This is very interesting, thank you for the thorough analysis. I wonder what the studies would show if we were to inject the BDNF, CDNF, and GDNF intranasally since it can bypass the BBB, but the issue would be storing those factors in the first place and not invoking immune response. I would love your feedback on this. Thank you.
Regarding intranasal delivery of BDNF, CDNF, and GDNF, this is an active area of investigation. There is preclinical evidence, particularly in rodents, that intranasally administered proteins (including insulin) can bypass the BBB and reach brain parenchyma. However, the translational picture is less clear. The distances involved in the human brain are considerably larger than in rodent models, and whether diffusion-based transport can achieve therapeutically relevant concentrations across those distances remains an open question. There is simply not yet comparable experimental evidence in humans.
On storage and formulation, this is a real practical challenge. Neurotrophic factors are proteins, and maintaining their stability and bioactivity in a form suitable for intranasal delivery (whether lyophilized for reconstitution or suspended in an aerosolizable solution) would require careful formulation work. That said, it is a tractable engineering problem rather than a fundamental biological barrier.
On immune response, I am less concerned. These neurotrophic factors can be synthesized as recombinant human proteins, identical to endogenous forms. BDNF, for example, is normally present in both the CNS and peripheral blood (it is expressed in muscle tissue, among other sites). Administering human-sequence proteins should not provoke a significant immune response.
The bigger challenge, in my view, remains the delivery question --ensuring that sufficient concentrations reach the target regions deep in the brain like the hippocampus.
Thank you for your time to comment! What an interesting insight. I assumed storage would be harder than delivery but it seems that delivery to the brain is harder than I anticipated! I hope the engineering for the storage will be solved soon.
> Essentially, 100% of large-molecule pharmaceutics, including peptides, recombinant proteins, monoclonal antibodies, RNA interference (RNAi)-based drugs and gene therapies, do not cross the BBB.
This is absolutely wrong, moreover the general belief that peptides do not cross the BBB is so general it is meaningless.
The blood brain barrier is very permeable to small molecules and especially to small lipophillic molecules.
Peptides and peptide fragments, if anything, should generally be expected to cross the BBB more than proteins since they are roughly defined as being the set of "small proteins".
Indeed polypeptides are however unlikely to cross the BBB, and even then I wonder if they could if liposomal or esterified.
In addition to the ability of small and lipophillic peptides to cross the BBB, peptides have much more probability than proteins to be relevant in the CNS since peptides are generally much more potent (picomolar binding affinity)
Moreover, there exist dedicated peptide transport mechanisms for a subset of peptides:
A few major examples among many being vasopressin, delta sleep inducing peptide and leptin that cross the BBB.
Leptin is notable since it is 16 kilodaltons, hence showing that large proteins/peptides can too cross the BBB if they bind to specific transporters.
The premise that cerebrolysin pharmacology is driven by neurotrophic factors is simplist, being a brain extract it containts potentially thousands of distincts peptides.
Generally organ extracts have very significant health potential, as seen in e.g. thymus or adrenal extract, and a large part of their pharmacology derive from as of yet unidentified or understudied peptides.
Specifically for cerebrolysin and its cousin cortexin, I don't remember exactly my review of the literature but IIRC it's a mixed bag.
It does seems to show potent effects in select diseases
e.g. this curve in ALS patients is literally unmatched by any other pharmaceutical
Yeah, the entire affair is really sad. There are ~61 papers on Cebrolysin with Eliezer Masliah's name as a coauthor!! It's not clear if any are foundational papers, but many are pretty early (1999). They were not papers we came across during our investigation. We wonder how many others are fraudulent...
Turns out many, many other papers were fraudulent. About 8% of total have clear evidence of image manipulation. 8% is in line with a recent estimate by James Heathers that about 14% of the literature contains fraud. Still, it appears fraud played an outsized role here since many of the early papers contain fraud. Research in Cerebrolysin picked up after Masliah's fraudulent papers since he was an esteemed researcher from the US. https://forbetterscience.com/2024/10/08/cerebrolysin-sharmas-masliah-and-ever-pharma/
There has been meta analysis performed on hundreds of thousands of reddit posts sharing experiences with nootropics. Cerebrolysin is very high up there. The only things ranked higher are things like adderall or weight exercise. It is something that makes me think further research is needed on Cerebro because there might be something interesting there
I have Reddit blocked on all my devices, so it's not easy for me to access.. which survey are you referring to? Cerebrolysin wasn't included in the 2017 one (https://darktka.github.io/).
I've seen the more recent survey, I don't recall seeing Cerebrolysin on it either.
