BRAIN OPTIMIZATION QUEST ARTICLE 1
A deep dive on Noopept
Noopept is Russian pharmacology at its finest. It is bioavailable orally, being N-phenylacetyl-L-prolyl-glycine ethyl ester, the phenylacetyl and ethyl ester protect it from peptidases. It was developed as an alternative to racetams, and is what I consider to be a legitimate nootropic, as compared to adderall which is a neurotoxic slum of excitotoxicity (this is a harsh overexaggeration– it’s dose dependent).
I do believe the societal perception of nootropics is skewed. We expect to instantaneously be able to feel them, craving the catecholamine cascade. Noopept works on a more fundamental, deep and architectural level. Its main application is learning and sports performance (It is not explicitly on the WADA prohibited list). Just to be clear, noopept is NOT a racetam.
If you are new here, In addition to hard, consistent learning and training bouts I am attempting to stack all of the possible variables to become as high performing as I possibly can. A day natty is a day wasted– we have tools. So lets learn how to use them!
For this article I included Layman’s explanations. I plan to do them for the ones ahead– I fear I can get carried away sometimes.
Metabolite-Driven Effects
Noopept itself has quite a short halflife, but in animal studies its metabolite cycloprolyglycine is found to linger, thus thought to be responsible for its nootropic effects. Cycloprolyglycine (CPG) is a metabolite of IGF-1 (Gudasheva.) Noopept almost acts as a CPG prodrug, and GPG endogenously modulates neuroprotection and synaptic plasticity (Guan.)
CPG competes for binding with IGFBP-3 in the bloodstream (which typically holds a large amount of IGF-1) potentially increasing IGF bioavailability as a whole. This does not imply more anabolism, just moves the needle positively to more bioavailability– which has a greater sway on the brain than the muscles.
Noopept has two other metabolites in addition to CPG, being phenylacetic acid and prolylglycine. Phenylacetic acid doesn’t have any nootropic effects, and is inert. Prolylglycine is a precursor to Cycloprolyglycine. Cycloprolyglycine is the heavy hitter, the concentration of which was found 2.5 fold higher after 1 hour whereas everything else was undetectable in rodent studies (Gudasheva)
LAYMANS EXPLINATION:
Noopept itself quickly turns into another compound called cycloprolylglycine, which exerts the effects. Cycloprolylglycine is something the body already makes, and it plays a role in protecting brain cells and supporting learning. It is a metabolite of IGF-1. Since its effects are based on something that is natural to our body, it makes its effects slightly more predictable and understandable even with a smaller amount of data.
Noopepts Mechanism of Action
(If you do not want a complicated explanation, check the next section for a layman’s synopsis.) The generally overarching MOA is that Noopept enhances activity-dependent plasticity signaling, most likely by facilitating or amplifying signaling toward CREB phosphorylation, which in turn yields neurotrophin expression such as BDNF. CREB is a step in the cascade that, when activated, initiates transcription of plasticity-related genes (see visual). This cascade is biased toward ACTIVE circuits. For example, it will not make you better at baseball if you have not picked up a bat in five years, but it could potentially enhance learning within circuits that are being actively engaged.
Cycloprolylglycine’s positive modulation of NMDA-dependent signaling is relevant here, as it appears to make NMDA signaling more effective for plasticity rather than simply stronger. This does not mean there is an overall increase in excitation. The effects appear to rely on intact AMPA signaling while biasing NMDA pathways toward plasticity.
NMDA-mediated calcium signaling is one of the primary pathways leading to CREB activation during learning, which in turn drives the transcription of plasticity-related genes. I do not intend on being overly reductive.
Preclinical work also suggests a neuroprotective aspect of Noopept, particularly under conditions of metabolic or excitotoxic stress– such as increased neuron survival with excess glutamate. This increase, at least in rodent models, seems to be localized to the hippocampus.
LAYMANS EXPLANATION:
Noopept does not impact unused circuits/skills. It seems to support and strengthen learning in areas of the brain that are active, especially those involved in memory. It does this by making areas of the brain more receptive to signals that are key for memory formation.
SUMMARY OF AVAILABLE EVIDENCE
ANIMAL STUDIES:
- Increasing of NGF & BDNF in the rat hippocampus (Ostrovskaya)
Reduced inflammatory cytokines in response to an inflammatory insult. This carries over to humans as it deals with conserved pathways. (Alekseeva)
- Phagocytic activity enhancement (Kovalenko)
- Prevention of memory impairment with cholinergic blockage– as CREB is a critical component activated by acetylcholine, it seems as though with this blockage noopept can activate it independent of acetylcholine (My hypothesis). In my mind, this makes sense as CGP may be an additional evolutionary safeguard that creates redundancy. (Belnik)
CELL CULTURE STUDIES
- Neuroprotective effects (Ostrovskaya)
- Improved survival when exposed to glutamate (Antipova).
