and cholinesterase in the body. Pyridostigmine is available in tablet form, and it would hard to accidently overdose on them, if there is a source selling it as a powder or liquid I highly recommend not using this due to the overdose risk. Huperazine is also measured in micrograms not milligrams, increasing overdose risk.

If you overdose on either of these compounds you need to seek help urgently, it is not like accidently injecting too much HGH where your blood sugar could tank in abit, or nothing might happen or you might have a headache etc, they can be **rapidly** lethal(as in you wont survive a trip to the hospital, you need to call for an ambulance rapid depending on the dose taken) and require specific drugs to reverse it. They can also cause significant cognitive deficits if you survive a large overdose. Before using these, ensure you know of overdose symptoms and correct dosage.

*note there are diffrences between cholinesterase and acetylcholinesterase however it not that relevant right now and this is already WAY too long, putting this here so you are aware I have taken this into account*

Pyridostigmine :
Pyridostigmine is a medication that inhibits an enzyme called cholinesterase. Cholinesterase exists in the synaptic cleft to remove acetylcholine, an inhibitory neurotransmitter used in the peripheral nervous system from repeatedly stimulating the post synaptic neurone.

Pyridostigmine has been shown to stimulate the release of HGH when given alone[16], and its mechanism of action has been postulated as an inhibitor of hypothalamic SST secretion [17][18]. The evidence for pyridostigmine is very strong.

Huperzine A:
Huperzine A is an acetylcholinesterase inhibitor. It also increases parasympathetic response via this mechanism. However, the evidence for it directly suppressing somatostatin is not studied, however, there are many discussions online supporting its use, and a theoretical link exists. I do not reccomened the use of Huperzine A if you have a respiratory disorder such as asthma or COPD as it can increase bronchial secretions and the evidence for its use is weak.


ALPHA GPC & Choline:
These are also proven to inhibit somatostatin, and increase GH, see the thread linked above for more info on these.


3. Reduce stress & Prevent chronic stress, this decreases SST.

Upon 2 weeks of chronic mild stress in rats, somatostatin-2 receptors are significantly upregulated in the medial habenula, while the plasma somatostatin levels are also increased, suggesting that somatostatin and its receptors are involved in the stress response [44]. Longer duration (e.g., 7 weeks) of chronic mild stress in rats can cause decreases in consumption of sucrose solution and changes in somatostatin-2 receptors in response to antidepressant treatment [45]

This extract is from source 11, however for conivence I have included the sources it references for its claim. I recommend taking ashwagandha for this (provided you aren’t supplementing thyroid hormones).

4. L-arginine:
A low risk supplement, which has more evidence than huperazine A but is less efficaous compared to pyridostigmine.

L-arginine both supresses somatostatin releases and induces the release of GHRH (growth hormone releasing hormone). [19][20]




5. Injecting IGF1 (NOT LR3 or DES):
If you have this im very jealous. You most likely have been scammed if someone sold you this though as it is incredibly hard to source. There is no evidence that I could find that SST inhibits the effects of IGF1 at the tissue level or the effectiveness of IGF binding proteins, so theoretically IGF1 can bypass this entire mechanisms.


Risks of supressing SST:
  • Messing with body’s homeostatic and regulatory mechanisms can be dangerous
  • Low SST in the brain has been associated with conditions such as schizophrenia and depression
  • There is an incredibly complex relationship between hormones and neurotransmitters in the brain that I do not fully understand, this post does not even go 1 meter deep into it.
TLDR:

Magnesium* = More evidence than to the contrary to supports its use
Oral GABA = Evidence supports use
Pyridostigmine = Evidence supports use, exercise caution when dosing due to overdose risk
Stress reduction = Evidence is unclear, however recommended as no evidence to the contrary.
Huperzine A = Theoretical link, not recommended due to overdose risk.
L-Arginine = Evidence supports use
Calorific Surplus = Evidence supports use, Evidence supports negative effect when in defecit. Strongly reccomended to maintain high/sufficent glucose in blood


*a form of magneisum that is effective at crossing the blood brain barrier must be used. This is discussed in the nootropic guide*

I personally would take ATA Magnesium, oral Gaba and L-arginine as my additives to my stack.

FAQ:
- Will be added here as people reply to this thread
  • Dosages? A: For magnesium: 200-800mg, is effective, reccomend starting at 400mg and titrating based on side effects and blood test results. For GABA: 3g orally per day, pyridostigmine 60mg daily, titrate to effect 30-120mg, divide into 2 doses over the day. L arginine: 10g per day. Huperazine A (dont reccomend this) dosage is 50-150mcg daily.


Disclaimer:
- Please note that this information is based on the current understanding and research available as of 2023 and may be subject to change as new research emerges.
- This is posted for entertainment purposes only, it is your responsibility to verify information in this, I am not a healthcare professional. I am not responsible if you come to harm as a result of following this post.
- If you spot any errors in this thread please let me know by replying, peer reviewing is important!
- Ensure you double check side effects and dosages of medication to ensure it is suitable for you


Sources:
[1]: Murray RD, Kim K, Ren SG, Chelly M, Umehara Y, Melmed S. Central and peripheral actions of somatostatin on the growth hormone-IGF-I axis. J Clin Invest. 2004 Aug;114(3):349-56. doi: 10.1172/JCI19933. PMID: 15286801; PMCID: PMC484973.
[2]: Sarah M. Gray, Michael O. Thorner, Spatiotemporal Regulation of Insulin-Like Growth Factor-1 and Its Receptor in the Brain: Is There a Role for Growth Hormone?, _Endocrinology_, Volume 158, Issue 2, 1 February 2017, Pages 229–232, [https://doi.org/10.1210/en.2016-1884](https://doi.org/10.1210/en.2016-1884)
[^3]: Aguirre, G.A., De Ita, J.R., de la Garza, R.G. _et al._ Insulin-like growth factor-1 deficiency and metabolic syndrome. _J Transl Med_ **14**, 3 (2016). https://doi.org/10.1186/s12967-015-0762-z
[^4]: Mathew Daunt, Oliver Dale, Paul A. Smith, Somatostatin Inhibits Oxidative Respiration in Pancreatic β-Cells, _Endocrinology_, Volume 147, Issue 3, 1 March 2006, Pages 1527–1535, [https://doi.org/10.1210/en.2005-0873](https://doi.org/10.1210/en.2005-0873)
[^5]: Zgliczyński, W., Zdunowski, P., Czajka-Oraniec, I. _et al._ The role of somatostatin analogues in treatment of TSH secreting pituitary adenomas. _Thyroid Res_ **6** (Suppl 2), A64 (2013). https://doi.org/10.1186/1756-6614-6-S2-A64
[^6]: Pedrón VT, Varani AP, Bettler B, Balerio GN. GABAB receptors modulate morphine antinociception: Pharmacological and genetic approaches. Pharmacol Biochem Behav. 2019 May;180:11-21.
[^7]: Kondziella D. The Top 5 Neurotransmitters from a Clinical Neurologist's Perspective. Neurochem Res. 2017 Jun;42(6):1767-1771. [[PubMed](https://pubmed.ncbi.nlm.nih.gov/27822666)] [[Reference list](https://www.ncbi.nlm.nih.gov/books/NBK513311/#article-22012.r2)]
[^8]: Olsen RW. GABAA receptor: Positive and negative allosteric modulators. Neuropharmacology. 2018 Jul 01;136(Pt A):10-22.
[^9]: Kusunoki M, Yamamura T, Ichii S, Fujita S, Nakai T, Utsunomiya J, The effects of sodium valproate on plasma somatostatin and insulin in humans. _J Clin Endocrinol Metab_ (1988) 67(5):1060–3. doi: 10.1210/jcem-67-5-1060
[^10]: Iwasawa, C., Kuzumaki, N., Suda, Y. _et al._ Reduced expression of somatostatin in GABAergic interneurons derived from induced pluripotent stem cells of patients with _parkin_ mutations. _Mol Brain_ **12**, 5 (2019). https://doi.org/10.1186/s13041-019-0426-7
[^11]: Hou X, Rong C, Wang F, Liu X, Sun Y, Zhang HT. GABAergic System in Stress: Implications of GABAergic Neuron Subpopulations and the Gut-Vagus-Brain Pathway. Neural Plast. 2020 Aug 1;2020:8858415. doi: 10.1155/2020/8858415. PMID: 32802040; PMCID: PMC7416252.
[^12]: Pittaluga, A.; Roggeri, A.; Vallarino, G.; Olivero, G. Somatostatin, a Presynaptic Modulator of Glutamatergic Signal in the Central Nervous System. _Int. J. Mol. Sci._ **2021**, _22_, 5864. https://doi.org/10.3390/ijms22115864
[^13]: Akiko Muroyama, Shunsuke Uehara, Shouki Yatsushiro, Noriko Echigo, Riyo Morimoto, Mitsuhiro Morita, Mitsuko Hayashi, Akitsugu Yamamoto, Duk-Su Koh, Yoshinori Moriyama; A Novel Variant of Ionotropic Glutamate Receptor Regulates Somatostatin Secretion From δ-Cells of Islets of Langerhans. __Diabetes__ 1 July 2004; 53 (7): 1743–1753. [https://doi.org/10.2337/diabetes.53.7.1743](https://doi.org/10.2337/diabetes.53.7.1743)
[^14]: Powers ME, Yarrow JF, McCoy SC, Borst SE. Growth hormone isoform responses to GABA ingestion at rest and after exercise. Med Sci Sports Exerc. 2008 Jan;40(1):104-10. doi: 10.1249/mss.0b013e318158b518. PMID: 18091016.
[^15]: Hepsomali P, Groeger JA, Nishihira J, Scholey A. Effects of Oral Gamma-Aminobutyric Acid (GABA) Administration on Stress and Sleep in Humans: A Systematic Review. Front Neurosci. 2020 Sep 17;14:923. doi: 10.3389/fnins.2020.00923. PMID: 33041752; PMCID: PMC7527439.
[^16]: W B Wehrenberg, S D Wiviott, D M Voltz, A Giustina, Pyridostigmine-mediated growth hormone release: evidence for somatostatin involvement., _Endocrinology_, Volume 130, Issue 3, 1 March 1992, Pages 1445–1450, [https://doi.org/10.1210/endo.130.3.1347008](https://doi.org/10.1210/endo.130.3.1347008)
[^17]: Angela Peñalva, Bartolome Burguera, Xesus Casabiell, Jesus A.F. Tresguerres, Carlos Dieguez, Felipe F. Casanueva; Activation of Cholinergic Neurotransmission by Pyridostigmine Reverses the Inhibitory Effect of Hyperglycemia on Growth Hormone (GH) Releasing Hormone-Induced GH Secretion in Man: Does Acute Hyperglycemia Act through Hypothalamic Release of Somatostatin?. __Neuroendocrinology__ 1 May 1989; 49 (5): 551–554. [https://doi.org/10.1159/000125166](https://doi.org/10.1159/000125166)
[^18]: Hanew, K., Utsumi, A., Sugawara, A. _et al._ The evaluation of hypothalamic somatostatin tone using pyridostigmine and thyrotropin releasing hormone in patients with acromegaly. _J Endocrinol Invest_ **17**, 313–321 (1994). https://doi.org/10.1007/BF03348989
[^19]: Parvin Goli, Maryam Yazdi, Motahar Heidari-Beni, Roya Kelishadi, "Growth Hormone Response to L-Arginine Alone and Combined with Different Doses of Growth Hormone-Releasing Hormone: A Systematic Review and Meta-Analysis", _International Journal of Endocrinology_, vol. 2022, Article ID 8739289, 11 pages, 2022. https://doi.org/10.1155/2022/873928
[^20]: Jose Córdoba-Chacón, Manuel D. Gahete, Ana I. Pozo-Salas, Justo P. Castaño, Rhonda D. Kineman, Raul M. Luque, Endogenous Somatostatin Is Critical in Regulating the Acute Effects of l-Arginine on Growth Heilormone and Insulin Release in Mice, _Endocrinology_, Volume 154, Issue 7, 1 July 2013, Pages 72–26, [https://doi.org/26.05./en.11-1126
[^44]: A. Faron-Górecka, M. Kuśmider, M. Kolasa et al., “Chronic mild stress alters the somatostatin receptors in the rat brain,” _Psychopharmacology_, vol. 233, no. 2, pp. 255–266, 2016.
[^45]: A. Faron-Górecka, M. Kuśmider, J. Solich et al., “Regulation of somatostatin receptor 2 in the context of antidepressant treatment response in chronic mild stress in rat,” _Psychopharmacology_, vol. 235, no. 7, pp. 2137–2149, 2018.
[/spoiler]
I have checked and read through all sources manually so they should all be correct and support claims made, if you spot any errors let me know.

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if anyone has a legit source for pyro lemme know
 
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Looks like a good thread. My reacts are disabled though.
 
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will i read? perhaps
 
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I highly reccomend you do if you want to maximise your chances at growing and avoiding wasting your money on HGH that might not have an effect in the end. It could be the difference.
 
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I'm damn sure GHRH also inhibits somatostatin.
 
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increlex, the drug of the gods. pure bio identical IGF1. if only us lower class civilians could source it.
 
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Research on this topic is lacking on this forum, and I have not seen a detailed thread specifically about this yet. This is an undervalued part of heightmaxxing that not many people know about.

Please leave a reaction so it can reach the minimum required to get into BOTB.

Somatostatin could be why some people respond really well to heightmaxxing and others dont, and it could be a way to get past your genetic limit.


TLDR AT BOTTOM.


oops did not see https://looksmax.org/threads/the-unknown-key-to-unlocking-hgh-igf-1-somatostatin.704036/ this thread that already exists on this topic until after I posted it luckily we dont have the exact same reccomendations and we look into a few different things, so reccomened reading both threads to get even more knowledge on the topic

btw idk how to use bbcode i use markdown in my personal notes so lmk if formatting is fucked


What is somatostatin & Introduction?

Somatostatin is a hormone that regulates the secretion of several other hormones, including growth hormone, which affects the growth of bones and tissues. It is released primarily by the hypothalamus, pituitary gland & pancreas, however other glands in the body such as the stomach and thyroid can also release it.