Interesting article, but I thought I’d share my first hand experience with it. I had been taking Cerebrolysin on and off for around 1 year for an issue that gave me constant muscle twitching and body part jerking from a TBI confirmed on a Brain SPECT. After about 2 weeks of Cerebrolysin my twitching and body part jerking went away 95%. Then on the 2nd cycle it went away completely. Also my cognitive impairment went away almost completely and I can now think clearly. Just wanted to share my experience despite you sharing this article. I do think it’s doing something effective in people as there are a lot of people that swear by it helping them.
It's totally fine. Someone on Reddit posted something similar.
I assume you would have recovered anyway or that there was a placebo effect. However there are a number of very dramatic stories which do give us pause. Still, I tend to think such stories are not good evidence that the drug actually works beyond placebo.
The fact you cycled on and off is interesting - did you notice any difference on on weeks vs off weeks. Also, do you remember what dose you were taking and how frequently?
I hadn’t started taking Cerebrolysin till around 1.5 years after my injury and only started it because I couldn’t take the symptoms anymore. I don’t believe it could be placebo if after 2 weeks into the cycle my very noticeable twitching and body part jerking stopped around 95%. Then I took a few months break from Cerebrolysin and ran it again for another full month which is when all those same symptoms stopped completely. If it was placebo I’m not sure that it would have stopped something that was happening to me for 1.5 years in about 2 weeks. The first cycle I was taking 5ml for 5 days on and 2 days off for a month. The second cycle I was taking upwards of 40ml for 5 days on and 2 days off as well for a month. On weeks I was taking I didn’t notice much difference daily except for possibly some agitation. Your article is very well written, but I wonder why it’s been so effective for people like myself excluding the placebo theory.
What were you symptoms like, you said you were twitching?
It's possible the amino acids had an effect, although it seems a bit of a stretch. For instance, twitching can be caused by dopamine dsyfunction, and amino acids are import rate-limiting precursors for dopamine (for instance tyrosine, when taken in pure form, boosts dopamine).
You have shown , once again, that the only good way to get ground-up animal stuff into one’s body is by …eating it. I’m impressed and grateful for your thorough cleaning up of this junk science-mimicking marketing .
Really outstanding analysis This falls into the category of what I've started to call Elpis (λπς) Activating Agents (EAA)... One day ... someone will dig a little deeper into EAAs ... They seem to work for some people without leaving an actual physical trace or explanation :-) ( look up Elpis (λπς); also check what was left over in Pandora's box )
Yeah, I've been reading reviews of the drug among "biohackers" on Reddit, and people are over the moon about it, talking about how their memory and cognitive function have improved dramatically! It's really quite something to behold.
Depressing that self-described "rationalists" would fall for such obvious quackery. It's the kind of thing you'd expect to see advertised on Truth Social.
I don't think it's wildly popular among rationalists. One guy at Manifest (a rationalist-adjacent conference) talked about it highly. I know one other rationalist-adjacent person who is trying it.
It's pretty uniformly described online as a peptide combination, and experimental peptides are sort of "all the rage" right now.
But anyway, yeah I was very disappointed with Bryan Johnson once I started researching what Cerebrolysin actually is. He calls it "a peptide". Johnson has otherwise been following a relatively rational and science-based approach.
Bryan Johnson is promoting a sketchy supplement and bad science? I am truly, utterly shocked. But seriously, good on these authors for calling out scientific BS where they see it!
Bryan Johnson is relatively good, but a number of the supplements he takes are questionable.
To his credit, he did say it's a trial, and he had a disclaimer about. I hope he publishes the results of his N=1 trial. He said he's going to evaluate using cognitive tests and MRI "biomarkers" (not sure how that will work exactly).
This is very interesting, thank you for the thorough analysis. I wonder what the studies would show if we were to inject the BDNF, CDNF, and GDNF intranasally since it can bypass the BBB, but the issue would be storing those factors in the first place and not invoking immune response. I would love your feedback on this. Thank you.
Hi, Kay. Thank you for the thoughtful comment.
Regarding intranasal delivery of BDNF, CDNF, and GDNF, this is an active area of investigation. There is preclinical evidence, particularly in rodents, that intranasally administered proteins (including insulin) can bypass the BBB and reach brain parenchyma. However, the translational picture is less clear. The distances involved in the human brain are considerably larger than in rodent models, and whether diffusion-based transport can achieve therapeutically relevant concentrations across those distances remains an open question. There is simply not yet comparable experimental evidence in humans.