- HIF-1 threefold mode of activation– independent of stress (HIF-1 responds to low oxygen conditions and helps cells adapt and repair). Its threefold effects include increased activity without stress, increased activity under stress, and stabilization of its subunits (Zainullina)
HUMAN STUDIES:
The most quoted human study is the Russian Academy of science in Moscow (n=53) using doses of 10mg twice a day– with positive results. Unfortunately, the data is eh as it is not placebo controlled OR blinded… the human studies we do have I do not feel comfortable giving validity. They are very poor, but at least we do have an idea that noopept is bioavailable orally.
CGP STUDIES:
Luckily since the metabolite of noopept is one endogenous, we can extrapolate some of its effects when looking at research of CGP.
Here is what we know:
- Many studies on rodents show antidepressant effects under stress.
- We know that it positively modulates AMPA receptor activity, and blocking this receptor nulls protection. (Gudasheva)
A part in my journey to optimize learning.
I remember being engaged in bountiful conversation with a friend, the subject of which has since lost me. But the one thing I do recall is how he told me that he believed true intelligence is in the retention of the information– for what value is intelligence if you cannot retain the information you learned? Noopept is my first nootropic as a part of this journey— which stands alongside supplements, sleep, learning my own neurological phenotype, anxiety management, and novel learning techniques such as anki.
There are three aspects of memory:
encoding, consolidation, and retrieval.
Noopept mostly graces ENCODING.
Memory consolidation is affected though noopept, due to its increases NGF and BDNF (though AMPA and NMDA modulation) These are the most important molecules driving neuroplasticity– increasing the brains capacity to change or stabilize new circuits. BDNF specifically plays a critical role in long term potentiation. LTP is a synaptic strength with usage (Yan). An example of LTP is after shooting that double leg daily for years, the strength of those circuits are immense. Noopept BDNF expression is constrained by negative feedback mechanisms.
My theory on noopept in schizophrenia / schizoaffective disorders
I do think that nootropics such as Noopept simply will have a higher sway in certain population groups. Schizophrenia and other schizo-akin disorders have NMDA hypoactivation– where things like D-serine and to some extent glycine can have a positive effect. Along with Glutamate, a coagonist is needed for the synapses to fire– and that coagonist is D-serine. Adding in this one variable can have positive effects on memory, cognition, and executive functioning. Since it seems that noopept can improve the efficiency of NMDA dependent plasticity, I think this could be a relevant tool.
This is why understanding your own neurochemistry is IMMENSELY important.
You want to ensure you are modulating relevant pathways. Not to mention, these disorders often come along with neuroinflammation which noopept could potentially aid in.
Just a mechanistic theory… there is no data on this– and per the subsequent section should only be used in a state of remission from these disorders (when you are functioning as good as you possibly can).
This section is purely speculative and should not be interpreted as a treatment recommendation
When you SHOULDN’T use noopept
I should note with plasticity inducing drugs such as noopept you should ONLY be used when you are in a very good well functioning mental state! You do not want to solidify negative circuits! The CREB/BDNF circuits stabilize whatever is active. You do not want to stabilize these maladaptive behaviors.
When you SHOULD use noopept
Noopept should be used when you are in good, well adjusted periods of your life when you are attempting complicated sports or learning endeavors. Think about it, more brain IGF availability, and all of the neurochemical cascades I spoke of earlier, are only optimal to be triggered during an activity you are trying to consolidate. It is a wonderful adjunct to any learning intensive sphere– sports, language learning, hard reading, chemistry, etc. All of these circuits could garner more long term potentiation (in theory) though noopept. The beautiful thing is noopept is very much on target and its mechanism inherently biases change to circuits being activity used. I love certain aspects of the modern world and the joy they can bring! It is a moderate shift of an already present physiology to bias it to a more learning rich state!
Noopept adjacent drugs in pharma today
Noopept is not the only cGP derived drug to be experimented with (although it certainly is the most accessible!) A pharma company called neuren pharmaceuticals is experimenting with a more metabolically stable and half life increased version of CGP. currently in the pipeline for many diseases– and they have already had success with a similar IGF-1 analog. It’s currently in stage 3 for Phelan-McDermid Syndrome and prima facie looks favorable– as the main outcomes of this drug that make it clinically viable are the nootropic effects (neuroprotection, synaptic plasticity, etc.) Unfortunately the stage 2 is low power as we are dealing with rare diseases, there is no placebo arm. Regulators don’t require placebo for rare pediatric diseases, and families might decline to participate in a placebo controlled trial. This is super interesting to me as noopept and their drugs are strikingly similar just with a few pharmacological tweaks– its a pharma optimized version of noopept with FAR more specificity.