Acronyms used here:
  • SST, SRIF both refer to somatostatin
  • CNS refers to the central nervous system, the brain and spine
  • CSF refers to cerebro spinal fluid
  • PNS refers to peripheral nervous system
  • 'Peripheral effects of SST’ used on its own refers to effect of SST on the liver
  • Where a quotation is provided it is from the last refrenced study unless otherwise stated
  • Sourcing is done via numbers in brackets in superscript, the corresponding link to the study is provided at the bottom of this post.
Unfortunately, to measure your somatostatin levels you may need to go through a doctor, as I cant find any blood tests online that do it, additionally, plasma somatostatin levels may not be indictive of somatostatin levels in the brain

View attachment 2643580


Relevant effects of somatostatin
  • Inhibits HGH release from the pituitary gland → Lower serum HGH levels
  • Inhibit synthesis of IGF1 in the liver → Lower serum IGF levels → Less growth
  • Inhibit insulin production in the pancreas [4] : This is desired effect, and another reason why inhibiting somatostatin is complex and dangerous. If inject HGH into our body, the IGF produced will cause blood sugar levels to drop, if somatostatin was not there, more insulin levels would also be produced which can potentially be dangerous.
  • Prevent secretion of TSH [5] → lower metabolism. This further supports the use of thryoid hormones while heightmaxxing.
  • Preserves pulsatile release of HGH, the pulsatile release of HGH is due to alternating secretion of GH releasing hormone and Somatostatin in the brain.


How can we inhibit somatostatin:
Lets explore what increases the amount of somatostatin released, and what we can do to inhibit its release:

What wont work:


1. Injecting HGH and assuming you bypassed it.
You cant just inject HGH and think you have bypassed it, because as described already it inhibits the synthesis of IGF1 [1] at the liver, and both increased HGH levels & IGF1 levels cause more somatostatin to be released:
(Source 1)

View attachment 2643593
Octreotide is a medication that stimulates somatostatin receptors, the researchers are using that to simulate somatostatin. The mechanism by which IGF1 increases synthesis of SST is not fully understood however the following is the current theory:

It is believed IGF1 crosses the blood brain barrier via IGF BP3 [2]



^ these to excerpts from the source show how IGF1 is believed to enter the brain.



^ This following excerpt from the source could be misinterpreted to mean that what I just isn’t true, however this is referring to GH and IGF-1 produced in the brain that remains in the brain. All 3 extracts are from source [2]


So how do we do it:

1. Increasing GABA & Reducing glutamate

GABA is a neurotransmitter in the brain, a more detailed explanation is provided in the magnesium section below. In the pancreas, GABA inhibits the release of somatostatin when glucose is high, whereas it increases secretion of somatostatin. The amount of somatostatin produced in the pancreas is at levels as high in the brain so it can have a significant effect on the peripheral action of somatostatin (inhibiting IGF synthesis at the liver).

It has been shown increased plasma GABA levels lead to decreased plasma SST levels, the study which showed this gave a patient sodium valproate, something that increases the synthesis of GABA and found lower plasma somatostatin levels [9] . This also shows that the majority of the time, GABA will inhibit the release of SST and you do not need to follow a specific diet to keep the glucose levels high, as the patient in the study was on no such instructions. The practicality of sodium valproate for Heightmaxxing will be discussed further in this post.

However, there is slightly conflicting evidence, while plasma somatostatin may be reduced with increased GABA (due to inhibition of somatostatin in the pancreas), some evidence suggests that somatostatin release is upregulated in the brain. Somatostatin acts as a co-neurotransmitter to GABA. Both somatostatin and GABA are released in SST(somatostatin)+ GABAergic cells [10]. Additionally, it has been shown that increases GABA signalling increase somatostatin secretion in those cells. [11]



It has also been shown that a low SST level decreases GABA levels, it is unclear if this holds true for the opposite (i.e low GABA = low SST) or if this relationship is one way. If this relationship is one way, then increasing GABA levels in the brain would be beneficial as it would offset the decrease due to us artifically lowering SST.



Both extracts are from source 11.

However, the sodium valproate study shows us that increased gaba = reduced SST overall, and the evidence that low SST = low GABA is proven, whereas the reverse statement low gaba = low SST is an assumption. Therefore it is my recommendation to include the suggestion that increasing GABA levels in both the brain and blood is beneficial for inhibiting the release of SST(Somatostatin). The evidence in this field is highly recent & changing and different sources may contradict each other, I have attempted to use the strongest evidence base for each claim. Some sources also claim that SST released from GABAergic neurones mainly acts locally (without having an effect on HGH levels) and what diffuses out of the synapse stays in the CSF and will not affect synthesis of IGF1 in the liver [12]





Additionally, GABA supplementation has been shown to increase HGH levels in the blood [14], this evidence agrees with my conclusion that more GABA = good. It was thought that oral GABA could not cross the blood brain barrier, however recent research contests that.[15]. This supports the idea that more GABA in brain = good for heightmaxxing.

Now moving onto glutamate. Glutamate is the prominent excitatory neurotransmitter in the brain, essentially the opposite of GABA. It has been shown that glutamate triggers the secretion of somatostatin under low-glucose conditions in the pancreas [16]. Glutamate does not appear to inhibit the release of somatostatin at high glucose conditions, so we should aim to decrease it.

In the CNS, as is with GABA, it is alot more complex.


Somatostatin inhibits glutamate, and unfortunately the evidence relating to this is too complicated to understand fully, however the research paper (source 13) is linked if you would like to read it. Going off an assumption that lowering glutamate means our brains homeostatic mechanisms will reduce the amount of somatostatin to compensate for this, it follows that reduced glutamate = somatostatin.


How do we reduce glutamate and increase GABA?

Magnesium:
Magnesium is a true panacea, EVERYONE should be taking it, its beneficial to almost everything you want to try and do (except if you are taking Adderall it might reduce its effectiveness.). I will introduce the effects of magnesium first and then describe why those are good at inhibiting somatostatin, it will be copy pasted from my nootropics guide so some of the links may be broken (cba to fix it rn, but i have provided the source list below). I have not posted my nootropic guide as there are alot of posts about this already but if people want it then I can post it.



Source list for the above: (i tried usign a spoiler but the formatting killed itself so i made it small text)
[6] de Baaij JH, Hoenderop JG, Bindels RJ. Magnesium in man: implications for health and Lasike . Physiol Rev. 2015 Jan;95(1):1-46. doi: 10.1152/physrev.00012.2014. PMID: 25540137.
[7] Slutsky I, Abumaria N, Wu LJ, Huang C, Zhang L, Li B, Zhao X, Govindarajan A, Zhao MG, Zhuo M, Tonegawa S, Liu G. Enhancement of learning and memory by elevating brain magnesium. Neuron. 2010 Jan 28;65(2):165-77. doi: 10.1016/j.neuron.2009.12.026. PMID: 20152124.
[8]Hou H, Wang L, Fu T, Papasergi M, Yule DI, Xia H. Magnesium Acts as a Second Messenger in the Regulation of NMDA Receptor-Mediated CREB Signaling in Neurons. Mol Neurobiol. 2020 Jun;57(6):2539-2550. doi: 10.1007/s12035-020-01871-z. Epub 2020 Mar 25. PMID: 32215817; PMCID: PMC8202957.
[9] Lewerenz J, Maher P. Chronic Glutamate Toxicity in Neurodegenerative Diseases-What is the Evidence? Front Neurosci. 2015 Dec 16;9:469. doi: 10.3389/fnins.2015.00469. PMID: 26733784; PMCID: PMC4679930.
[10] : Chahal H et al., Modulation by magnesium of N-methyl-D-aspartate receptors in developing human brain.Arch Dis Child Fetal Neonatal Ed. 1998 Mar;78(2):F116-20.doi: 10.1136/fn.78.f116.
[11] Pedrón VT, Varani AP, Bettler B, Balerio GN. GABAB receptors modulate morphine antinociception: Pharmacological and genetic approaches. Pharmacol Biochem Behav. 2019 May;180:11-21.
[12] Kondziella D. The Top 5 Neurotransmitters from a Clinical Neurologist's Perspective. Neurochem Res. 2017 Jun;42(6):1767-1771. [[PubMed](https://pubmed.ncbi.nlm.nih.gov/27822666)] [[Reference list](https://www.ncbi.nlm.nih.gov/books/NBK513311/#article-22012.r2)]
[13] Olsen RW. GABAA receptor: Positive and negative allosteric modulators. Neuropharmacology. 2018 Jul 01;136(Pt A):10-22.
[14] Boyle NB, Lawton C, Dye L. The Effects of Magnesium Supplementation on Subjective Anxiety and Stress-A Systematic Review. Nutrients. 2017 Apr 26;9(5):429. doi: 10.3390/nu9050429. PMID: 28445426; PMCID: PMC5452159.


So to summarise, magnesium increases GABA levels in the brain, and inhibit release of glutamate. Additionally, magnesium supports calcium absorption into bones, so it is important in Heightmaxxing for that purpose too.

Oral GABA supplementation:
These can be purchased at nootropic websites, the dose used in the study described previously used a dose of 3g orally once per day.

2. Increased parasympathetic activity via inhibition of cholinesterase
WARNING: DO NOT USE IF YOU HAVE ASTHMA OR COPD !!

Cholinesterase & acetylcholinesterase is very important, it effectively reduces the parasympathetic response of the body (really its more accurate to say it prevents it from going out of hand..). Nerve agents, the most deadly compounds ever created by us, irrevsibly inhibit them (non-competitive inhibition, technically reversible by treatment with oxime within a certain time period dependant on exact agent used) which causes death by severe refractory bradycardia (extreme slowing of heart rate), paralysis and respiratory arrest.

I am saying this to give you an idea of the dangerous of pyridostigmine overdose and the role of the parasympathetic neverous system and cholinesterase in the body. Pyridostigmine is available in tablet form, and it would hard to accidently overdose on them, if there is a source selling it as a powder or liquid I highly recommend not using this due to the overdose risk. Huperazine is also measured in micrograms not milligrams, increasing overdose risk.

If you overdose on either of these compounds you need to seek help urgently, it is not like accidently injecting too much HGH where your blood sugar could tank in abit, or nothing might happen or you might have a headache etc, they can be **rapidly** lethal(as in you wont survive a trip to the hospital, you need to call for an ambulance rapid depending on the dose taken) and require specific drugs to reverse it. They can also cause significant cognitive deficits if you survive a large overdose. Before using these, ensure you know of overdose symptoms and correct dosage.

*note there are diffrences between cholinesterase and acetylcholinesterase however it not that relevant right now and this is already WAY too long, putting this here so you are aware I have taken this into account*

Pyridostigmine :
Pyridostigmine is a medication that inhibits an enzyme called cholinesterase. Cholinesterase exists in the synaptic cleft to remove acetylcholine, an inhibitory neurotransmitter used in the peripheral nervous system from repeatedly stimulating the post synaptic neurone.

Pyridostigmine has been shown to stimulate the release of HGH when given alone[16], and its mechanism of action has been postulated as an inhibitor of hypothalamic SST secretion [17][18]. The evidence for pyridostigmine is very strong.

Huperzine A:
Huperzine A is an acetylcholinesterase inhibitor. It also increases parasympathetic response via this mechanism. However, the evidence for it directly suppressing somatostatin is not studied, however, there are many discussions online supporting its use, and a theoretical link exists. I do not reccomened the use of Huperzine A if you have a respiratory disorder such as asthma or COPD as it can increase bronchial secretions and the evidence for its use is weak.

3. Reduce stress & Prevent chronic stress, this decreases SST.



This extract is from source 11, however for conivence I have included the sources it references for its claim. I recommend taking ashwagandha for this (provided you aren’t supplementing thyroid hormones).

4. L-arginine:
A low risk supplement, which has more evidence than huperazine A but is less efficaous compared to pyridostigmine.

L-arginine both supresses somatostatin releases and induces the release of GHRH (growth hormone releasing hormone). [19][20]




5. Injecting IGF1 (NOT LR3 or DES):
If you have this im very jealous. You most likely have been scammed if someone sold you this though as it is incredibly hard to source. There is no evidence that I could find that SST inhibits the effects of IGF1 at the tissue level or the effectiveness of IGF binding proteins, so theoretically IGF1 can bypass this entire mechanisms.


Risks of supressing SST:
  • Messing with body’s homeostatic and regulatory mechanisms can be dangerous
  • Low SST in the brain has been associated with conditions such as schizophrenia and depression
  • There is an incredibly complex relationship between hormones and neurotransmitters in the brain that I do not fully understand, this post does not even go 1 meter deep into it.
TLDR:

Magnesium* = More evidence than to the contrary to supports its use
Oral GABA = Evidence supports use
Pyridostigmine = Evidence supports use, exercise caution when dosing due to overdose risk
Stress reduction = Evidence is unclear, however recommended as no evidence to the contrary.
Huperzine A = Theoretical link, not recommended due to overdose risk.
L-Arginine = Evidence supports use
Calorific Surplus = Evidence supports use, Evidence supports negative effect when in defecit. Strongly reccomended to maintain high/sufficent glucose in blood


*a form of magneisum that is effective at crossing the blood brain barrier must be used. This is discussed in the nootropic guide*

I personally would take ATA Magnesium, oral Gaba and L-arginine as my additives to my stack.

FAQ:
- Will be added here as people reply to this thread
  • Dosages? A: For magnesium: 200-800mg, is effective, reccomend starting at 400mg and titrating based on side effects and blood test results. For GABA: 3g orally per day, pyridostigmine 60mg daily, titrate to effect 30-120mg, divide into 2 doses over the day. L arginine: 10g per day. Huperazine A (dont reccomend this) dosage is 50-150mcg daily.


