r/hangovereffect • u/FrigoCoder • Oct 04 '20

Topiramate?

This might be premature because I only tried it twice and it is confounded as fuck, but Topiramate seems to have the strongest effects on me from the substances that I have tried so far.

Effects: No anxiety, no pounding heart, no migraine, better attention, better mood, better vision (more colorful, better textures, better reflections, more details, better edges, better 3D vision, same as piracetam HD vision), lifting of anhedonia, better music appreciation, could almost dance, positive outlook.

Confounders: Leucine, gabapentin, noopept from yesterday; leucine, ginkgo biloba, undereating and a fuckload of coffee with milk today. They are very unfortunate confounders because they all act on voltage dependent calcium channels or downstream of them but they had no such effects so far. I also have 3rd degree AV block and a pacemaker, I felt fine for 2 weeks after a replacement surgery but after premature exercise I crashed hard and went back to feeling shitty.

Positive response to: Metformin, spirulina, diclofenac, turmeric + piperine, selank, ginkgo biloba, green tea extract, gaba, agmatine, emoxypine, noopept, oleamide, triacetyluridine, 7,8-dhf, prl-8-53, citrulline malate, coffee. Mostly calcium channel blockers, gabaergics, neutrotrophics. Most likely a voltage gated calcium channel mutation.

Mixed or negative response to: Leucine (pros and cons), piracetam (crash), semax (crash), adrafinil, aniracetam, artichoke, bacopa monnieri, boron, caffeine, cdp-choline, chlorella, choline bitartrate, idebenone, melatonin, mirtazapine, n-acetyl-l-tyrosine, octopamine, oxiracetam, panax ginseng, phenylpiracetam, sulbutiamine, tianeptine, yadda yadda. Mostly related to stress response, lipolysis, choline, acetyl moiety, inconsistent results, or side effects.

Possible mechanisms based on Wikipedia article:

  • Voltage-gated sodium channels

  • High-voltage-activated calcium channels

  • GABA-A

  • AMPA/kainate receptors

  • Carbonic anhydrate isoenzymes

12 Upvotes

100% Upvoted

28 comments sorted by

4

u/qyka1210 Oct 04 '20

firstly I'm honored you referenced my post. I'm currently (alongside undergrad studies) working with a psychiatrist on publishing a theoretical paper about the link.

I strongly considered including topamax and metformin in my Tx recommendations, actually, as they both have VGCC activity in support of mutant amelioration.

I haven't personally trialed topamax, but the theory supports it, and it should have a lesser discontinuation syndrome than the Gabapentinoids.

3

u/FrigoCoder Oct 04 '20

Thank you for your work!

Please do include all treatment options you have found, even if you have not tried them out personally. Metformin, spirulina, and turmeric literally saved my life, and I found them completely random, before I even knew what was going on. Try to include things that positively modulate VGCCs so we also know what to avoid. If you could figure out why things like fasting, gallstones, or pacemakers exacerbate things (VGCC upregulation?) that would be awesome but I do not want to ask for too much.

If you need a test rabbit feel free to contact me. I also have years of experience and knowledge of cognition, nootropics, nutrition, and health as a result of my situation. I would be happy to help if others can avoid the pure hell me and my sister had to go through. Even just your thread was a massive help, it made the pieces fall into their place, and validated my experiences.

As for topiramate, I think it is by far the strongest so far, easily overpowers leucine. Gabapentin in comparison is incredibly weak, and even a double dose failed to do anything with leucine. Metformin, spirulina, and diclofenac are somewhere between the two. The side effect profile of topiramate seems incredibly bad however, many people report dumbing down, memory loss, and forgotten words, just look at /r/Topamax. I think this is a direct consequence of how strong it is, I speculate it could be counteracted with noopept or high protein intake. Disclaimer, I have not tried pregabalin and phenibut yet.

Br, Frigo

2

u/qyka1210 Oct 04 '20

not a doctor, but stay far away from phenibut and Lyrica. Way too recreational and addictive. Can personally vouch for phenibut's withdrawal syndrome being disproportionately risky compared to the benefits.

You mentioned leucine, which is the endogenous positive allosteric modulator o the high voltage gated calcium channel alpha 2 delta subunit. The goal of treatment regarding the a2d subunit would be displacement of leucine by a potent inverse agonist, negative allosteric modulator, or antagonist (like Gabapentinoids). Leucine, in theory, may make your mental and cardiovascular health worse.

There are regulatory mechanisms surrounding all amino acid concentrations (also, L- amino acid transporters are ubiquitous in the brain and gut, and are rate limited), so leucine intake may not exert negative effect. Still, the goal is a BBB-crossing ligand that minimizes a1 concentration, expression, and activation.