Dosing
If you do not instantly feel noopept– there is no need to hike the dose. Its effects are subtle and affect the scaffolding of your brain. Generally, oral dosing start off with 10mg-20mg split daily.I personally utilize nasal Noopept, just so the effects are not as contingent on transporters in the gut. If I can bypass digestion, I will take that option. For nasal dosing (since it is more bioavailable) start small. 3mg daily is what I would recommend. It is worth noting all studies on noopept are oral– so take that as you will.
For usage after traumatic brain events or when recovering from a concussion, I can understand the dosage being pushed higher. This is the context of most of the studies we have.
Alpha GPC? Noopept does not increase acetylcholine turnover like racetams, only increases sensitivity. Alpha GPC is not needed as an adjunct here but I use it because I pop zyns.
This is not medical advice
My personal anecdote:
I have been using noopept for a few weeks now– and thus far I adore it. The main, quantifiable thing I noticed was an increase in REM sleep. This has been substantiated in my sleep tracking and shocked me, but this makes sense. CREB and BDNF are upregulated during REM, and neuroplastic change happens during REM. I take this as a good sign. Cholinergic tone is another driver of REM and noopept increases cholinergic sensitivity. I would have loved to write a deeper section on this but unfortunately this is all a mechanistic hypothesis.
I normally do not utilize caffeine— as I have no need to slosh more catacholimines around my psyche, but I noticed a potentiation of caffeine when used in conjunction with noopept. It actually seems to make caffeine feel smooth and enjoyable to me, typically it feels foggy. Since caffeine blocks adenosine which increases cholinergic firing rate (Arrigoni), it is reasonable to believe that since noopept increases cholinergic sensitivity this could be one of the reasons for potentiation. But who knows– could be the placebo effect.
A note on rodent studies versus humans
The applicability of rodent studies to yield insight on human effects is slim, but it is contingent on the exact physiological metric we are evaluating. Some carry over better than others. In regards to neurochemistry, we have a unique capability in rodents to analyze the exact locality of changes.
For example, measuring BDNF in humans requires blood BDNF/NGF which we cannot extrapolate to a specific brain circuit. This is convoluted by the fact that platelets release BDNF during clotting (which is then extrapolated to brain levels) an ode to how immensely complex human physiology is (Naegelin). The usefulness of serum BDNF levels has been debated, but with the presence of successful correlations of serum BDNF to pathologies like depression, it seems as though many researchers agree that it has utility (André.)
Studies like this (Aid) highlight key differences in rodent transcriptional dynamics and demonstrate that we can or cannot extrapolate. We cannot extrapolate percentage increases, timing, or context. We can extrapolate pathways, downstream cascades, and toxicity.
There is much more to be said on this topic which will be concluded in a separate article, but this isolated insight on BDNF in rodent verses humans is relevant to the topic of this article.
Russian pharma grade noopept pills (not sponsored)
https://rupharma.com/noopept/?searchid=973475&search_query=noopept
SOURCES
Ostrovskaya RU, Gudasheva TA, Zaplina AP, Vahitova JV, Salimgareeva MH, Jamidanov RS, Seredenin SB. Noopept stimulates the expression of NGF and BDNF in rat hippocampus. Bull Exp Biol Med. 2008 Sep;146(3):334-7. doi: 10.1007/s10517-008-0297-x. PMID: 19240853.
Gudasheva, T.A., Boyko, S.S., Ostrovskaya, R.U. et al. The major metabolite of dipeptide piracetam analogue GVS-111 in rat brain and its similarity to endogenous neuropeptide cyclo-l-prolylglycine. European Journal of Drug Metabolism and Pharmacokinetics 22, 245–252 (1997). https://doi.org/10.1007/BF03189814
Guan J, Li F, Kang D, Anderson T, Pitcher T, Dalrymple-Alford J, Shorten P, Singh-Mallah G. Cyclic Glycine-Proline (cGP) Normalises Insulin-Like Growth Factor-1 (IGF-1) Function: Clinical Significance in the Ageing Brain and in Age-Related Neurological Conditions. Molecules. 2023 Jan 19;28(3):1021. doi: 10.3390/molecules28031021. PMID: 36770687; PMCID: PMC9919809.