Disclaimer:
- Please note that this information is based on the current understanding and research available as of 2023 and may be subject to change as new research emerges.
- This is posted for entertainment purposes only, it is your responsibility to verify information in this, I am not a healthcare professional. I am not responsible if you come to harm as a result of following this post.
- If you spot any errors in this thread please let me know by replying, peer reviewing is important!
- Ensure you double check side effects and dosages of medication to ensure it is suitable for you


Sources:
[1]: Murray RD, Kim K, Ren SG, Chelly M, Umehara Y, Melmed S. Central and peripheral actions of somatostatin on the growth hormone-IGF-I axis. J Clin Invest. 2004 Aug;114(3):349-56. doi: 10.1172/JCI19933. PMID: 15286801; PMCID: PMC484973.
[2]: Sarah M. Gray, Michael O. Thorner, Spatiotemporal Regulation of Insulin-Like Growth Factor-1 and Its Receptor in the Brain: Is There a Role for Growth Hormone?, _Endocrinology_, Volume 158, Issue 2, 1 February 2017, Pages 229–232, [https://doi.org/10.1210/en.2016-1884](https://doi.org/10.1210/en.2016-1884)
[^3]: Aguirre, G.A., De Ita, J.R., de la Garza, R.G. _et al._ Insulin-like growth factor-1 deficiency and metabolic syndrome. _J Transl Med_ **14**, 3 (2016). https://doi.org/10.1186/s12967-015-0762-z
[^4]: Mathew Daunt, Oliver Dale, Paul A. Smith, Somatostatin Inhibits Oxidative Respiration in Pancreatic β-Cells, _Endocrinology_, Volume 147, Issue 3, 1 March 2006, Pages 1527–1535, [https://doi.org/10.1210/en.2005-0873](https://doi.org/10.1210/en.2005-0873)
[^5]: Zgliczyński, W., Zdunowski, P., Czajka-Oraniec, I. _et al._ The role of somatostatin analogues in treatment of TSH secreting pituitary adenomas. _Thyroid Res_ **6** (Suppl 2), A64 (2013). https://doi.org/10.1186/1756-6614-6-S2-A64
[^6]: Pedrón VT, Varani AP, Bettler B, Balerio GN. GABAB receptors modulate morphine antinociception: Pharmacological and genetic approaches. Pharmacol Biochem Behav. 2019 May;180:11-21.
[^7]: Kondziella D. The Top 5 Neurotransmitters from a Clinical Neurologist's Perspective. Neurochem Res. 2017 Jun;42(6):1767-1771. [[PubMed](https://pubmed.ncbi.nlm.nih.gov/27822666)] [[Reference list](https://www.ncbi.nlm.nih.gov/books/NBK513311/#article-22012.r2)]
[^8]: Olsen RW. GABAA receptor: Positive and negative allosteric modulators. Neuropharmacology. 2018 Jul 01;136(Pt A):10-22.
[^9]: Kusunoki M, Yamamura T, Ichii S, Fujita S, Nakai T, Utsunomiya J, The effects of sodium valproate on plasma somatostatin and insulin in humans. _J Clin Endocrinol Metab_ (1988) 67(5):1060–3. doi: 10.1210/jcem-67-5-1060
[^10]: Iwasawa, C., Kuzumaki, N., Suda, Y. _et al._ Reduced expression of somatostatin in GABAergic interneurons derived from induced pluripotent stem cells of patients with _parkin_ mutations. _Mol Brain_ **12**, 5 (2019). https://doi.org/10.1186/s13041-019-0426-7
[^11]: Hou X, Rong C, Wang F, Liu X, Sun Y, Zhang HT. GABAergic System in Stress: Implications of GABAergic Neuron Subpopulations and the Gut-Vagus-Brain Pathway. Neural Plast. 2020 Aug 1;2020:8858415. doi: 10.1155/2020/8858415. PMID: 32802040; PMCID: PMC7416252.
[^12]: Pittaluga, A.; Roggeri, A.; Vallarino, G.; Olivero, G. Somatostatin, a Presynaptic Modulator of Glutamatergic Signal in the Central Nervous System. _Int. J. Mol. Sci._ **2021**, _22_, 5864. https://doi.org/10.3390/ijms22115864
[^13]: Akiko Muroyama, Shunsuke Uehara, Shouki Yatsushiro, Noriko Echigo, Riyo Morimoto, Mitsuhiro Morita, Mitsuko Hayashi, Akitsugu Yamamoto, Duk-Su Koh, Yoshinori Moriyama; A Novel Variant of Ionotropic Glutamate Receptor Regulates Somatostatin Secretion From δ-Cells of Islets of Langerhans. __Diabetes__ 1 July 2004; 53 (7): 1743–1753. [https://doi.org/10.2337/diabetes.53.7.1743](https://doi.org/10.2337/diabetes.53.7.1743)
[^14]: Powers ME, Yarrow JF, McCoy SC, Borst SE. Growth hormone isoform responses to GABA ingestion at rest and after exercise. Med Sci Sports Exerc. 2008 Jan;40(1):104-10. doi: 10.1249/mss.0b013e318158b518. PMID: 18091016.
[^15]: Hepsomali P, Groeger JA, Nishihira J, Scholey A. Effects of Oral Gamma-Aminobutyric Acid (GABA) Administration on Stress and Sleep in Humans: A Systematic Review. Front Neurosci. 2020 Sep 17;14:923. doi: 10.3389/fnins.2020.00923. PMID: 33041752; PMCID: PMC7527439.
[^16]: W B Wehrenberg, S D Wiviott, D M Voltz, A Giustina, Pyridostigmine-mediated growth hormone release: evidence for somatostatin involvement., _Endocrinology_, Volume 130, Issue 3, 1 March 1992, Pages 1445–1450, [https://doi.org/10.1210/endo.130.3.1347008](https://doi.org/10.1210/endo.130.3.1347008)
[^17]: Angela Peñalva, Bartolome Burguera, Xesus Casabiell, Jesus A.F. Tresguerres, Carlos Dieguez, Felipe F. Casanueva; Activation of Cholinergic Neurotransmission by Pyridostigmine Reverses the Inhibitory Effect of Hyperglycemia on Growth Hormone (GH) Releasing Hormone-Induced GH Secretion in Man: Does Acute Hyperglycemia Act through Hypothalamic Release of Somatostatin?. __Neuroendocrinology__ 1 May 1989; 49 (5): 551–554. [https://doi.org/10.1159/000125166](https://doi.org/10.1159/000125166)
[^18]: Hanew, K., Utsumi, A., Sugawara, A. _et al._ The evaluation of hypothalamic somatostatin tone using pyridostigmine and thyrotropin releasing hormone in patients with acromegaly. _J Endocrinol Invest_ **17**, 313–321 (1994). https://doi.org/10.1007/BF03348989
[^19]: Parvin Goli, Maryam Yazdi, Motahar Heidari-Beni, Roya Kelishadi, "Growth Hormone Response to L-Arginine Alone and Combined with Different Doses of Growth Hormone-Releasing Hormone: A Systematic Review and Meta-Analysis", _International Journal of Endocrinology_, vol. 2022, Article ID 8739289, 11 pages, 2022. https://doi.org/10.1155/2022/873928
[^20]: Jose Córdoba-Chacón, Manuel D. Gahete, Ana I. Pozo-Salas, Justo P. Castaño, Rhonda D. Kineman, Raul M. Luque, Endogenous Somatostatin Is Critical in Regulating the Acute Effects of l-Arginine on Growth Heilormone and Insulin Release in Mice, _Endocrinology_, Volume 154, Issue 7, 1 July 2013, Pages 72–26, [https://doi.org/26.05./en.11-1126
[^44]: A. Faron-Górecka, M. Kuśmider, M. Kolasa et al., “Chronic mild stress alters the somatostatin receptors in the rat brain,” _Psychopharmacology_, vol. 233, no. 2, pp. 255–266, 2016.
[^45]: A. Faron-Górecka, M. Kuśmider, J. Solich et al., “Regulation of somatostatin receptor 2 in the context of antidepressant treatment response in chronic mild stress in rat,” _Psychopharmacology_, vol. 235, no. 7, pp. 2137–2149, 2018.
[/spoiler]
I have checked and read through all sources manually so they should all be correct and support claims made, if you spot any errors let me know.

Please leave a reaction so it can reach the minimum required to get into BOTB.
water sea GIF
 
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where is a good place to buy the magnesium?
 
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HGH does not deal with somatostatin inhibition to any extent that it reduces its effectiveness significantly. Somatostatin inhibition isn't needed when using HGH because HGH will already be pushing up your IGF-1 levels high enough that you wouldn't even need to care about inhibiting somatostatin. So while yes, somatostatin is a limiting factor even when you use exogenous HGH, it's not to any extent that someone should worry, unlike the way it seems like you suggest in your post.
 
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Huperzine A shouldn't normally be brought up in a post about somatostatin inhibition unless it's a post exposing that it isn't one. There isn't a single actual study proving that it can inhibit somatostatin and the only reason why people thought it could is because it falls into the same family of drugs ( inhibitors of acetylcholinesterase) as physostigmine, but their chemical structures are completely different, demonstrating that they work through two different mechanisms.

Evidence lf


This post on looksmax also explains it well aswell
 
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I'm damn sure GHRH also inhibits somatostatin.
Well, from my research and DatBTrue's threads, it doesn't seem to be the case.

PROOFYY


GHRH can increase IGF-1 levels and stimulate growth hormone release with somewhat effectiveness in the presence of somatostatin, but it's nothing substantial or to go crazy about. GHRP's like GHRP-6, and MK677 however, can be seen as somatostatin inhibitors as they inhibit somatostatin, and it's the reason why we combine GHRPs and GHRH for maximum effectiveness. However, the increased presence of somatostatin does also lead to the reduced effectiveness of GHRP's as well though, so it's a double-edged sword, it works at inhibiting, but can also be inhibited by the same thing it can inhibit.


A study called, "Effect of combined administration of growth hormone (GH)-releasing hormone, GH-releasing peptide-6, and pyridostigmine in normal and obese subjects," shows this as when they used pyridostigmine alongside the GHRP-6, the increase in plasma GH didn't get any bigger, indicating that GHRP-6 already does that by itself!

HEHEFFO
 
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While theoretically speaking, Magnesium should be able to inhibit somatostatin, I doubt at any normal dosage can effectively inhibit somatostatin, and the only reason why I'm casting a shadow of doubt, is because there's never been a study proving that Magnesium directly enhances growth hormone in any way shape or form. However, magnesium should overall be used because it's been proven to increase your serum IGF-1 levels, but likely not through somatostatin inhibition.

Screenshot 637
 
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I'm surprised that you didn't include any Alpha-GPC or CDP-Choline? Been proven in a few studies to inhibit somatostatin via increasing acetylcholine levels rapidly, leading to a direct decrease of somatostatin since acetylcholine antagonizes somatostatin and has also been proven to simply increase growth hormone levels.

1704010470212



Vnvnvn
 
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read every word

arginine should be limited to 8-9g though bc a study found that there is a threshold (about 10g) which causes the measured GH increase from arginine to tank hard, and i think the effect from 8-9.9g was exactly the same anyway
 
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Huperzine A shouldn't normally be brought up in a post about somatostatin inhibition unless it's a post exposing that it isn't one. There isn't a single actual study proving that it can inhibit somatostatin and the only reason why people thought it could is because it falls into the same family of drugs ( inhibitors of acetylcholinesterase) as physostigmine, but their chemical structures are completely different, demonstrating that they work through two different mechanisms.

View attachment 2643935

This post on looksmax also explains it well aswell
included because still seeing some people say it works, i stated in the post there is no evidence to show that it works.
I'm surprised that you didn't include any Alpha-GPC or CDP-Choline? Been proven in a few studies to inhibit somatostatin via increasing acetylcholine levels rapidly, leading to a direct decrease of somatostatin since acetylcholine antagonizes somatostatin and has also been proven to simply increase growth hormone levels.

View attachment 2643970


View attachment 2643969
my 4 am brain forgot, ill add later but you already have a thread on it so ive just added a thing linking to your thread. Ill add the own section later & if i can still edit the thread

HGH does not deal with somatostatin inhibition to any extent that it reduces its effectiveness significantly. Somatostatin inhibition isn't needed when using HGH because HGH will already be pushing up your IGF-1 levels high enough that you wouldn't even need to care about inhibiting somatostatin. So while yes, somatostatin is a limiting factor even when you use exogenous HGH, it's not to any extent that someone should worry, unlike the way it seems like you suggest in your post.
As seen in this graph:
1704033074627


from [1]: it can be seen that even with exogenus GH administration, IGF levels (IGF1 mrna measures the amount of IGF synthesis) are lower when somatostatin is present. While the difference isnt massive, it is there, and due to the genetic differences some people may express a different amount of somatostatin receptors, so some may be more senstive to this effect. The cost of supressing somatostatin with things such as GABA and L-arginine are low cost and well tolerated so I think it is important everyone does it.


[1]: Murray RD, Kim K, Ren SG, Chelly M, Umehara Y, Melmed S. Central and peripheral actions of somatostatin on the growth hormone-IGF-I axis. J Clin Invest. 2004 Aug;114(3):349-56. doi: 10.1172/JCI19933. PMID: 15286801; PMCID: PMC484973.


While theoretically speaking, Magnesium should be able to inhibit somatostatin, I doubt at any normal dosage can effectively inhibit somatostatin, and the only reason why I'm casting a shadow of doubt, is because there's never been a study proving that Magnesium directly enhances growth hormone in any way shape or form. However, magnesium should overall be used because it's been proven to increase your serum IGF-1 levels, but likely not through somatostatin inhibition.

View attachment 2643961
imo the theortical link is very strong.
 
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Remember, OP. It's your responsibility to tag Moderators for BOTB.
 
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Research on this topic is lacking on this forum, and I have not seen a detailed thread specifically about this yet. This is an undervalued part of heightmaxxing that not many people know about.

Please leave a reaction so it can reach the minimum required to get into BOTB.

Somatostatin could be why some people respond really well to heightmaxxing and others dont, and it could be a way to get past your genetic limit.


TLDR AT BOTTOM.


oops did not see https://looksmax.org/threads/the-unknown-key-to-unlocking-hgh-igf-1-somatostatin.704036/ this thread that already exists on this topic until after I posted it luckily we dont have the exact same reccomendations and we look into a few different things, so reccomened reading both threads to get even more knowledge on the topic

btw idk how to use bbcode i use markdown in my personal notes so lmk if formatting is fucked


What is somatostatin & Introduction?

Somatostatin is a hormone that regulates the secretion of several other hormones, including growth hormone, which affects the growth of bones and tissues. It is released primarily by the hypothalamus, pituitary gland & pancreas, however other glands in the body such as the stomach and thyroid can also release it.

Acronyms used here:
  • SST, SRIF both refer to somatostatin
  • CNS refers to the central nervous system, the brain and spine
  • CSF refers to cerebro spinal fluid
  • PNS refers to peripheral nervous system
  • 'Peripheral effects of SST’ used on its own refers to effect of SST on the liver
  • Where a quotation is provided it is from the last refrenced study unless otherwise stated
  • Sourcing is done via numbers in brackets in superscript, the corresponding link to the study is provided at the bottom of this post.
Unfortunately, to measure your somatostatin levels you may need to go through a doctor, as I cant find any blood tests online that do it, additionally, plasma somatostatin levels may not be indictive of somatostatin levels in the brain

View attachment 2643580


Relevant effects of somatostatin
  • Inhibits HGH release from the pituitary gland → Lower serum HGH levels
  • Inhibit synthesis of IGF1 in the liver → Lower serum IGF levels → Less growth
  • Inhibit insulin production in the pancreas [4] : This is desired effect, and another reason why inhibiting somatostatin is complex and dangerous. If inject HGH into our body, the IGF produced will cause blood sugar levels to drop, if somatostatin was not there, more insulin levels would also be produced which can potentially be dangerous.
  • Prevent secretion of TSH [5] → lower metabolism. This further supports the use of thryoid hormones while heightmaxxing.
  • Preserves pulsatile release of HGH, the pulsatile release of HGH is due to alternating secretion of GH releasing hormone and Somatostatin in the brain.