On storage and formulation, this is a real practical challenge. Neurotrophic factors are proteins, and maintaining their stability and bioactivity in a form suitable for intranasal delivery (whether lyophilized for reconstitution or suspended in an aerosolizable solution) would require careful formulation work. That said, it is a tractable engineering problem rather than a fundamental biological barrier.
On immune response, I am less concerned. These neurotrophic factors can be synthesized as recombinant human proteins, identical to endogenous forms. BDNF, for example, is normally present in both the CNS and peripheral blood (it is expressed in muscle tissue, among other sites). Administering human-sequence proteins should not provoke a significant immune response.
The bigger challenge, in my view, remains the delivery question --ensuring that sufficient concentrations reach the target regions deep in the brain like the hippocampus.
Thank you for your time to comment! What an interesting insight. I assumed storage would be harder than delivery but it seems that delivery to the brain is harder than I anticipated! I hope the engineering for the storage will be solved soon.
Interesting read.
How do you interpret this article? https://pmc.ncbi.nlm.nih.gov/articles/PMC4926802/
Is this included in the swath of fraudulent findings?
> Essentially, 100% of large-molecule pharmaceutics, including peptides, recombinant proteins, monoclonal antibodies, RNA interference (RNAi)-based drugs and gene therapies, do not cross the BBB.
This is absolutely wrong, moreover the general belief that peptides do not cross the BBB is so general it is meaningless.
The blood brain barrier is very permeable to small molecules and especially to small lipophillic molecules.
Peptides and peptide fragments, if anything, should generally be expected to cross the BBB more than proteins since they are roughly defined as being the set of "small proteins".
Indeed polypeptides are however unlikely to cross the BBB, and even then I wonder if they could if liposomal or esterified.
In addition to the ability of small and lipophillic peptides to cross the BBB, peptides have much more probability than proteins to be relevant in the CNS since peptides are generally much more potent (picomolar binding affinity)
Moreover, there exist dedicated peptide transport mechanisms for a subset of peptides:
https://pmc.ncbi.nlm.nih.gov/articles/PMC5354301/#S1:~:text=Peptide%20transport%20system%2D1%3A%20the%20first%20BBB%20transporter%20for%20peptides
A few major examples among many being vasopressin, delta sleep inducing peptide and leptin that cross the BBB.
Leptin is notable since it is 16 kilodaltons, hence showing that large proteins/peptides can too cross the BBB if they bind to specific transporters.
The premise that cerebrolysin pharmacology is driven by neurotrophic factors is simplist, being a brain extract it containts potentially thousands of distincts peptides.
Generally organ extracts have very significant health potential, as seen in e.g. thymus or adrenal extract, and a large part of their pharmacology derive from as of yet unidentified or understudied peptides.
Specifically for cerebrolysin and its cousin cortexin, I don't remember exactly my review of the literature but IIRC it's a mixed bag.
It does seems to show potent effects in select diseases
e.g. this curve in ALS patients is literally unmatched by any other pharmaceutical
https://pubmed.ncbi.nlm.nih.gov/38585517/#&gid=article-figures&pid=figure-1-uid-0
sadly, I haven't yet found an actually long term trial
a number of papers on cerebrolysin may be partially based on fraudulent data according to this story:
https://www.science.org/content/article/research-misconduct-finding-neuroscientist-eliezer-masliah-papers-under-suspicion
Yeah, the entire affair is really sad. There are ~61 papers on Cebrolysin with Eliezer Masliah's name as a coauthor!! It's not clear if any are foundational papers, but many are pretty early (1999). They were not papers we came across during our investigation. We wonder how many others are fraudulent...
Turns out many, many other papers were fraudulent. About 8% of total have clear evidence of image manipulation. 8% is in line with a recent estimate by James Heathers that about 14% of the literature contains fraud. Still, it appears fraud played an outsized role here since many of the early papers contain fraud. Research in Cerebrolysin picked up after Masliah's fraudulent papers since he was an esteemed researcher from the US. https://forbetterscience.com/2024/10/08/cerebrolysin-sharmas-masliah-and-ever-pharma/
There has been meta analysis performed on hundreds of thousands of reddit posts sharing experiences with nootropics. Cerebrolysin is very high up there. The only things ranked higher are things like adderall or weight exercise. It is something that makes me think further research is needed on Cerebro because there might be something interesting there
I have Reddit blocked on all my devices, so it's not easy for me to access.. which survey are you referring to? Cerebrolysin wasn't included in the 2017 one (https://darktka.github.io/).
I've seen the more recent survey, I don't recall seeing Cerebrolysin on it either.
