5 ms·

Very interesting. Memantine is an antiviral/nootropic (NMDA agonist) that's considered one of the best conventional therapies for Alzheimer's. For e.g., https

Very interesting. Memantine is an antiviral/nootropic (NMDA agonist) that's considered one of the best conventional therapies for Alzheimer's. For e.g., https://pubmed.ncbi.nlm.nih.gov/32914577/ https://pubmed.ncbi.nlm.nih.gov/32914577/ Amantadine is a related compound that's seemingly more potent as an antiviral, and less potent at the NMDA receptor. Medical hypothesis: This makes me wonder if amantadine might be an effective drug in Alzheimer's treatment. It would come as a total shock to the med chem community if memantine's activity had to do with its suppression of viral replication, and much less to do with its activity at the NMDA receptor. As an aside, the Russians have a similar drug called bromantane which is sold OTC as a sort of mental energy booster. It's not really a stimulant, and its effects are mild enough for daily use. It might also be very interesting in this context. https://en.wikipedia.org/wiki/Bromantane https://en.wikipedia.org/wiki/Bromantane

johnisgood 2y ago
I believe most nootropics work for Alzheimer's, probably Huperzine A, too. Perhaps even Noopept. NMDA agonists and acetylcholinesterase (they inhibit the breakdown of the neurotransmitter acetylcholine) in general. Benadryl (DPH) and first-generation antihistamines are the opposite of that, they can cause delirium (and it messes up your memory and cognition in general) and whatnot, they are anticholinergic, some more than others. I had anticholinergic toxicity from DPH before. I take Alpha-GPC (a very soluble form of choline) and Huperzine A for cognition / memory, others couple it with racetams (e.g. piracetam, pramiracetam, aniracetam, etc.).
- TechDebtDevin 2y ago
  My primary care doctor is telling all of her patients not to take Zyrtec for an anti-histamine because it is causing dementia side effects in her older patients. Antecdotal but interesting.
  - johnisgood 2y ago
    For the reasons I mentioned, yes. :) But Zyrtec is second-generation. It shows 20,000-fold or greater selectivity for the H1 receptor over the five muscarinic acetylcholine receptors, and hence does not exhibit anticholinergic effects, so it should be OK. May still cause drowsiness, however.
    - wildylion 2y ago
      What about desloratadine?
      - johnisgood 2y ago
        Desloratadine (Clarinex, Aerius) is a selective H1-antihistamine which functions as an inverse agonist at the histamine H1 receptor. From Wikipedia: > At very high doses, it is also an antagonist at various subtypes of the muscarinic acetylcholine receptors. This effect is not relevant for the drug's action at therapeutic doses. Thus, it is an anticholinergic only at very high doses, and it does not readily pass the BBB, therefore drowsiness is NOT likely (probably at very high doses only). At any rate, it does not affect the CNS at therapeutic doses, so memory / cognition issues, along with drowsiness are not an issue. FWIW "2% of Caucasians and 18% of people from African descent are desloratadine poor metabolizers.", meaning "In these people, the drug reaches threefold higher plasma concentrations at seven hours after intake, and it has a half-life of 89 hours (compared to a 27-hour half-life in normal metabolizers). Adverse effects were reported at similar rates in poor metabolizers, suggesting that it is not clinically relevant.".
        throwaway2037 2y ago
        Is BBB == "blood-brain barrier"?
        johnisgood 2y ago
        Yes.
        TechDebtDevin 2y ago
- OutOfHere 2y ago
  I advise against taking aGPC because it is very much associated with TMAO production due to adverse gut fermentation, leading to harmful effects on blood vessels. Switch to citicoline which doesn't look to have this issue.
  - johnisgood 2y ago