How can we inhibit somatostatin:
Lets explore what increases the amount of somatostatin released, and what we can do to inhibit its release:

What wont work:


1. Injecting HGH and assuming you bypassed it.
You cant just inject HGH and think you have bypassed it, because as described already it inhibits the synthesis of IGF1 [1] at the liver, and both increased HGH levels & IGF1 levels cause more somatostatin to be released:
(Source 1)

View attachment 2643593
Octreotide is a medication that stimulates somatostatin receptors, the researchers are using that to simulate somatostatin. The mechanism by which IGF1 increases synthesis of SST is not fully understood however the following is the current theory:

It is believed IGF1 crosses the blood brain barrier via IGF BP3 [2]



^ these to excerpts from the source show how IGF1 is believed to enter the brain.



^ This following excerpt from the source could be misinterpreted to mean that what I just isn’t true, however this is referring to GH and IGF-1 produced in the brain that remains in the brain. All 3 extracts are from source [2]


So how do we do it:

1. Increasing GABA & Reducing glutamate

GABA is a neurotransmitter in the brain, a more detailed explanation is provided in the magnesium section below. In the pancreas, GABA inhibits the release of somatostatin when glucose is high, whereas it increases secretion of somatostatin. The amount of somatostatin produced in the pancreas is at levels as high in the brain so it can have a significant effect on the peripheral action of somatostatin (inhibiting IGF synthesis at the liver).

It has been shown increased plasma GABA levels lead to decreased plasma SST levels, the study which showed this gave a patient sodium valproate, something that increases the synthesis of GABA and found lower plasma somatostatin levels [9] . This also shows that the majority of the time, GABA will inhibit the release of SST and you do not need to follow a specific diet to keep the glucose levels high, as the patient in the study was on no such instructions. The practicality of sodium valproate for Heightmaxxing will be discussed further in this post.

However, there is slightly conflicting evidence, while plasma somatostatin may be reduced with increased GABA (due to inhibition of somatostatin in the pancreas), some evidence suggests that somatostatin release is upregulated in the brain. Somatostatin acts as a co-neurotransmitter to GABA. Both somatostatin and GABA are released in SST(somatostatin)+ GABAergic cells [10]. Additionally, it has been shown that increases GABA signalling increase somatostatin secretion in those cells. [11]



It has also been shown that a low SST level decreases GABA levels, it is unclear if this holds true for the opposite (i.e low GABA = low SST) or if this relationship is one way. If this relationship is one way, then increasing GABA levels in the brain would be beneficial as it would offset the decrease due to us artifically lowering SST.



Both extracts are from source 11.

However, the sodium valproate study shows us that increased gaba = reduced SST overall, and the evidence that low SST = low GABA is proven, whereas the reverse statement low gaba = low SST is an assumption. Therefore it is my recommendation to include the suggestion that increasing GABA levels in both the brain and blood is beneficial for inhibiting the release of SST(Somatostatin). The evidence in this field is highly recent & changing and different sources may contradict each other, I have attempted to use the strongest evidence base for each claim. Some sources also claim that SST released from GABAergic neurones mainly acts locally (without having an effect on HGH levels) and what diffuses out of the synapse stays in the CSF and will not affect synthesis of IGF1 in the liver [12]





Additionally, GABA supplementation has been shown to increase HGH levels in the blood [14], this evidence agrees with my conclusion that more GABA = good. It was thought that oral GABA could not cross the blood brain barrier, however recent research contests that.[15]. This supports the idea that more GABA in brain = good for heightmaxxing.

Now moving onto glutamate. Glutamate is the prominent excitatory neurotransmitter in the brain, essentially the opposite of GABA. It has been shown that glutamate triggers the secretion of somatostatin under low-glucose conditions in the pancreas [16]. Glutamate does not appear to inhibit the release of somatostatin at high glucose conditions, so we should aim to decrease it.

In the CNS, as is with GABA, it is alot more complex.


Somatostatin inhibits glutamate, and unfortunately the evidence relating to this is too complicated to understand fully, however the research paper (source 13) is linked if you would like to read it. Going off an assumption that lowering glutamate means our brains homeostatic mechanisms will reduce the amount of somatostatin to compensate for this, it follows that reduced glutamate = somatostatin.


How do we reduce glutamate and increase GABA?

Magnesium:
Magnesium is a true panacea, EVERYONE should be taking it, its beneficial to almost everything you want to try and do (except if you are taking Adderall it might reduce its effectiveness.). I will introduce the effects of magnesium first and then describe why those are good at inhibiting somatostatin, it will be copy pasted from my nootropics guide so some of the links may be broken (cba to fix it rn, but i have provided the source list below). I have not posted my nootropic guide as there are alot of posts about this already but if people want it then I can post it.



Source list for the above: (i tried usign a spoiler but the formatting killed itself so i made it small text)
[6] de Baaij JH, Hoenderop JG, Bindels RJ. Magnesium in man: implications for health and Lasike . Physiol Rev. 2015 Jan;95(1):1-46. doi: 10.1152/physrev.00012.2014. PMID: 25540137.
[7] Slutsky I, Abumaria N, Wu LJ, Huang C, Zhang L, Li B, Zhao X, Govindarajan A, Zhao MG, Zhuo M, Tonegawa S, Liu G. Enhancement of learning and memory by elevating brain magnesium. Neuron. 2010 Jan 28;65(2):165-77. doi: 10.1016/j.neuron.2009.12.026. PMID: 20152124.
[8]Hou H, Wang L, Fu T, Papasergi M, Yule DI, Xia H. Magnesium Acts as a Second Messenger in the Regulation of NMDA Receptor-Mediated CREB Signaling in Neurons. Mol Neurobiol. 2020 Jun;57(6):2539-2550. doi: 10.1007/s12035-020-01871-z. Epub 2020 Mar 25. PMID: 32215817; PMCID: PMC8202957.
[9] Lewerenz J, Maher P. Chronic Glutamate Toxicity in Neurodegenerative Diseases-What is the Evidence? Front Neurosci. 2015 Dec 16;9:469. doi: 10.3389/fnins.2015.00469. PMID: 26733784; PMCID: PMC4679930.
[10] : Chahal H et al., Modulation by magnesium of N-methyl-D-aspartate receptors in developing human brain.Arch Dis Child Fetal Neonatal Ed. 1998 Mar;78(2):F116-20.doi: 10.1136/fn.78.f116.
[11] Pedrón VT, Varani AP, Bettler B, Balerio GN. GABAB receptors modulate morphine antinociception: Pharmacological and genetic approaches. Pharmacol Biochem Behav. 2019 May;180:11-21.
[12] Kondziella D. The Top 5 Neurotransmitters from a Clinical Neurologist's Perspective. Neurochem Res. 2017 Jun;42(6):1767-1771. [[PubMed](https://pubmed.ncbi.nlm.nih.gov/27822666)] [[Reference list](https://www.ncbi.nlm.nih.gov/books/NBK513311/#article-22012.r2)]
[13] Olsen RW. GABAA receptor: Positive and negative allosteric modulators. Neuropharmacology. 2018 Jul 01;136(Pt A):10-22.
[14] Boyle NB, Lawton C, Dye L. The Effects of Magnesium Supplementation on Subjective Anxiety and Stress-A Systematic Review. Nutrients. 2017 Apr 26;9(5):429. doi: 10.3390/nu9050429. PMID: 28445426; PMCID: PMC5452159.


So to summarise, magnesium increases GABA levels in the brain, and inhibit release of glutamate. Additionally, magnesium supports calcium absorption into bones, so it is important in Heightmaxxing for that purpose too.

Oral GABA supplementation:
These can be purchased at nootropic websites, the dose used in the study described previously used a dose of 3g orally once per day.

2. Increased parasympathetic activity via inhibition of cholinesterase
WARNING: DO NOT USE IF YOU HAVE ASTHMA OR COPD !!

Cholinesterase & acetylcholinesterase is very important, it effectively reduces the parasympathetic response of the body (really its more accurate to say it prevents it from going out of hand..). Nerve agents, the most deadly compounds ever created by us, irrevsibly inhibit them (non-competitive inhibition, technically reversible by treatment with oxime within a certain time period dependant on exact agent used) which causes death by severe refractory bradycardia (extreme slowing of heart rate), paralysis and respiratory arrest.

I am saying this to give you an idea of the dangerous of pyridostigmine overdose and the role of the parasympathetic neverous system and cholinesterase in the body. Pyridostigmine is available in tablet form, and it would hard to accidently overdose on them, if there is a source selling it as a powder or liquid I highly recommend not using this due to the overdose risk. Huperazine is also measured in micrograms not milligrams, increasing overdose risk.

If you overdose on either of these compounds you need to seek help urgently, it is not like accidently injecting too much HGH where your blood sugar could tank in abit, or nothing might happen or you might have a headache etc, they can be **rapidly** lethal(as in you wont survive a trip to the hospital, you need to call for an ambulance rapid depending on the dose taken) and require specific drugs to reverse it. They can also cause significant cognitive deficits if you survive a large overdose. Before using these, ensure you know of overdose symptoms and correct dosage.

*note there are diffrences between cholinesterase and acetylcholinesterase however it not that relevant right now and this is already WAY too long, putting this here so you are aware I have taken this into account*

Pyridostigmine :
Pyridostigmine is a medication that inhibits an enzyme called cholinesterase. Cholinesterase exists in the synaptic cleft to remove acetylcholine, an inhibitory neurotransmitter used in the peripheral nervous system from repeatedly stimulating the post synaptic neurone.

Pyridostigmine has been shown to stimulate the release of HGH when given alone[16], and its mechanism of action has been postulated as an inhibitor of hypothalamic SST secretion [17][18]. The evidence for pyridostigmine is very strong.

Huperzine A:
Huperzine A is an acetylcholinesterase inhibitor. It also increases parasympathetic response via this mechanism. However, the evidence for it directly suppressing somatostatin is not studied, however, there are many discussions online supporting its use, and a theoretical link exists. I do not reccomened the use of Huperzine A if you have a respiratory disorder such as asthma or COPD as it can increase bronchial secretions and the evidence for its use is weak.


ALPHA GPC & Choline:
These are also proven to inhibit somatostatin, and increase GH, see the thread linked above for more info on these.


3. Reduce stress & Prevent chronic stress, this decreases SST.



This extract is from source 11, however for conivence I have included the sources it references for its claim. I recommend taking ashwagandha for this (provided you aren’t supplementing thyroid hormones).

4. L-arginine:
A low risk supplement, which has more evidence than huperazine A but is less efficaous compared to pyridostigmine.

L-arginine both supresses somatostatin releases and induces the release of GHRH (growth hormone releasing hormone). [19][20]




5. Injecting IGF1 (NOT LR3 or DES):
If you have this im very jealous. You most likely have been scammed if someone sold you this though as it is incredibly hard to source. There is no evidence that I could find that SST inhibits the effects of IGF1 at the tissue level or the effectiveness of IGF binding proteins, so theoretically IGF1 can bypass this entire mechanisms.


Risks of supressing SST:
  • Messing with body’s homeostatic and regulatory mechanisms can be dangerous
  • Low SST in the brain has been associated with conditions such as schizophrenia and depression
  • There is an incredibly complex relationship between hormones and neurotransmitters in the brain that I do not fully understand, this post does not even go 1 meter deep into it.
TLDR:

Magnesium* = More evidence than to the contrary to supports its use
Oral GABA = Evidence supports use
Pyridostigmine = Evidence supports use, exercise caution when dosing due to overdose risk
Stress reduction = Evidence is unclear, however recommended as no evidence to the contrary.
Huperzine A = Theoretical link, not recommended due to overdose risk.
L-Arginine = Evidence supports use
Calorific Surplus = Evidence supports use, Evidence supports negative effect when in defecit. Strongly reccomended to maintain high/sufficent glucose in blood


*a form of magneisum that is effective at crossing the blood brain barrier must be used. This is discussed in the nootropic guide*

I personally would take ATA Magnesium, oral Gaba and L-arginine as my additives to my stack.

FAQ:
- Will be added here as people reply to this thread
  • Dosages? A: For magnesium: 200-800mg, is effective, reccomend starting at 400mg and titrating based on side effects and blood test results. For GABA: 3g orally per day, pyridostigmine 60mg daily, titrate to effect 30-120mg, divide into 2 doses over the day. L arginine: 10g per day. Huperazine A (dont reccomend this) dosage is 50-150mcg daily.