Zainullina, L.F., Ivanova, T.V., Sadovnikov, S.V. et al. Cognitive Enhancer Noopept Activates Transcription Factor HIF-1. Dokl Biochem Biophys 494, 256–260 (2020). https://doi.org/10.1134/S1607672920050129
Silva-Reis, S. C.; Sampaio-Dias, I. E.; Costa, V. M.; Correia, X. C.; Costa-Almeida, H. F.; García-Mera, X.; Rodríguez-Borges, J. E.
Concise Overview of Glypromate Neuropeptide Research: From Chemistry to Pharmacological Applications in Neurosciences.
ACS Chem. Neurosci. 2023, 14 (4), 487–501.
https://doi.org/10.1021/acschemneuro.2c00675
Arrigoni E, Chamberlin NL, Saper CB, McCarley RW. Adenosine inhibits basal forebrain cholinergic and noncholinergic neurons in vitro. Neuroscience. 2006 Jun 30;140(2):403-13. doi: 10.1016/j.neuroscience.2006.02.010. Epub 2006 Mar 20. PMID: 16542780.
Yan, P.; Xue, Z.; Li, D.; Ni, S.; Wang, C.; Jin, X.; Zhou, D.; Li, X.; Zhao, X.; Chen, X.; et al. Dysregulated CRTC1-BDNF signaling pathway in the hippocampus contributes to Aβ oligomer-induced long-term synaptic plasticity and memory impairment. Exp. Neurol. 2021, 345, 113812. [Google Scholar] [CrossRef] [PubMed]
- Zeidán-Chuliá, F.; de Oliveira, B.-H.; Salmina, A.B.; Casanova, M.F.; Gelain, D.P.; Noda, M.; Verkhratsky, A.; Moreira, J.C. Altered expression of Alzheimer’s disease-related genes in the cerebellum of autistic patients: A model for disrupted brain connectome and therapy. Cell Death Dis. 2014, 5, e1250. [Google Scholar] [CrossRef]
Naegelin Y, Dingsdale H, Säuberli K, Schädelin S, Kappos L, Barde YA. Measuring and Validating the Levels of Brain-Derived Neurotrophic Factor in Human Serum. eNeuro. 2018 Mar 22;5(2):ENEURO.0419-17.2018. doi: 10.1523/ENEURO.0419-17.2018. PMID: 29662942; PMCID: PMC5898630.
André Russowsky Brunoni, Mariana Lopes, Felipe Fregni, A systematic review and meta-analysis of clinical studies on major depression and BDNF levels: implications for the role of neuroplasticity in depression, International Journal of Neuropsychopharmacology, Volume 11, Issue 8, December 2008, Pages 1169–1180, https://doi.org/10.1017/S1461145708009309
Aid T, Kazantseva A, Piirsoo M, Palm K, Timmusk T. Mouse and rat BDNF gene structure and expression revisited. J Neurosci Res. 2007 Feb 15;85(3):525-35. doi: 10.1002/jnr.21139. PMID: 17149751; PMCID: PMC1878509.
Allen A. Of mice and men: The problems with animal testing. Slate 2006 June 1; available at http://www.slate.com/articles/health_and_science/medical_examiner/2006/06/of_mice_or_men.html (last accessed 10 Dec 2014).
Follow the yellow brick road. Nature Reviews Drug Discovery 2003;2:167, at 167.
Alekseeva SV, Kovalenko LP, Tallerova AV, Gudasheva TA, Durnev AD. [An experimental study of the anti-inflammatory action of noopept and its effect on the level of cytokines]. Eksp Klin Farmakol. 2012;75(9):25-7. Russian. PMID: 23156084.
Kovalenko LP, Shipaeva EV, Alekseeva SV, Pronin AV, Durnev AD, Gudasheva TA, Ostrovskaja RU, Seredenin SB. Immunopharmacological properties of noopept. Bull Exp Biol Med. 2007 Jul;144(1):49-52. English, Russian. doi: 10.1007/s10517-007-0251-3. PMID: 18256750.
Copy
Down
Belnik AP, Ostrovskaya RU, Poletaeva II. Dipeptide preparation Noopept prevents scopolamine-induced deficit of spatial memory in BALB/c mice. Bull Exp Biol Med. 2007 Apr;143(4):431-3. doi: 10.1007/s10517-007-0148-1. PMID: 18214292.
Antipova TA, Nikolaev SV, Ostrovskaya PU, Gudasheva TA, Seredenin SB. Dipeptide Piracetam Analogue Noopept Improves Viability of Hippocampal HT-22 Neurons in the Glutamate Toxicity Model. Bull Exp Biol Med. 2016 May;161(1):58-60. doi: 10.1007/s10517-016-3344-z. Epub 2016 Jun 6. PMID: 27265136.