Hey Dan, thanks for sharing your work!
Here is a link to the analysis I believe Bitomat is referencing (spreadsheet linked in the reddit comment)
https://www.reddit.com/r/Cerebrolysin/comments/jdlpcd/cerebrolysin_poll/g98w2zt/
Interesting article, but I thought I’d share my first hand experience with it. I had been taking Cerebrolysin on and off for around 1 year for an issue that gave me constant muscle twitching and body part jerking from a TBI confirmed on a Brain SPECT. After about 2 weeks of Cerebrolysin my twitching and body part jerking went away 95%. Then on the 2nd cycle it went away completely. Also my cognitive impairment went away almost completely and I can now think clearly. Just wanted to share my experience despite you sharing this article. I do think it’s doing something effective in people as there are a lot of people that swear by it helping them.
It's totally fine. Someone on Reddit posted something similar.
I assume you would have recovered anyway or that there was a placebo effect. However there are a number of very dramatic stories which do give us pause. Still, I tend to think such stories are not good evidence that the drug actually works beyond placebo.
The fact you cycled on and off is interesting - did you notice any difference on on weeks vs off weeks. Also, do you remember what dose you were taking and how frequently?
I hadn’t started taking Cerebrolysin till around 1.5 years after my injury and only started it because I couldn’t take the symptoms anymore. I don’t believe it could be placebo if after 2 weeks into the cycle my very noticeable twitching and body part jerking stopped around 95%. Then I took a few months break from Cerebrolysin and ran it again for another full month which is when all those same symptoms stopped completely. If it was placebo I’m not sure that it would have stopped something that was happening to me for 1.5 years in about 2 weeks. The first cycle I was taking 5ml for 5 days on and 2 days off for a month. The second cycle I was taking upwards of 40ml for 5 days on and 2 days off as well for a month. On weeks I was taking I didn’t notice much difference daily except for possibly some agitation. Your article is very well written, but I wonder why it’s been so effective for people like myself excluding the placebo theory.
What were you symptoms like, you said you were twitching?
It's possible the amino acids had an effect, although it seems a bit of a stretch. For instance, twitching can be caused by dopamine dsyfunction, and amino acids are import rate-limiting precursors for dopamine (for instance tyrosine, when taken in pure form, boosts dopamine).
You have shown , once again, that the only good way to get ground-up animal stuff into one’s body is by …eating it. I’m impressed and grateful for your thorough cleaning up of this junk science-mimicking marketing .
Yes, those are our thoughts exactly -- you're better off just eating some grass fed lean beef!
Or, if you want to quickly get amino acids to the brain (ie to replenish neurotransmitter levels), drink an amino acid mix: (Bryan Johnson was using this one: https://www.amazon.com/THORNE-Amino-Complex-Clinically-Validated-Post-Workout/dp/B00K0WQK0W )
Extremely high quality analysis. Good job.
Thank you Will! That means a lot coming from you!
Really outstanding analysis This falls into the category of what I've started to call Elpis (λπς) Activating Agents (EAA)... One day ... someone will dig a little deeper into EAAs ... They seem to work for some people without leaving an actual physical trace or explanation :-) ( look up Elpis (λπς); also check what was left over in Pandora's box )
Yeah, I've been reading reviews of the drug among "biohackers" on Reddit, and people are over the moon about it, talking about how their memory and cognitive function have improved dramatically! It's really quite something to behold.
Depressing that self-described "rationalists" would fall for such obvious quackery. It's the kind of thing you'd expect to see advertised on Truth Social.
I don't think it's wildly popular among rationalists. One guy at Manifest (a rationalist-adjacent conference) talked about it highly. I know one other rationalist-adjacent person who is trying it.
It's pretty uniformly described online as a peptide combination, and experimental peptides are sort of "all the rage" right now.
But anyway, yeah I was very disappointed with Bryan Johnson once I started researching what Cerebrolysin actually is. He calls it "a peptide". Johnson has otherwise been following a relatively rational and science-based approach.
Greg, Dan- thanks for taking the time to research and write on this topic. Very well laid out, logical and easy to follow for those not in this field.
Bryan Johnson is promoting a sketchy supplement and bad science? I am truly, utterly shocked. But seriously, good on these authors for calling out scientific BS where they see it!
Bryan Johnson is relatively good, but a number of the supplements he takes are questionable.
To his credit, he did say it's a trial, and he had a disclaimer about. I hope he publishes the results of his N=1 trial. He said he's going to evaluate using cognitive tests and MRI "biomarkers" (not sure how that will work exactly).
Thank you for researching it!