Disclaimer:
- Please note that this information is based on the current understanding and research available as of 2023 and may be subject to change as new research emerges.
- This is posted for entertainment purposes only, it is your responsibility to verify information in this, I am not a healthcare professional. I am not responsible if you come to harm as a result of following this post.
- If you spot any errors in this thread please let me know by replying, peer reviewing is important!
- Ensure you double check side effects and dosages of medication to ensure it is suitable for you


Sources:
[1]: Murray RD, Kim K, Ren SG, Chelly M, Umehara Y, Melmed S. Central and peripheral actions of somatostatin on the growth hormone-IGF-I axis. J Clin Invest. 2004 Aug;114(3):349-56. doi: 10.1172/JCI19933. PMID: 15286801; PMCID: PMC484973.
[2]: Sarah M. Gray, Michael O. Thorner, Spatiotemporal Regulation of Insulin-Like Growth Factor-1 and Its Receptor in the Brain: Is There a Role for Growth Hormone?, _Endocrinology_, Volume 158, Issue 2, 1 February 2017, Pages 229–232, [https://doi.org/10.1210/en.2016-1884](https://doi.org/10.1210/en.2016-1884)
[^3]: Aguirre, G.A., De Ita, J.R., de la Garza, R.G. _et al._ Insulin-like growth factor-1 deficiency and metabolic syndrome. _J Transl Med_ **14**, 3 (2016). https://doi.org/10.1186/s12967-015-0762-z
[^4]: Mathew Daunt, Oliver Dale, Paul A. Smith, Somatostatin Inhibits Oxidative Respiration in Pancreatic β-Cells, _Endocrinology_, Volume 147, Issue 3, 1 March 2006, Pages 1527–1535, [https://doi.org/10.1210/en.2005-0873](https://doi.org/10.1210/en.2005-0873)
[^5]: Zgliczyński, W., Zdunowski, P., Czajka-Oraniec, I. _et al._ The role of somatostatin analogues in treatment of TSH secreting pituitary adenomas. _Thyroid Res_ **6** (Suppl 2), A64 (2013). https://doi.org/10.1186/1756-6614-6-S2-A64
[^6]: Pedrón VT, Varani AP, Bettler B, Balerio GN. GABAB receptors modulate morphine antinociception: Pharmacological and genetic approaches. Pharmacol Biochem Behav. 2019 May;180:11-21.
[^7]: Kondziella D. The Top 5 Neurotransmitters from a Clinical Neurologist's Perspective. Neurochem Res. 2017 Jun;42(6):1767-1771. [[PubMed](https://pubmed.ncbi.nlm.nih.gov/27822666)] [[Reference list](https://www.ncbi.nlm.nih.gov/books/NBK513311/#article-22012.r2)]
[^8]: Olsen RW. GABAA receptor: Positive and negative allosteric modulators. Neuropharmacology. 2018 Jul 01;136(Pt A):10-22.
[^9]: Kusunoki M, Yamamura T, Ichii S, Fujita S, Nakai T, Utsunomiya J, The effects of sodium valproate on plasma somatostatin and insulin in humans. _J Clin Endocrinol Metab_ (1988) 67(5):1060–3. doi: 10.1210/jcem-67-5-1060
[^10]: Iwasawa, C., Kuzumaki, N., Suda, Y. _et al._ Reduced expression of somatostatin in GABAergic interneurons derived from induced pluripotent stem cells of patients with _parkin_ mutations. _Mol Brain_ **12**, 5 (2019). https://doi.org/10.1186/s13041-019-0426-7
[^11]: Hou X, Rong C, Wang F, Liu X, Sun Y, Zhang HT. GABAergic System in Stress: Implications of GABAergic Neuron Subpopulations and the Gut-Vagus-Brain Pathway. Neural Plast. 2020 Aug 1;2020:8858415. doi: 10.1155/2020/8858415. PMID: 32802040; PMCID: PMC7416252.
[^12]: Pittaluga, A.; Roggeri, A.; Vallarino, G.; Olivero, G. Somatostatin, a Presynaptic Modulator of Glutamatergic Signal in the Central Nervous System. _Int. J. Mol. Sci._ **2021**, _22_, 5864. https://doi.org/10.3390/ijms22115864
[^13]: Akiko Muroyama, Shunsuke Uehara, Shouki Yatsushiro, Noriko Echigo, Riyo Morimoto, Mitsuhiro Morita, Mitsuko Hayashi, Akitsugu Yamamoto, Duk-Su Koh, Yoshinori Moriyama; A Novel Variant of Ionotropic Glutamate Receptor Regulates Somatostatin Secretion From δ-Cells of Islets of Langerhans. __Diabetes__ 1 July 2004; 53 (7): 1743–1753. [https://doi.org/10.2337/diabetes.53.7.1743](https://doi.org/10.2337/diabetes.53.7.1743)
[^14]: Powers ME, Yarrow JF, McCoy SC, Borst SE. Growth hormone isoform responses to GABA ingestion at rest and after exercise. Med Sci Sports Exerc. 2008 Jan;40(1):104-10. doi: 10.1249/mss.0b013e318158b518. PMID: 18091016.
[^15]: Hepsomali P, Groeger JA, Nishihira J, Scholey A. Effects of Oral Gamma-Aminobutyric Acid (GABA) Administration on Stress and Sleep in Humans: A Systematic Review. Front Neurosci. 2020 Sep 17;14:923. doi: 10.3389/fnins.2020.00923. PMID: 33041752; PMCID: PMC7527439.
[^16]: W B Wehrenberg, S D Wiviott, D M Voltz, A Giustina, Pyridostigmine-mediated growth hormone release: evidence for somatostatin involvement., _Endocrinology_, Volume 130, Issue 3, 1 March 1992, Pages 1445–1450, [https://doi.org/10.1210/endo.130.3.1347008](https://doi.org/10.1210/endo.130.3.1347008)
[^17]: Angela Peñalva, Bartolome Burguera, Xesus Casabiell, Jesus A.F. Tresguerres, Carlos Dieguez, Felipe F. Casanueva; Activation of Cholinergic Neurotransmission by Pyridostigmine Reverses the Inhibitory Effect of Hyperglycemia on Growth Hormone (GH) Releasing Hormone-Induced GH Secretion in Man: Does Acute Hyperglycemia Act through Hypothalamic Release of Somatostatin?. __Neuroendocrinology__ 1 May 1989; 49 (5): 551–554. [https://doi.org/10.1159/000125166](https://doi.org/10.1159/000125166)
[^18]: Hanew, K., Utsumi, A., Sugawara, A. _et al._ The evaluation of hypothalamic somatostatin tone using pyridostigmine and thyrotropin releasing hormone in patients with acromegaly. _J Endocrinol Invest_ **17**, 313–321 (1994). https://doi.org/10.1007/BF03348989
[^19]: Parvin Goli, Maryam Yazdi, Motahar Heidari-Beni, Roya Kelishadi, "Growth Hormone Response to L-Arginine Alone and Combined with Different Doses of Growth Hormone-Releasing Hormone: A Systematic Review and Meta-Analysis", _International Journal of Endocrinology_, vol. 2022, Article ID 8739289, 11 pages, 2022. https://doi.org/10.1155/2022/873928
[^20]: Jose Córdoba-Chacón, Manuel D. Gahete, Ana I. Pozo-Salas, Justo P. Castaño, Rhonda D. Kineman, Raul M. Luque, Endogenous Somatostatin Is Critical in Regulating the Acute Effects of l-Arginine on Growth Heilormone and Insulin Release in Mice, _Endocrinology_, Volume 154, Issue 7, 1 July 2013, Pages 72–26, [https://doi.org/26.05./en.11-1126
[^44]: A. Faron-Górecka, M. Kuśmider, M. Kolasa et al., “Chronic mild stress alters the somatostatin receptors in the rat brain,” _Psychopharmacology_, vol. 233, no. 2, pp. 255–266, 2016.
[^45]: A. Faron-Górecka, M. Kuśmider, J. Solich et al., “Regulation of somatostatin receptor 2 in the context of antidepressant treatment response in chronic mild stress in rat,” _Psychopharmacology_, vol. 235, no. 7, pp. 2137–2149, 2018.
[/spoiler]
I have checked and read through all sources manually so they should all be correct and support claims made, if you spot any errors let me know.

Please leave a reaction so it can reach the minimum required to get into BOTB.
Dangerous
 
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Great thread, pinned
 
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  • Love it
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u mfs better go into science and fix cancer when you're out of high school

don't let this autism go to waste
 
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included because still seeing some people say it works, i stated in the post there is no evidence to show that it works.

my 4 am brain forgot, ill add later but you already have a thread on it so ive just added a thing linking to your thread. Ill add the own section later & if i can still edit the thread


As seen in this graph: View attachment 2644473

from [1]: it can be seen that even with exogenus GH administration, IGF levels (IGF1 mrna measures the amount of IGF synthesis) are lower when somatostatin is present. While the difference isnt massive, it is there, and due to the genetic differences some people may express a different amount of somatostatin receptors, so some may be more senstive to this effect. The cost of supressing somatostatin with things such as GABA and L-arginine are low cost and well tolerated so I think it is important everyone does it.


[1]: Murray RD, Kim K, Ren SG, Chelly M, Umehara Y, Melmed S. Central and peripheral actions of somatostatin on the growth hormone-IGF-I axis. J Clin Invest. 2004 Aug;114(3):349-56. doi: 10.1172/JCI19933. PMID: 15286801; PMCID: PMC484973.

A fair response to all of my critiques! However, the magnesium one is still iffy for me, I don't know why, but I just feel like we would've have an study released proving that it enhances GH release but I could be wrong!

My only thing with inhibiting somatostatin is timing. I want to find out a way to learn an efficient timing to inhibit it. Because it's unclear if we should be inhibiting all day (so that whatever peptide or HGH we are using is constantly working) or like 60 minutes before bed time. It's tricky
imo the theortical link is very strong.
 
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increlex, the drug of the gods. pure bio identical IGF1. if only us lower class civilians could source it.
Increlex isn't that amazing or at least what we've seen so far in studies done on children that have IGF-1 receptor issues. We currently don't have a great understanding of our IGF-1 receptor or another possibility is that exogenous IGF-1 for some reason can't fix IGF-1 receptor issues.

A study called, "Profile of mecasermin for the long-term treatment of growth failure in children and adolescents with severe primary IGF-1 deficiency," explains it perfectly, as they state that, "The availability of rhIGF1 for treatment of severe primary IGFD had improved the possibility for subjects affected by this rare condition to achieve higher adult height and to improve the outcomes of some of the clinical features of this syndrome. Efficacy of rhIGF1 (mecasermin) therapy is not comparable to GH treatment in GHD children, with still poor results on final adult height. This may be due to our incomplete knowledge of the IGFD syndrome."

PICKNE
 
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A fair response to all of my critiques! However, the magnesium one is still iffy for me, I don't know why, but I just feel like we would've have an study released proving that it enhances GH release but I could be wrong!

My only thing with inhibiting somatostatin is timing. I want to find out a way to learn an efficient timing to inhibit it. Because it's unclear if we should be inhibiting all day (so that whatever peptide or HGH we are using is constantly working) or like 60 minutes before bed time. It's tricky
you raise a very good point with this, because there is a chance if we inhibit it all the day that we could develop some sort of tolerance/increased production of somatostatin by the body and this could mean if we stop taking or miss a dose it could cause a large amount of SST. This is all hypothetical of course, and I may be completely wrong. We know for sure that alternating GHRH and SST release is what allows for a pulsatile HGH release pattern, but thats as far as we know in terms of timings. I cant find any descriptions of anyone who has has their somatostatin levels tested while taking HGH online sadly, i did a quick search on this forum and meso but didnt find anything.
 
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@coispet @Gengar @NumbThePain Can this be moved into BOTB? I think it has all the requirements for BOTB elibilitly now that it has surpassed 20 reactions.
 
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q thread
 
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When taking a long acting ghrp like cjc-1295 dac should I try to keep the somatostatin levels moderate to avoid a HGH bleed? I think I read somewhere that HGH bleed is bad and it happens from cjc-1295 dac because the somatostatin isn’t strong enough to surpress the constant HGH pulses from the cjc.
 
When taking a long acting ghrp like cjc-1295 dac should I try to keep the somatostatin levels moderate to avoid a HGH bleed? I think I read somewhere that HGH bleed is bad and it happens from cjc-1295 dac because the somatostatin isn’t strong enough to surpress the constant HGH pulses from the cjc.
You want the bleed bruh or else cjc dac 1295 just becomes useless.
 
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Increlex isn't that amazing or at least what we've seen so far in studies done on children that have IGF-1 receptor issues. We currently don't have a great understanding of our IGF-1 receptor or another possibility is that exogenous IGF-1 for some reason can't fix IGF-1 receptor issues.

A study called, "Profile of mecasermin for the long-term treatment of growth failure in children and adolescents with severe primary IGF-1 deficiency," explains it perfectly, as they state that, "The availability of rhIGF1 for treatment of severe primary IGFD had improved the possibility for subjects affected by this rare condition to achieve higher adult height and to improve the outcomes of some of the clinical features of this syndrome. Efficacy of rhIGF1 (mecasermin) therapy is not comparable to GH treatment in GHD children, with still poor results on final adult height. This may be due to our incomplete knowledge of the IGFD syndrome."

View attachment 2645470
I cant find any literature on whether ghs like mk677 is equally effective in its somostatin reduction as its identical cousin ghrp-6.

Is there any studies that show it being equally effective at sst reduction.

Also, did the ghrp-6 study on sst do research on to the duration at which the sst reduction persisted.

I'm assuming it's duration is equal to the half life of ghrp-6.Am I correct.

Can we then extrapolate the sst reduction duration in mk677 be equivalent to its- half life?
 
this is the worst tasting supplement ive ever fucking tasted holy shit it tastes like cum
How do you know what cum tastes like?
 
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Research on this topic is lacking on this forum, and I have not seen a detailed thread specifically about this yet. This is an undervalued part of heightmaxxing that not many people know about.

Please leave a reaction so it can reach the minimum required to get into BOTB.

Somatostatin could be why some people respond really well to heightmaxxing and others dont, and it could be a way to get past your genetic limit.


TLDR AT BOTTOM.


oops did not see https://looksmax.org/threads/the-unknown-key-to-unlocking-hgh-igf-1-somatostatin.704036/ this thread that already exists on this topic until after I posted it luckily we dont have the exact same reccomendations and we look into a few different things, so reccomened reading both threads to get even more knowledge on the topic

btw idk how to use bbcode i use markdown in my personal notes so lmk if formatting is fucked


What is somatostatin & Introduction?

Somatostatin is a hormone that regulates the secretion of several other hormones, including growth hormone, which affects the growth of bones and tissues. It is released primarily by the hypothalamus, pituitary gland & pancreas, however other glands in the body such as the stomach and thyroid can also release it.

Acronyms used here:
  • SST, SRIF both refer to somatostatin
  • CNS refers to the central nervous system, the brain and spine
  • CSF refers to cerebro spinal fluid
  • PNS refers to peripheral nervous system
  • 'Peripheral effects of SST’ used on its own refers to effect of SST on the liver
  • Where a quotation is provided it is from the last refrenced study unless otherwise stated
  • Sourcing is done via numbers in brackets in superscript, the corresponding link to the study is provided at the bottom of this post.
Unfortunately, to measure your somatostatin levels you may need to go through a doctor, as I cant find any blood tests online that do it, additionally, plasma somatostatin levels may not be indictive of somatostatin levels in the brain

View attachment 2643580


Relevant effects of somatostatin
  • Inhibits HGH release from the pituitary gland → Lower serum HGH levels
  • Inhibit synthesis of IGF1 in the liver → Lower serum IGF levels → Less growth
  • Inhibit insulin production in the pancreas [4] : This is desired effect, and another reason why inhibiting somatostatin is complex and dangerous. If inject HGH into our body, the IGF produced will cause blood sugar levels to drop, if somatostatin was not there, more insulin levels would also be produced which can potentially be dangerous.
  • Prevent secretion of TSH [5] → lower metabolism. This further supports the use of thryoid hormones while heightmaxxing.
  • Preserves pulsatile release of HGH, the pulsatile release of HGH is due to alternating secretion of GH releasing hormone and Somatostatin in the brain.