    Yes, Citicoline is great, too, I agree. As long as it is not Choline bitartrate (most common form) which is pretty useless, the body cannot utilize it whatsoever. As for what you said regarding alpha-GPC, it is somewhat true: > Although alpha-GPC is largely considered to be safe due to its structural feature, multiple studies have indicated that a high plasma choline level is associated with an increased risk of cardiovascular disease through trimethylamine-N-oxide (TMAO) produced by gut microbiota from choline. Some studies have highlighted that TMAO increases the likelihood of stroke and cardiovascular disease.11 > In line with this observation, a recent animal model study revealed that even though alpha-GPC supplements improved neurological functions, they increased the risk of atherosclerosis in hyperlipidemic rats. In the future, scientists must elucidate the possible mechanism that associates alpha-GPC with increased cardiovascular risks. https://examine.com/supplements/alpha-gpc/?show_conditions=true https://examine.com/supplements/alpha-gpc/?show_conditions=t... https://www.news-medical.net/health/Alpha-GPC-What-Science-Says-About-Its-Role-in-Brain-Health.aspx https://www.news-medical.net/health/Alpha-GPC-What-Science-S... https://pmc.ncbi.nlm.nih.gov/articles/PMC8708068/ https://pmc.ncbi.nlm.nih.gov/articles/PMC8708068/ https://www.sciencedirect.com/science/article/pii/S0021925824024670 https://www.sciencedirect.com/science/article/pii/S002192582... That said, "However, the currently available evidence is preliminary in nature, so randomized controlled trials and large cohort studies are needed to confirm these findings.".
    - johnisgood 2y ago
      BTW Citicoline's other name is CDP-Choline, forgot to edit in time.
    - johnisgood 2y ago
      Oh also, it says "multiple studies have indicated that a high plasma choline level is associated with an increased risk of cardiovascular disease", but I wonder why it does not apply to CDP-Choline (Citicoline) since it does increase plasma choline level, too, but perhaps not as highly? I am not sure of the exact mechanisms.
jadbox 2y ago
I've had some experience here and will add a couple notes. Memantine has been useful for slowing down Alzheimer's and temporarily improving responsiveness. However, Memantine has not shown any effectiveness in reversing Alzheimer's or fully stopping its progression (sadly). Memantine does seem to increase self-awareness clarity but, counterintuitively, seems to also disrupt memory recall. Word of caution, in one rat study, I had read that Memantine could have long term side-effects of hindering memory recall. Amantadine has a fascinating structure, but it seems like it's not super useful by itself from studies. It seems more like a very promising 'base structure' to build future compounds upon (like Memantine and bromantane). Anyways, this family is rather interesting for a number of its properties and are still not very well known or understood. Please do share any more insights.
- A_D_E_P_T 2y ago
  Random notes: - Unlike amantadine, chemically-related tromantadine is potently effective against HSV. https://pmc.ncbi.nlm.nih.gov/articles/PMC185716/ https://pmc.ncbi.nlm.nih.gov/articles/PMC185716/ - There's another paper which may shed some light on the herpes-Alzheimer's connection, and it notes that treatment with tromantadine (among others) is starkly beneficial: https://pmc.ncbi.nlm.nih.gov/articles/PMC5935641/ https://pmc.ncbi.nlm.nih.gov/articles/PMC5935641/ - If the connection is established, it could be that a tromantadine-like molecule with activity against herpes simplex -- plus mild activity at the NMDA receptor reducing excitotoxicity and protecting neurons -- could potentially be a good prophylactic against Alzheimer's. - It would be interesting to test amide-linked amantadine-phenylalanine and memantine-phenylalanine conjugates. Such things would probably penetrate the BBB very well, as they could take advantage of amino acid transporters. (The LAT1 transporter in particular.) And they resemble tromantadine -- where it is said that the amide itself is a necessary moiety in countering HSV. Structure: https://i.ibb.co/7tS4MGGL/Amantadine-Phe.png https://i.ibb.co/7tS4MGGL/Amantadine-Phe.png
  - DrAwdeOccarim 2y ago
    Are you a drug developer by trade? You certainly think like someone who’s seen some SARs…
chriscappuccio 2y ago
Memantine is an NMDA antagonist like ketamine and other dissociatives.
- OutOfHere 2y ago
  Memantine is in no way a disassociative though at therapeutic doses. It also has dopaminergic activity which manifests gradually over months while the NMDAr antagonist activity dials down.
TechDebtDevin 2y ago
My doc put my on amantadine for post covid symptoms and I felt like it gave me mild dementia and had to stop :/ edit: Fun fact, the side effects were so bad I made a very big mishap that destroyed a (very very expensive) f-class flight simulator.

