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Comment by A_D_E_P_T | Hacker News Reader

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/

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

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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.

Random notes:

- Unlike amantadine, chemically-related tromantadine is potently effective against HSV. 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/

- 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

Are you a drug developer by trade? You certainly think like someone who’s seen some SARs…

Thanks, man. I'm more of a general-purpose chemist. I've done medicinal chemistry for drug development, but also inorganic compound development, metallurgy, all kinds of other stuff. It's a broad and fun field.

Very cool. I’m a bloodhound for spotting talent. Are you still in the space?

Yeah, and in fact working on some interesting projects. Feel free to email me if you'd like to chat: jakeganor [at] gmail

Super cool :) Do you have a preferred social media handle to follow for any future adamantane and other related research posts?

Afraid not. I only post here, lol

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.).

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.

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.

What about desloratadine?

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.".

Is BBB == "blood-brain barrier"?

Yes.

Do you know if there are any SNPs correlated with poor desloratadine metabolizers?

I do not think that there are any definitive single nucleotide polymorphisms (SNPs) currently known to be specifically correlated with poor desloratadine metabolism.

I think perhaps the genetic variation in the enzymes involves in its metabolism like UGT2B10 and CYP2C8 may contribute to differences in metabolism. There is just no conclusive identification of specific SNPs that definitively determine poor metabolizer status. The precise genetic variants (if any) have not yet been definitively pinpointed.

For all we know, the differences may be attributable to variations in study design, sample sizes, definition of what constitutes a "poor metabolizer", and genetic heterogeneity among populations. Some reported rates of poor metabolizers vary, some studies report around 7% overall and 20% in African descent individuals, while others suggest the figures I have mentioned. There was a somewhat recent randomized study in healthy Chinese subjects, and found no statistically significant association between the UGT2B10 or CYP2C8 genotypes.

What is clear is that while genetic factors are likely involved and poor metabolizer phenotype exists for the drug, no single genetic marker has yet been found to predict poor metabolism of this drug, and there is a notable interethnic difference in desloratadine metabolism.

TL;DR: Currently there is no definitive evidence linking specific SNPs to poor desloratadine metabolism, but genetic variation in enzymes like UGT2B10 and CYP2C8 is implicated, but further research is needed.

I hope this answers your question, but the bottom line is that more research is needed. If you know something, let me know though!

Interesting, and thank you for the informative response. I have very weird reactions to cholinergic/anticholinergic drugs ranging from severe hallucinations to massive impacts to working memory. I've always figured there is something unique about that part of my biology but don't really no where to look to try and identify why.

I have weird or controversial reactions to most medications, especially psychiatric and drugs. I have no clue why. I have MS, I have brain lesions, they might play a part.

- For example nothing happened from 190 x 1 mg alprazolam + 0.5 L whiskey.

- None of the psychiatric medications worked for me (tried almost all there is, it took a long time). No pros, nor cons.

- Opiates do not cause euphoria, nor sedation for me. Without tolerance.

- The list goes on...

I have never figured out why medications affect me extremely differently from other people.

I took 5 x 50 mg DPH, nothing happened, then the next day I took it again, and I got anticholinergic toxicity. Perhaps it accumulated in this case, but yeah, it was one of the worst experiences I have had (delirium with dysphoric hallucinations, cognitive decline, memory issues). Took me months to recover. I have had auditory hallucinations for a couple of days, too.

What cholinergics and anticholinergics have you tried and what were your experiences?

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.

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=t...

https://www.news-medical.net/health/Alpha-GPC-What-Science-S...

https://pmc.ncbi.nlm.nih.gov/articles/PMC8708068/

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.".

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.

BTW Citicoline's other name is CDP-Choline, forgot to edit in time.

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.

Memantine is an NMDA antagonist like ketamine and other dissociatives.

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.

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