How can we inhibit somatostatin:
Lets explore what increases the amount of somatostatin released, and what we can do to inhibit its release:

What wont work:


1. Injecting HGH and assuming you bypassed it.
You cant just inject HGH and think you have bypassed it, because as described already it inhibits the synthesis of IGF1 [1] at the liver, and both increased HGH levels & IGF1 levels cause more somatostatin to be released:
(Source 1)

View attachment 2643593
Octreotide is a medication that stimulates somatostatin receptors, the researchers are using that to simulate somatostatin. The mechanism by which IGF1 increases synthesis of SST is not fully understood however the following is the current theory:

It is believed IGF1 crosses the blood brain barrier via IGF BP3 [2]



^ these to excerpts from the source show how IGF1 is believed to enter the brain.



^ This following excerpt from the source could be misinterpreted to mean that what I just isn’t true, however this is referring to GH and IGF-1 produced in the brain that remains in the brain. All 3 extracts are from source [2]


So how do we do it:

1. Increasing GABA & Reducing glutamate

GABA is a neurotransmitter in the brain, a more detailed explanation is provided in the magnesium section below. In the pancreas, GABA inhibits the release of somatostatin when glucose is high, whereas it increases secretion of somatostatin. The amount of somatostatin produced in the pancreas is at levels as high in the brain so it can have a significant effect on the peripheral action of somatostatin (inhibiting IGF synthesis at the liver).

It has been shown increased plasma GABA levels lead to decreased plasma SST levels, the study which showed this gave a patient sodium valproate, something that increases the synthesis of GABA and found lower plasma somatostatin levels [9] . This also shows that the majority of the time, GABA will inhibit the release of SST and you do not need to follow a specific diet to keep the glucose levels high, as the patient in the study was on no such instructions. The practicality of sodium valproate for Heightmaxxing will be discussed further in this post.

However, there is slightly conflicting evidence, while plasma somatostatin may be reduced with increased GABA (due to inhibition of somatostatin in the pancreas), some evidence suggests that somatostatin release is upregulated in the brain. Somatostatin acts as a co-neurotransmitter to GABA. Both somatostatin and GABA are released in SST(somatostatin)+ GABAergic cells [10]. Additionally, it has been shown that increases GABA signalling increase somatostatin secretion in those cells. [11]



It has also been shown that a low SST level decreases GABA levels, it is unclear if this holds true for the opposite (i.e low GABA = low SST) or if this relationship is one way. If this relationship is one way, then increasing GABA levels in the brain would be beneficial as it would offset the decrease due to us artifically lowering SST.



Both extracts are from source 11.

However, the sodium valproate study shows us that increased gaba = reduced SST overall, and the evidence that low SST = low GABA is proven, whereas the reverse statement low gaba = low SST is an assumption. Therefore it is my recommendation to include the suggestion that increasing GABA levels in both the brain and blood is beneficial for inhibiting the release of SST(Somatostatin). The evidence in this field is highly recent & changing and different sources may contradict each other, I have attempted to use the strongest evidence base for each claim. Some sources also claim that SST released from GABAergic neurones mainly acts locally (without having an effect on HGH levels) and what diffuses out of the synapse stays in the CSF and will not affect synthesis of IGF1 in the liver [12]





Additionally, GABA supplementation has been shown to increase HGH levels in the blood [14], this evidence agrees with my conclusion that more GABA = good. It was thought that oral GABA could not cross the blood brain barrier, however recent research contests that.[15]. This supports the idea that more GABA in brain = good for heightmaxxing.

Now moving onto glutamate. Glutamate is the prominent excitatory neurotransmitter in the brain, essentially the opposite of GABA. It has been shown that glutamate triggers the secretion of somatostatin under low-glucose conditions in the pancreas [16]. Glutamate does not appear to inhibit the release of somatostatin at high glucose conditions, so we should aim to decrease it.

In the CNS, as is with GABA, it is alot more complex.


Somatostatin inhibits glutamate, and unfortunately the evidence relating to this is too complicated to understand fully, however the research paper (source 13) is linked if you would like to read it. Going off an assumption that lowering glutamate means our brains homeostatic mechanisms will reduce the amount of somatostatin to compensate for this, it follows that reduced glutamate = somatostatin.


How do we reduce glutamate and increase GABA?

Magnesium:
Magnesium is a true panacea, EVERYONE should be taking it, its beneficial to almost everything you want to try and do (except if you are taking Adderall it might reduce its effectiveness.). I will introduce the effects of magnesium first and then describe why those are good at inhibiting somatostatin, it will be copy pasted from my nootropics guide so some of the links may be broken (cba to fix it rn, but i have provided the source list below). I have not posted my nootropic guide as there are alot of posts about this already but if people want it then I can post it.



Source list for the above: (i tried usign a spoiler but the formatting killed itself so i made it small text)
[6] de Baaij JH, Hoenderop JG, Bindels RJ. Magnesium in man: implications for health and Lasike . Physiol Rev. 2015 Jan;95(1):1-46. doi: 10.1152/physrev.00012.2014. PMID: 25540137.
[7] Slutsky I, Abumaria N, Wu LJ, Huang C, Zhang L, Li B, Zhao X, Govindarajan A, Zhao MG, Zhuo M, Tonegawa S, Liu G. Enhancement of learning and memory by elevating brain magnesium. Neuron. 2010 Jan 28;65(2):165-77. doi: 10.1016/j.neuron.2009.12.026. PMID: 20152124.
[8]Hou H, Wang L, Fu T, Papasergi M, Yule DI, Xia H. Magnesium Acts as a Second Messenger in the Regulation of NMDA Receptor-Mediated CREB Signaling in Neurons. Mol Neurobiol. 2020 Jun;57(6):2539-2550. doi: 10.1007/s12035-020-01871-z. Epub 2020 Mar 25. PMID: 32215817; PMCID: PMC8202957.
[9] Lewerenz J, Maher P. Chronic Glutamate Toxicity in Neurodegenerative Diseases-What is the Evidence? Front Neurosci. 2015 Dec 16;9:469. doi: 10.3389/fnins.2015.00469. PMID: 26733784; PMCID: PMC4679930.
[10] : Chahal H et al., Modulation by magnesium of N-methyl-D-aspartate receptors in developing human brain.Arch Dis Child Fetal Neonatal Ed. 1998 Mar;78(2):F116-20.doi: 10.1136/fn.78.f116.
[11] Pedrón VT, Varani AP, Bettler B, Balerio GN. GABAB receptors modulate morphine antinociception: Pharmacological and genetic approaches. Pharmacol Biochem Behav. 2019 May;180:11-21.
[12] Kondziella D. The Top 5 Neurotransmitters from a Clinical Neurologist's Perspective. Neurochem Res. 2017 Jun;42(6):1767-1771. [[PubMed](https://pubmed.ncbi.nlm.nih.gov/27822666)] [[Reference list](https://www.ncbi.nlm.nih.gov/books/NBK513311/#article-22012.r2)]
[13] Olsen RW. GABAA receptor: Positive and negative allosteric modulators. Neuropharmacology. 2018 Jul 01;136(Pt A):10-22.
[14] Boyle NB, Lawton C, Dye L. The Effects of Magnesium Supplementation on Subjective Anxiety and Stress-A Systematic Review. Nutrients. 2017 Apr 26;9(5):429. doi: 10.3390/nu9050429. PMID: 28445426; PMCID: PMC5452159.


So to summarise, magnesium increases GABA levels in the brain, and inhibit release of glutamate. Additionally, magnesium supports calcium absorption into bones, so it is important in Heightmaxxing for that purpose too.

Oral GABA supplementation:
These can be purchased at nootropic websites, the dose used in the study described previously used a dose of 3g orally once per day.

2. Increased parasympathetic activity via inhibition of cholinesterase
WARNING: DO NOT USE IF YOU HAVE ASTHMA OR COPD !!

Cholinesterase & acetylcholinesterase is very important, it effectively reduces the parasympathetic response of the body (really its more accurate to say it prevents it from going out of hand..). Nerve agents, the most deadly compounds ever created by us, irrevsibly inhibit them (non-competitive inhibition, technically reversible by treatment with oxime within a certain time period dependant on exact agent used) which causes death by severe refractory bradycardia (extreme slowing of heart rate), paralysis and respiratory arrest.

I am saying this to give you an idea of the dangerous of pyridostigmine overdose and the role of the parasympathetic neverous system and cholinesterase in the body. Pyridostigmine is available in tablet form, and it would hard to accidently overdose on them, if there is a source selling it as a powder or liquid I highly recommend not using this due to the overdose risk. Huperazine is also measured in micrograms not milligrams, increasing overdose risk.

If you overdose on either of these compounds you need to seek help urgently, it is not like accidently injecting too much HGH where your blood sugar could tank in abit, or nothing might happen or you might have a headache etc, they can be **rapidly** lethal(as in you wont survive a trip to the hospital, you need to call for an ambulance rapid depending on the dose taken) and require specific drugs to reverse it. They can also cause significant cognitive deficits if you survive a large overdose. Before using these, ensure you know of overdose symptoms and correct dosage.

*note there are diffrences between cholinesterase and acetylcholinesterase however it not that relevant right now and this is already WAY too long, putting this here so you are aware I have taken this into account*

Pyridostigmine :
Pyridostigmine is a medication that inhibits an enzyme called cholinesterase. Cholinesterase exists in the synaptic cleft to remove acetylcholine, an inhibitory neurotransmitter used in the peripheral nervous system from repeatedly stimulating the post synaptic neurone.

Pyridostigmine has been shown to stimulate the release of HGH when given alone[16], and its mechanism of action has been postulated as an inhibitor of hypothalamic SST secretion [17][18]. The evidence for pyridostigmine is very strong.

Huperzine A:
Huperzine A is an acetylcholinesterase inhibitor. It also increases parasympathetic response via this mechanism. However, the evidence for it directly suppressing somatostatin is not studied, however, there are many discussions online supporting its use, and a theoretical link exists. I do not reccomened the use of Huperzine A if you have a respiratory disorder such as asthma or COPD as it can increase bronchial secretions and the evidence for its use is weak.


ALPHA GPC & Choline:
These are also proven to inhibit somatostatin, and increase GH, see the thread linked above for more info on these.


3. Reduce stress & Prevent chronic stress, this decreases SST.



This extract is from source 11, however for conivence I have included the sources it references for its claim. I recommend taking ashwagandha for this (provided you aren’t supplementing thyroid hormones).

4. L-arginine:
A low risk supplement, which has more evidence than huperazine A but is less efficaous compared to pyridostigmine.

L-arginine both supresses somatostatin releases and induces the release of GHRH (growth hormone releasing hormone). [19][20]




5. Injecting IGF1 (NOT LR3 or DES):
If you have this im very jealous. You most likely have been scammed if someone sold you this though as it is incredibly hard to source. There is no evidence that I could find that SST inhibits the effects of IGF1 at the tissue level or the effectiveness of IGF binding proteins, so theoretically IGF1 can bypass this entire mechanisms.


Risks of supressing SST:
  • Messing with body’s homeostatic and regulatory mechanisms can be dangerous
  • Low SST in the brain has been associated with conditions such as schizophrenia and depression
  • There is an incredibly complex relationship between hormones and neurotransmitters in the brain that I do not fully understand, this post does not even go 1 meter deep into it.
TLDR:

Magnesium* = More evidence than to the contrary to supports its use
Oral GABA = Evidence supports use
Pyridostigmine = Evidence supports use, exercise caution when dosing due to overdose risk
Stress reduction = Evidence is unclear, however recommended as no evidence to the contrary.
Huperzine A = Theoretical link, not recommended due to overdose risk.
L-Arginine = Evidence supports use
Calorific Surplus = Evidence supports use, Evidence supports negative effect when in defecit. Strongly reccomended to maintain high/sufficent glucose in blood


*a form of magneisum that is effective at crossing the blood brain barrier must be used. This is discussed in the nootropic guide*

I personally would take ATA Magnesium, oral Gaba and L-arginine as my additives to my stack.

FAQ:
- Will be added here as people reply to this thread
  • Dosages? A: For magnesium: 200-800mg, is effective, reccomend starting at 400mg and titrating based on side effects and blood test results. For GABA: 3g orally per day, pyridostigmine 60mg daily, titrate to effect 30-120mg, divide into 2 doses over the day. L arginine: 10g per day. Huperazine A (dont reccomend this) dosage is 50-150mcg daily.


Disclaimer:
- Please note that this information is based on the current understanding and research available as of 2023 and may be subject to change as new research emerges.
- This is posted for entertainment purposes only, it is your responsibility to verify information in this, I am not a healthcare professional. I am not responsible if you come to harm as a result of following this post.
- If you spot any errors in this thread please let me know by replying, peer reviewing is important!
- Ensure you double check side effects and dosages of medication to ensure it is suitable for you