johnisgood 2y ago

I believe most nootropics work for Alzheimer's, probably Huperzine A, too. Perhaps even Noopept. NMDA agonists and acetylcholinesterase (they inhibit the breakdown of the neurotransmitter acetylcholine) in general. Benadryl (DPH) and first-generation antihistamines are the opposite of that, they can cause delirium (and it messes up your memory and cognition in general) and whatnot, they are anticholinergic, some more than others. I had anticholinergic toxicity from DPH before. I take Alpha-GPC (a very soluble form of choline) and Huperzine A for cognition / memory, others couple it with racetams (e.g. piracetam, pramiracetam, aniracetam, etc.).

TechDebtDevin 2y ago
My primary care doctor is telling all of her patients not to take Zyrtec for an anti-histamine because it is causing dementia side effects in her older patients. Antecdotal but interesting.
- johnisgood 2y ago
  For the reasons I mentioned, yes. :) But Zyrtec is second-generation. It shows 20,000-fold or greater selectivity for the H1 receptor over the five muscarinic acetylcholine receptors, and hence does not exhibit anticholinergic effects, so it should be OK. May still cause drowsiness, however.
  - wildylion 2y ago
    What about desloratadine?
    - johnisgood 2y ago
      Desloratadine (Clarinex, Aerius) is a selective H1-antihistamine which functions as an inverse agonist at the histamine H1 receptor. From Wikipedia: > At very high doses, it is also an antagonist at various subtypes of the muscarinic acetylcholine receptors. This effect is not relevant for the drug's action at therapeutic doses. Thus, it is an anticholinergic only at very high doses, and it does not readily pass the BBB, therefore drowsiness is NOT likely (probably at very high doses only). At any rate, it does not affect the CNS at therapeutic doses, so memory / cognition issues, along with drowsiness are not an issue. FWIW "2% of Caucasians and 18% of people from African descent are desloratadine poor metabolizers.", meaning "In these people, the drug reaches threefold higher plasma concentrations at seven hours after intake, and it has a half-life of 89 hours (compared to a 27-hour half-life in normal metabolizers). Adverse effects were reported at similar rates in poor metabolizers, suggesting that it is not clinically relevant.".
      - throwaway2037 2y ago
        Is BBB == "blood-brain barrier"?
        johnisgood 2y ago
        Yes.
      - TechDebtDevin 2y ago
OutOfHere 2y ago
I advise against taking aGPC because it is very much associated with TMAO production due to adverse gut fermentation, leading to harmful effects on blood vessels. Switch to citicoline which doesn't look to have this issue.
- johnisgood 2y ago
  Yes, Citicoline is great, too, I agree. As long as it is not Choline bitartrate (most common form) which is pretty useless, the body cannot utilize it whatsoever. As for what you said regarding alpha-GPC, it is somewhat true: > Although alpha-GPC is largely considered to be safe due to its structural feature, multiple studies have indicated that a high plasma choline level is associated with an increased risk of cardiovascular disease through trimethylamine-N-oxide (TMAO) produced by gut microbiota from choline. Some studies have highlighted that TMAO increases the likelihood of stroke and cardiovascular disease.11 > In line with this observation, a recent animal model study revealed that even though alpha-GPC supplements improved neurological functions, they increased the risk of atherosclerosis in hyperlipidemic rats. In the future, scientists must elucidate the possible mechanism that associates alpha-GPC with increased cardiovascular risks. https://examine.com/supplements/alpha-gpc/?show_conditions=true https://examine.com/supplements/alpha-gpc/?show_conditions=t... https://www.news-medical.net/health/Alpha-GPC-What-Science-Says-About-Its-Role-in-Brain-Health.aspx https://www.news-medical.net/health/Alpha-GPC-What-Science-S... https://pmc.ncbi.nlm.nih.gov/articles/PMC8708068/ https://pmc.ncbi.nlm.nih.gov/articles/PMC8708068/ https://www.sciencedirect.com/science/article/pii/S0021925824024670 https://www.sciencedirect.com/science/article/pii/S002192582... That said, "However, the currently available evidence is preliminary in nature, so randomized controlled trials and large cohort studies are needed to confirm these findings.".
  - johnisgood 2y ago
    BTW Citicoline's other name is CDP-Choline, forgot to edit in time.
  - johnisgood 2y ago
    Oh also, it says "multiple studies have indicated that a high plasma choline level is associated with an increased risk of cardiovascular disease", but I wonder why it does not apply to CDP-Choline (Citicoline) since it does increase plasma choline level, too, but perhaps not as highly? I am not sure of the exact mechanisms.