Sources:
[1]: Murray RD, Kim K, Ren SG, Chelly M, Umehara Y, Melmed S. Central and peripheral actions of somatostatin on the growth hormone-IGF-I axis. J Clin Invest. 2004 Aug;114(3):349-56. doi: 10.1172/JCI19933. PMID: 15286801; PMCID: PMC484973.
[2]: Sarah M. Gray, Michael O. Thorner, Spatiotemporal Regulation of Insulin-Like Growth Factor-1 and Its Receptor in the Brain: Is There a Role for Growth Hormone?, _Endocrinology_, Volume 158, Issue 2, 1 February 2017, Pages 229–232, [https://doi.org/10.1210/en.2016-1884](https://doi.org/10.1210/en.2016-1884)
[^3]: Aguirre, G.A., De Ita, J.R., de la Garza, R.G. _et al._ Insulin-like growth factor-1 deficiency and metabolic syndrome. _J Transl Med_ **14**, 3 (2016). https://doi.org/10.1186/s12967-015-0762-z
[^4]: Mathew Daunt, Oliver Dale, Paul A. Smith, Somatostatin Inhibits Oxidative Respiration in Pancreatic β-Cells, _Endocrinology_, Volume 147, Issue 3, 1 March 2006, Pages 1527–1535, [https://doi.org/10.1210/en.2005-0873](https://doi.org/10.1210/en.2005-0873)
[^5]: Zgliczyński, W., Zdunowski, P., Czajka-Oraniec, I. _et al._ The role of somatostatin analogues in treatment of TSH secreting pituitary adenomas. _Thyroid Res_ **6** (Suppl 2), A64 (2013). https://doi.org/10.1186/1756-6614-6-S2-A64
[^6]: Pedrón VT, Varani AP, Bettler B, Balerio GN. GABAB receptors modulate morphine antinociception: Pharmacological and genetic approaches. Pharmacol Biochem Behav. 2019 May;180:11-21.
[^7]: Kondziella D. The Top 5 Neurotransmitters from a Clinical Neurologist's Perspective. Neurochem Res. 2017 Jun;42(6):1767-1771. [[PubMed](https://pubmed.ncbi.nlm.nih.gov/27822666)] [[Reference list](https://www.ncbi.nlm.nih.gov/books/NBK513311/#article-22012.r2)]
[^8]: Olsen RW. GABAA receptor: Positive and negative allosteric modulators. Neuropharmacology. 2018 Jul 01;136(Pt A):10-22.
[^9]: Kusunoki M, Yamamura T, Ichii S, Fujita S, Nakai T, Utsunomiya J, The effects of sodium valproate on plasma somatostatin and insulin in humans. _J Clin Endocrinol Metab_ (1988) 67(5):1060–3. doi: 10.1210/jcem-67-5-1060
[^10]: Iwasawa, C., Kuzumaki, N., Suda, Y. _et al._ Reduced expression of somatostatin in GABAergic interneurons derived from induced pluripotent stem cells of patients with _parkin_ mutations. _Mol Brain_ **12**, 5 (2019). https://doi.org/10.1186/s13041-019-0426-7
[^11]: Hou X, Rong C, Wang F, Liu X, Sun Y, Zhang HT. GABAergic System in Stress: Implications of GABAergic Neuron Subpopulations and the Gut-Vagus-Brain Pathway. Neural Plast. 2020 Aug 1;2020:8858415. doi: 10.1155/2020/8858415. PMID: 32802040; PMCID: PMC7416252.
[^12]: Pittaluga, A.; Roggeri, A.; Vallarino, G.; Olivero, G. Somatostatin, a Presynaptic Modulator of Glutamatergic Signal in the Central Nervous System. _Int. J. Mol. Sci._ **2021**, _22_, 5864. https://doi.org/10.3390/ijms22115864
[^13]: Akiko Muroyama, Shunsuke Uehara, Shouki Yatsushiro, Noriko Echigo, Riyo Morimoto, Mitsuhiro Morita, Mitsuko Hayashi, Akitsugu Yamamoto, Duk-Su Koh, Yoshinori Moriyama; A Novel Variant of Ionotropic Glutamate Receptor Regulates Somatostatin Secretion From δ-Cells of Islets of Langerhans. __Diabetes__ 1 July 2004; 53 (7): 1743–1753. [https://doi.org/10.2337/diabetes.53.7.1743](https://doi.org/10.2337/diabetes.53.7.1743)
[^14]: Powers ME, Yarrow JF, McCoy SC, Borst SE. Growth hormone isoform responses to GABA ingestion at rest and after exercise. Med Sci Sports Exerc. 2008 Jan;40(1):104-10. doi: 10.1249/mss.0b013e318158b518. PMID: 18091016.
[^15]: Hepsomali P, Groeger JA, Nishihira J, Scholey A. Effects of Oral Gamma-Aminobutyric Acid (GABA) Administration on Stress and Sleep in Humans: A Systematic Review. Front Neurosci. 2020 Sep 17;14:923. doi: 10.3389/fnins.2020.00923. PMID: 33041752; PMCID: PMC7527439.
[^16]: W B Wehrenberg, S D Wiviott, D M Voltz, A Giustina, Pyridostigmine-mediated growth hormone release: evidence for somatostatin involvement., _Endocrinology_, Volume 130, Issue 3, 1 March 1992, Pages 1445–1450, [https://doi.org/10.1210/endo.130.3.1347008](https://doi.org/10.1210/endo.130.3.1347008)
[^17]: Angela Peñalva, Bartolome Burguera, Xesus Casabiell, Jesus A.F. Tresguerres, Carlos Dieguez, Felipe F. Casanueva; Activation of Cholinergic Neurotransmission by Pyridostigmine Reverses the Inhibitory Effect of Hyperglycemia on Growth Hormone (GH) Releasing Hormone-Induced GH Secretion in Man: Does Acute Hyperglycemia Act through Hypothalamic Release of Somatostatin?. __Neuroendocrinology__ 1 May 1989; 49 (5): 551–554. [https://doi.org/10.1159/000125166](https://doi.org/10.1159/000125166)
[^18]: Hanew, K., Utsumi, A., Sugawara, A. _et al._ The evaluation of hypothalamic somatostatin tone using pyridostigmine and thyrotropin releasing hormone in patients with acromegaly. _J Endocrinol Invest_ **17**, 313–321 (1994). https://doi.org/10.1007/BF03348989
[^19]: Parvin Goli, Maryam Yazdi, Motahar Heidari-Beni, Roya Kelishadi, "Growth Hormone Response to L-Arginine Alone and Combined with Different Doses of Growth Hormone-Releasing Hormone: A Systematic Review and Meta-Analysis", _International Journal of Endocrinology_, vol. 2022, Article ID 8739289, 11 pages, 2022. https://doi.org/10.1155/2022/873928
[^20]: Jose Córdoba-Chacón, Manuel D. Gahete, Ana I. Pozo-Salas, Justo P. Castaño, Rhonda D. Kineman, Raul M. Luque, Endogenous Somatostatin Is Critical in Regulating the Acute Effects of l-Arginine on Growth Heilormone and Insulin Release in Mice, _Endocrinology_, Volume 154, Issue 7, 1 July 2013, Pages 72–26, [https://doi.org/26.05./en.11-1126
[^44]: A. Faron-Górecka, M. Kuśmider, M. Kolasa et al., “Chronic mild stress alters the somatostatin receptors in the rat brain,” _Psychopharmacology_, vol. 233, no. 2, pp. 255–266, 2016.
[^45]: A. Faron-Górecka, M. Kuśmider, J. Solich et al., “Regulation of somatostatin receptor 2 in the context of antidepressant treatment response in chronic mild stress in rat,” _Psychopharmacology_, vol. 235, no. 7, pp. 2137–2149, 2018.
[/spoiler]
I have checked and read through all sources manually so they should all be correct and support claims made, if you spot any errors let me know.

Please leave a reaction so it can reach the minimum required to get into BOTB.
Mirin haa thread. Goof work bro
 
Research on this topic is lacking on this forum, and I have not seen a detailed thread specifically about this yet. This is an undervalued part of heightmaxxing that not many people know about.

Please leave a reaction so it can reach the minimum required to get into BOTB.

Somatostatin could be why some people respond really well to heightmaxxing and others dont, and it could be a way to get past your genetic limit.


TLDR AT BOTTOM.


oops did not see https://looksmax.org/threads/the-unknown-key-to-unlocking-hgh-igf-1-somatostatin.704036/ this thread that already exists on this topic until after I posted it luckily we dont have the exact same reccomendations and we look into a few different things, so reccomened reading both threads to get even more knowledge on the topic

btw idk how to use bbcode i use markdown in my personal notes so lmk if formatting is fucked


What is somatostatin & Introduction?

Somatostatin is a hormone that regulates the secretion of several other hormones, including growth hormone, which affects the growth of bones and tissues. It is released primarily by the hypothalamus, pituitary gland & pancreas, however other glands in the body such as the stomach and thyroid can also release it.

Acronyms used here:
  • SST, SRIF both refer to somatostatin
  • CNS refers to the central nervous system, the brain and spine
  • CSF refers to cerebro spinal fluid
  • PNS refers to peripheral nervous system
  • 'Peripheral effects of SST’ used on its own refers to effect of SST on the liver
  • Where a quotation is provided it is from the last refrenced study unless otherwise stated
  • Sourcing is done via numbers in brackets in superscript, the corresponding link to the study is provided at the bottom of this post.
Unfortunately, to measure your somatostatin levels you may need to go through a doctor, as I cant find any blood tests online that do it, additionally, plasma somatostatin levels may not be indictive of somatostatin levels in the brain

View attachment 2643580


Relevant effects of somatostatin
  • Inhibits HGH release from the pituitary gland → Lower serum HGH levels
  • Inhibit synthesis of IGF1 in the liver → Lower serum IGF levels → Less growth
  • Inhibit insulin production in the pancreas [4] : This is desired effect, and another reason why inhibiting somatostatin is complex and dangerous. If inject HGH into our body, the IGF produced will cause blood sugar levels to drop, if somatostatin was not there, more insulin levels would also be produced which can potentially be dangerous.
  • Prevent secretion of TSH [5] → lower metabolism. This further supports the use of thryoid hormones while heightmaxxing.
  • Preserves pulsatile release of HGH, the pulsatile release of HGH is due to alternating secretion of GH releasing hormone and Somatostatin in the brain.


How can we inhibit somatostatin:
Lets explore what increases the amount of somatostatin released, and what we can do to inhibit its release:

What wont work:


1. Injecting HGH and assuming you bypassed it.
You cant just inject HGH and think you have bypassed it, because as described already it inhibits the synthesis of IGF1 [1] at the liver, and both increased HGH levels & IGF1 levels cause more somatostatin to be released:
(Source 1)

View attachment 2643593
Octreotide is a medication that stimulates somatostatin receptors, the researchers are using that to simulate somatostatin. The mechanism by which IGF1 increases synthesis of SST is not fully understood however the following is the current theory:

It is believed IGF1 crosses the blood brain barrier via IGF BP3 [2]



^ these to excerpts from the source show how IGF1 is believed to enter the brain.



^ This following excerpt from the source could be misinterpreted to mean that what I just isn’t true, however this is referring to GH and IGF-1 produced in the brain that remains in the brain. All 3 extracts are from source [2]


So how do we do it:

1. Increasing GABA & Reducing glutamate

GABA is a neurotransmitter in the brain, a more detailed explanation is provided in the magnesium section below. In the pancreas, GABA inhibits the release of somatostatin when glucose is high, whereas it increases secretion of somatostatin. The amount of somatostatin produced in the pancreas is at levels as high in the brain so it can have a significant effect on the peripheral action of somatostatin (inhibiting IGF synthesis at the liver).

It has been shown increased plasma GABA levels lead to decreased plasma SST levels, the study which showed this gave a patient sodium valproate, something that increases the synthesis of GABA and found lower plasma somatostatin levels [9] . This also shows that the majority of the time, GABA will inhibit the release of SST and you do not need to follow a specific diet to keep the glucose levels high, as the patient in the study was on no such instructions. The practicality of sodium valproate for Heightmaxxing will be discussed further in this post.

However, there is slightly conflicting evidence, while plasma somatostatin may be reduced with increased GABA (due to inhibition of somatostatin in the pancreas), some evidence suggests that somatostatin release is upregulated in the brain. Somatostatin acts as a co-neurotransmitter to GABA. Both somatostatin and GABA are released in SST(somatostatin)+ GABAergic cells [10]. Additionally, it has been shown that increases GABA signalling increase somatostatin secretion in those cells. [11]



It has also been shown that a low SST level decreases GABA levels, it is unclear if this holds true for the opposite (i.e low GABA = low SST) or if this relationship is one way. If this relationship is one way, then increasing GABA levels in the brain would be beneficial as it would offset the decrease due to us artifically lowering SST.



Both extracts are from source 11.

However, the sodium valproate study shows us that increased gaba = reduced SST overall, and the evidence that low SST = low GABA is proven, whereas the reverse statement low gaba = low SST is an assumption. Therefore it is my recommendation to include the suggestion that increasing GABA levels in both the brain and blood is beneficial for inhibiting the release of SST(Somatostatin). The evidence in this field is highly recent & changing and different sources may contradict each other, I have attempted to use the strongest evidence base for each claim. Some sources also claim that SST released from GABAergic neurones mainly acts locally (without having an effect on HGH levels) and what diffuses out of the synapse stays in the CSF and will not affect synthesis of IGF1 in the liver [12]





Additionally, GABA supplementation has been shown to increase HGH levels in the blood [14], this evidence agrees with my conclusion that more GABA = good. It was thought that oral GABA could not cross the blood brain barrier, however recent research contests that.[15]. This supports the idea that more GABA in brain = good for heightmaxxing.

Now moving onto glutamate. Glutamate is the prominent excitatory neurotransmitter in the brain, essentially the opposite of GABA. It has been shown that glutamate triggers the secretion of somatostatin under low-glucose conditions in the pancreas [16]. Glutamate does not appear to inhibit the release of somatostatin at high glucose conditions, so we should aim to decrease it.

In the CNS, as is with GABA, it is alot more complex.


Somatostatin inhibits glutamate, and unfortunately the evidence relating to this is too complicated to understand fully, however the research paper (source 13) is linked if you would like to read it. Going off an assumption that lowering glutamate means our brains homeostatic mechanisms will reduce the amount of somatostatin to compensate for this, it follows that reduced glutamate = somatostatin.


How do we reduce glutamate and increase GABA?

Magnesium:
Magnesium is a true panacea, EVERYONE should be taking it, its beneficial to almost everything you want to try and do (except if you are taking Adderall it might reduce its effectiveness.). I will introduce the effects of magnesium first and then describe why those are good at inhibiting somatostatin, it will be copy pasted from my nootropics guide so some of the links may be broken (cba to fix it rn, but i have provided the source list below). I have not posted my nootropic guide as there are alot of posts about this already but if people want it then I can post it.



Source list for the above: (i tried usign a spoiler but the formatting killed itself so i made it small text)
[6] de Baaij JH, Hoenderop JG, Bindels RJ. Magnesium in man: implications for health and Lasike . Physiol Rev. 2015 Jan;95(1):1-46. doi: 10.1152/physrev.00012.2014. PMID: 25540137.
[7] Slutsky I, Abumaria N, Wu LJ, Huang C, Zhang L, Li B, Zhao X, Govindarajan A, Zhao MG, Zhuo M, Tonegawa S, Liu G. Enhancement of learning and memory by elevating brain magnesium. Neuron. 2010 Jan 28;65(2):165-77. doi: 10.1016/j.neuron.2009.12.026. PMID: 20152124.
[8]Hou H, Wang L, Fu T, Papasergi M, Yule DI, Xia H. Magnesium Acts as a Second Messenger in the Regulation of NMDA Receptor-Mediated CREB Signaling in Neurons. Mol Neurobiol. 2020 Jun;57(6):2539-2550. doi: 10.1007/s12035-020-01871-z. Epub 2020 Mar 25. PMID: 32215817; PMCID: PMC8202957.
[9] Lewerenz J, Maher P. Chronic Glutamate Toxicity in Neurodegenerative Diseases-What is the Evidence? Front Neurosci. 2015 Dec 16;9:469. doi: 10.3389/fnins.2015.00469. PMID: 26733784; PMCID: PMC4679930.
[10] : Chahal H et al., Modulation by magnesium of N-methyl-D-aspartate receptors in developing human brain.Arch Dis Child Fetal Neonatal Ed. 1998 Mar;78(2):F116-20.doi: 10.1136/fn.78.f116.
[11] Pedrón VT, Varani AP, Bettler B, Balerio GN. GABAB receptors modulate morphine antinociception: Pharmacological and genetic approaches. Pharmacol Biochem Behav. 2019 May;180:11-21.
[12] Kondziella D. The Top 5 Neurotransmitters from a Clinical Neurologist's Perspective. Neurochem Res. 2017 Jun;42(6):1767-1771. [[PubMed](https://pubmed.ncbi.nlm.nih.gov/27822666)] [[Reference list](https://www.ncbi.nlm.nih.gov/books/NBK513311/#article-22012.r2)]
[13] Olsen RW. GABAA receptor: Positive and negative allosteric modulators. Neuropharmacology. 2018 Jul 01;136(Pt A):10-22.
[14] Boyle NB, Lawton C, Dye L. The Effects of Magnesium Supplementation on Subjective Anxiety and Stress-A Systematic Review. Nutrients. 2017 Apr 26;9(5):429. doi: 10.3390/nu9050429. PMID: 28445426; PMCID: PMC5452159.


So to summarise, magnesium increases GABA levels in the brain, and inhibit release of glutamate. Additionally, magnesium supports calcium absorption into bones, so it is important in Heightmaxxing for that purpose too.

Oral GABA supplementation:
These can be purchased at nootropic websites, the dose used in the study described previously used a dose of 3g orally once per day.

2. Increased parasympathetic activity via inhibition of cholinesterase
WARNING: DO NOT USE IF YOU HAVE ASTHMA OR COPD !!

Cholinesterase & acetylcholinesterase is very important, it effectively reduces the parasympathetic response of the body (really its more accurate to say it prevents it from going out of hand..). Nerve agents, the most deadly compounds ever created by us, irrevsibly inhibit them (non-competitive inhibition, technically reversible by treatment with oxime within a certain time period dependant on exact agent used) which causes death by severe refractory bradycardia (extreme slowing of heart rate), paralysis and respiratory arrest.

I am saying this to give you an idea of the dangerous of pyridostigmine overdose and the role of the parasympathetic neverous system and cholinesterase in the body. Pyridostigmine is available in tablet form, and it would hard to accidently overdose on them, if there is a source selling it as a powder or liquid I highly recommend not using this due to the overdose risk. Huperazine is also measured in micrograms not milligrams, increasing overdose risk.

If you overdose on either of these compounds you need to seek help urgently, it is not like accidently injecting too much HGH where your blood sugar could tank in abit, or nothing might happen or you might have a headache etc, they can be **rapidly** lethal(as in you wont survive a trip to the hospital, you need to call for an ambulance rapid depending on the dose taken) and require specific drugs to reverse it. They can also cause significant cognitive deficits if you survive a large overdose. Before using these, ensure you know of overdose symptoms and correct dosage.

*note there are diffrences between cholinesterase and acetylcholinesterase however it not that relevant right now and this is already WAY too long, putting this here so you are aware I have taken this into account*

Pyridostigmine :
Pyridostigmine is a medication that inhibits an enzyme called cholinesterase. Cholinesterase exists in the synaptic cleft to remove acetylcholine, an inhibitory neurotransmitter used in the peripheral nervous system from repeatedly stimulating the post synaptic neurone.

Pyridostigmine has been shown to stimulate the release of HGH when given alone[16], and its mechanism of action has been postulated as an inhibitor of hypothalamic SST secretion [17][18]. The evidence for pyridostigmine is very strong.

Huperzine A:
Huperzine A is an acetylcholinesterase inhibitor. It also increases parasympathetic response via this mechanism. However, the evidence for it directly suppressing somatostatin is not studied, however, there are many discussions online supporting its use, and a theoretical link exists. I do not reccomened the use of Huperzine A if you have a respiratory disorder such as asthma or COPD as it can increase bronchial secretions and the evidence for its use is weak.


ALPHA GPC & Choline:
These are also proven to inhibit somatostatin, and increase GH, see the thread linked above for more info on these.


3. Reduce stress & Prevent chronic stress, this decreases SST.



This extract is from source 11, however for conivence I have included the sources it references for its claim. I recommend taking ashwagandha for this (provided you aren’t supplementing thyroid hormones).

4. L-arginine:
A low risk supplement, which has more evidence than huperazine A but is less efficaous compared to pyridostigmine.

L-arginine both supresses somatostatin releases and induces the release of GHRH (growth hormone releasing hormone). [19][20]




5. Injecting IGF1 (NOT LR3 or DES):
If you have this im very jealous. You most likely have been scammed if someone sold you this though as it is incredibly hard to source. There is no evidence that I could find that SST inhibits the effects of IGF1 at the tissue level or the effectiveness of IGF binding proteins, so theoretically IGF1 can bypass this entire mechanisms.


Risks of supressing SST:
  • Messing with body’s homeostatic and regulatory mechanisms can be dangerous
  • Low SST in the brain has been associated with conditions such as schizophrenia and depression
  • There is an incredibly complex relationship between hormones and neurotransmitters in the brain that I do not fully understand, this post does not even go 1 meter deep into it.
TLDR:

Magnesium* = More evidence than to the contrary to supports its use
Oral GABA = Evidence supports use
Pyridostigmine = Evidence supports use, exercise caution when dosing due to overdose risk
Stress reduction = Evidence is unclear, however recommended as no evidence to the contrary.
Huperzine A = Theoretical link, not recommended due to overdose risk.
L-Arginine = Evidence supports use
Calorific Surplus = Evidence supports use, Evidence supports negative effect when in defecit. Strongly reccomended to maintain high/sufficent glucose in blood


*a form of magneisum that is effective at crossing the blood brain barrier must be used. This is discussed in the nootropic guide*

I personally would take ATA Magnesium, oral Gaba and L-arginine as my additives to my stack.

FAQ:
- Will be added here as people reply to this thread
  • Dosages? A: For magnesium: 200-800mg, is effective, reccomend starting at 400mg and titrating based on side effects and blood test results. For GABA: 3g orally per day, pyridostigmine 60mg daily, titrate to effect 30-120mg, divide into 2 doses over the day. L arginine: 10g per day. Huperazine A (dont reccomend this) dosage is 50-150mcg daily.


Disclaimer:
- Please note that this information is based on the current understanding and research available as of 2023 and may be subject to change as new research emerges.
- This is posted for entertainment purposes only, it is your responsibility to verify information in this, I am not a healthcare professional. I am not responsible if you come to harm as a result of following this post.
- If you spot any errors in this thread please let me know by replying, peer reviewing is important!
- Ensure you double check side effects and dosages of medication to ensure it is suitable for you


Sources:
[1]: Murray RD, Kim K, Ren SG, Chelly M, Umehara Y, Melmed S. Central and peripheral actions of somatostatin on the growth hormone-IGF-I axis. J Clin Invest. 2004 Aug;114(3):349-56. doi: 10.1172/JCI19933. PMID: 15286801; PMCID: PMC484973.
[2]: Sarah M. Gray, Michael O. Thorner, Spatiotemporal Regulation of Insulin-Like Growth Factor-1 and Its Receptor in the Brain: Is There a Role for Growth Hormone?, _Endocrinology_, Volume 158, Issue 2, 1 February 2017, Pages 229–232, [https://doi.org/10.1210/en.2016-1884](https://doi.org/10.1210/en.2016-1884)
[^3]: Aguirre, G.A., De Ita, J.R., de la Garza, R.G. _et al._ Insulin-like growth factor-1 deficiency and metabolic syndrome. _J Transl Med_ **14**, 3 (2016). https://doi.org/10.1186/s12967-015-0762-z
[^4]: Mathew Daunt, Oliver Dale, Paul A. Smith, Somatostatin Inhibits Oxidative Respiration in Pancreatic β-Cells, _Endocrinology_, Volume 147, Issue 3, 1 March 2006, Pages 1527–1535, [https://doi.org/10.1210/en.2005-0873](https://doi.org/10.1210/en.2005-0873)
[^5]: Zgliczyński, W., Zdunowski, P., Czajka-Oraniec, I. _et al._ The role of somatostatin analogues in treatment of TSH secreting pituitary adenomas. _Thyroid Res_ **6** (Suppl 2), A64 (2013). https://doi.org/10.1186/1756-6614-6-S2-A64
[^6]: Pedrón VT, Varani AP, Bettler B, Balerio GN. GABAB receptors modulate morphine antinociception: Pharmacological and genetic approaches. Pharmacol Biochem Behav. 2019 May;180:11-21.
[^7]: Kondziella D. The Top 5 Neurotransmitters from a Clinical Neurologist's Perspective. Neurochem Res. 2017 Jun;42(6):1767-1771. [[PubMed](https://pubmed.ncbi.nlm.nih.gov/27822666)] [[Reference list](https://www.ncbi.nlm.nih.gov/books/NBK513311/#article-22012.r2)]
[^8]: Olsen RW. GABAA receptor: Positive and negative allosteric modulators. Neuropharmacology. 2018 Jul 01;136(Pt A):10-22.
[^9]: Kusunoki M, Yamamura T, Ichii S, Fujita S, Nakai T, Utsunomiya J, The effects of sodium valproate on plasma somatostatin and insulin in humans. _J Clin Endocrinol Metab_ (1988) 67(5):1060–3. doi: 10.1210/jcem-67-5-1060
[^10]: Iwasawa, C., Kuzumaki, N., Suda, Y. _et al._ Reduced expression of somatostatin in GABAergic interneurons derived from induced pluripotent stem cells of patients with _parkin_ mutations. _Mol Brain_ **12**, 5 (2019). https://doi.org/10.1186/s13041-019-0426-7
[^11]: Hou X, Rong C, Wang F, Liu X, Sun Y, Zhang HT. GABAergic System in Stress: Implications of GABAergic Neuron Subpopulations and the Gut-Vagus-Brain Pathway. Neural Plast. 2020 Aug 1;2020:8858415. doi: 10.1155/2020/8858415. PMID: 32802040; PMCID: PMC7416252.
[^12]: Pittaluga, A.; Roggeri, A.; Vallarino, G.; Olivero, G. Somatostatin, a Presynaptic Modulator of Glutamatergic Signal in the Central Nervous System. _Int. J. Mol. Sci._ **2021**, _22_, 5864. https://doi.org/10.3390/ijms22115864
[^13]: Akiko Muroyama, Shunsuke Uehara, Shouki Yatsushiro, Noriko Echigo, Riyo Morimoto, Mitsuhiro Morita, Mitsuko Hayashi, Akitsugu Yamamoto, Duk-Su Koh, Yoshinori Moriyama; A Novel Variant of Ionotropic Glutamate Receptor Regulates Somatostatin Secretion From δ-Cells of Islets of Langerhans. __Diabetes__ 1 July 2004; 53 (7): 1743–1753. [https://doi.org/10.2337/diabetes.53.7.1743](https://doi.org/10.2337/diabetes.53.7.1743)
[^14]: Powers ME, Yarrow JF, McCoy SC, Borst SE. Growth hormone isoform responses to GABA ingestion at rest and after exercise. Med Sci Sports Exerc. 2008 Jan;40(1):104-10. doi: 10.1249/mss.0b013e318158b518. PMID: 18091016.
[^15]: Hepsomali P, Groeger JA, Nishihira J, Scholey A. Effects of Oral Gamma-Aminobutyric Acid (GABA) Administration on Stress and Sleep in Humans: A Systematic Review. Front Neurosci. 2020 Sep 17;14:923. doi: 10.3389/fnins.2020.00923. PMID: 33041752; PMCID: PMC7527439.
[^16]: W B Wehrenberg, S D Wiviott, D M Voltz, A Giustina, Pyridostigmine-mediated growth hormone release: evidence for somatostatin involvement., _Endocrinology_, Volume 130, Issue 3, 1 March 1992, Pages 1445–1450, [https://doi.org/10.1210/endo.130.3.1347008](https://doi.org/10.1210/endo.130.3.1347008)
[^17]: Angela Peñalva, Bartolome Burguera, Xesus Casabiell, Jesus A.F. Tresguerres, Carlos Dieguez, Felipe F. Casanueva; Activation of Cholinergic Neurotransmission by Pyridostigmine Reverses the Inhibitory Effect of Hyperglycemia on Growth Hormone (GH) Releasing Hormone-Induced GH Secretion in Man: Does Acute Hyperglycemia Act through Hypothalamic Release of Somatostatin?. __Neuroendocrinology__ 1 May 1989; 49 (5): 551–554. [https://doi.org/10.1159/000125166](https://doi.org/10.1159/000125166)
[^18]: Hanew, K., Utsumi, A., Sugawara, A. _et al._ The evaluation of hypothalamic somatostatin tone using pyridostigmine and thyrotropin releasing hormone in patients with acromegaly. _J Endocrinol Invest_ **17**, 313–321 (1994). https://doi.org/10.1007/BF03348989
[^19]: Parvin Goli, Maryam Yazdi, Motahar Heidari-Beni, Roya Kelishadi, "Growth Hormone Response to L-Arginine Alone and Combined with Different Doses of Growth Hormone-Releasing Hormone: A Systematic Review and Meta-Analysis", _International Journal of Endocrinology_, vol. 2022, Article ID 8739289, 11 pages, 2022. https://doi.org/10.1155/2022/873928
[^20]: Jose Córdoba-Chacón, Manuel D. Gahete, Ana I. Pozo-Salas, Justo P. Castaño, Rhonda D. Kineman, Raul M. Luque, Endogenous Somatostatin Is Critical in Regulating the Acute Effects of l-Arginine on Growth Heilormone and Insulin Release in Mice, _Endocrinology_, Volume 154, Issue 7, 1 July 2013, Pages 72–26, [https://doi.org/26.05./en.11-1126
[^44]: A. Faron-Górecka, M. Kuśmider, M. Kolasa et al., “Chronic mild stress alters the somatostatin receptors in the rat brain,” _Psychopharmacology_, vol. 233, no. 2, pp. 255–266, 2016.
[^45]: A. Faron-Górecka, M. Kuśmider, J. Solich et al., “Regulation of somatostatin receptor 2 in the context of antidepressant treatment response in chronic mild stress in rat,” _Psychopharmacology_, vol. 235, no. 7, pp. 2137–2149, 2018.
[/spoiler]
I have checked and read through all sources manually so they should all be correct and support claims made, if you spot any errors let me know.

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saving for later + amazing formatting my brother
 
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i have psychosis because my face got fucked man. Thats why i have psychosis. How can you even say that to me
no, you have psychosis because of other factors in your life causing you to BELIEVE your face was changed.
Literally every thread you ahve made (you ahve made so many atp) people are there telling u theres barely any difference.
i take back what i said, that was harsh of me, but you need to get off this forum and go to a doctor.
 

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