jadbox 2y ago

I've had some experience here and will add a couple notes. Memantine has been useful for slowing down Alzheimer's and temporarily improving responsiveness. However, Memantine has not shown any effectiveness in reversing Alzheimer's or fully stopping its progression (sadly). Memantine does seem to increase self-awareness clarity but, counterintuitively, seems to also disrupt memory recall. Word of caution, in one rat study, I had read that Memantine could have long term side-effects of hindering memory recall. Amantadine has a fascinating structure, but it seems like it's not super useful by itself from studies. It seems more like a very promising 'base structure' to build future compounds upon (like Memantine and bromantane). Anyways, this family is rather interesting for a number of its properties and are still not very well known or understood. Please do share any more insights.

A_D_E_P_T 2y ago
Random notes: - Unlike amantadine, chemically-related tromantadine is potently effective against HSV. https://pmc.ncbi.nlm.nih.gov/articles/PMC185716/ https://pmc.ncbi.nlm.nih.gov/articles/PMC185716/ - There's another paper which may shed some light on the herpes-Alzheimer's connection, and it notes that treatment with tromantadine (among others) is starkly beneficial: https://pmc.ncbi.nlm.nih.gov/articles/PMC5935641/ https://pmc.ncbi.nlm.nih.gov/articles/PMC5935641/ - If the connection is established, it could be that a tromantadine-like molecule with activity against herpes simplex -- plus mild activity at the NMDA receptor reducing excitotoxicity and protecting neurons -- could potentially be a good prophylactic against Alzheimer's. - It would be interesting to test amide-linked amantadine-phenylalanine and memantine-phenylalanine conjugates. Such things would probably penetrate the BBB very well, as they could take advantage of amino acid transporters. (The LAT1 transporter in particular.) And they resemble tromantadine -- where it is said that the amide itself is a necessary moiety in countering HSV. Structure: https://i.ibb.co/7tS4MGGL/Amantadine-Phe.png https://i.ibb.co/7tS4MGGL/Amantadine-Phe.png
- DrAwdeOccarim 2y ago
  Are you a drug developer by trade? You certainly think like someone who’s seen some SARs…

chriscappuccio 2y ago

Memantine is an NMDA antagonist like ketamine and other dissociatives.

OutOfHere 2y ago
Memantine is in no way a disassociative though at therapeutic doses. It also has dopaminergic activity which manifests gradually over months while the NMDAr antagonist activity dials down.

TechDebtDevin 2y ago

My doc put my on amantadine for post covid symptoms and I felt like it gave me mild dementia and had to stop :/ edit: Fun fact, the side effects were so bad I made a very big mishap that destroyed a (very very expensive) f-class flight simulator.