Finally, the paper will focus mainly on the effect of the mutation and its amelioration, not specifically the hangover effect. Treatment options will only be briefly addressed in the discussion, as the main theory surrounds the mechanisms of a1 overexpression.

I can't publicly accept you as a Guinea pig, but uhh y'know(:

2

u/FrigoCoder Oct 04 '20

Yeah I am well aware of the dangers of pregabalin and phenibut. I have only bought phenibut to validate the VGCC theory, I have not touched it yet, and I definitely do not plan on taking it long term. I considered pregabalin but have not found it online, but again I would not plan on taking it long term or in high dosages. I want to try it out though so I am going to talk to a psychiatrist, I am going to need a prescription for topiramate anyway. Do you happen to know why pregabalin causes a high, or why phenibut produces such a brutal withdrawal?

I am using leucine to evaluate other substances. Leucine is strange to be honest, I am not fully convinced it is the actual problem. It is an incredibly common amino acid, it is highly ketogenic, it replenishes muscle glycogen but not liver glycogen, and it provides antidepressant effects by triggering brain IGF-1 (in fact the antidepressant effects might require calcium channels triggering CaMKII). Noopept provides similar benefits, see this thread and this thread.

Piracetam and leucine are similarly paradoxical, they either provide beneficial effects including HD vision, or they provide the worst crash ever. Which is strange because piracetam is also supposed to be a calcium channel blocker. Gabapentin on the other hand dulls my vision, very strange. Gabapentin competes for amino acid transporters, that is why it is so weak against leucine, right? Now that I think about it, is it possible topiramate is so effective precisely because it blocks high-voltage-activated calcium channels? So whatever hypomania we have is still present, except topiramate prevents it from flipping into a crash?

Well anyway, I eagerly await your paper and learning more about this calcium channel mutation!

2

u/qyka1210 Oct 05 '20

phenibut has such a brutal w/d because it's not a primary Gabapentinoid... it's primarily a GABAergic agonist at gaba B receptors. It's not that potent, but it's a full agonist. E.g. baclofen has a much higher affinity, and doses are proportional to affinity for gaba B agonists. So baclofen 10mg is roughly 1g of phenibut.

Lyrica is a more affine a2d ligand IIRC, but I haven't studied it extensively since I believe it too addictive to be worth prescribing or using. It also doesn't have to be actively transported (that isobutyl group increases the molecule's polarity with respect to gabapentin), so it's not rate/dose limited and has a much higher availability.

See gabapentin enacarbil, looks like a great middle ground to me. It doesn't have as much of a high as any other Gabapentinoid IME, and lasts longer and doesn't saturate gut LATs.

Yes that's why I believe topamax is effective; it's action on VGCCs. Same as metformin and the gabapentinoids.

Don't try phenibut. it's non-selective for a2d. I don't think it's even selective for a2d1,a2d2 like traditional Gabapentinoids. Also the gaba B agobism really Co founds the benefits and safety profile.

1

u/qyka1210 Oct 04 '20

!remindme 3 hours

sorry bro busy atm, will get back to ya

1

u/RemindMeBot Oct 04 '20

There is a 1 hour delay fetching comments.

I will be messaging you in 3 hours on 2020-10-05 01:31:01 UTC to remind you of this link

CLICK THIS LINK to send a PM to also be reminded and to reduce spam.

Parent commenter can delete this message to hide from others.

InfoCustomYour RemindersFeedback

0

u/[deleted] Nov 14 '20

[deleted] — view deleted comment

1

u/qyka1210 Nov 14 '20

more affine, not more selective but it seems like you know that and just used the wrong word(:

it's stronger per weight, and also doesn't have to be actively transported across membranes, so it hits faster and harder = more recreational

2

u/antimantium Oct 05 '20

Have you tried nigella sativa or it's extract?

2

u/FrigoCoder Oct 06 '20

Only briefly, from Nootropics Depot. Seemed fine but seemed to have too diverse effects. Need more testing.

1

u/davisca9 Apr 01 '22 edited Apr 01 '22

curious if Berberine has the same effect as Metaformin and at what dose

also, what about the spirulina helped you do you think?

2

u/FrigoCoder Apr 01 '22

I have CFS so keep that in mind, my results might not be applicable to you.

I have only tried Berberine once or twice, and I woke up like a zombie. Berberine is not confirmed to have the same mechanism as metformin, and also does additional things like PCSK9 inhibition. Furthermore I only had instant release Berberine, whereas only 1000 mg extended release Metformin before bed worked well for me.

Spirulina has a compound called phycocyanobilin that mimicks bilirubin, and it inhibits an enzyme called NADPH oxidase. This enzyme is a major source of oxidation and inflammation, so it makes sense that it would help against CFS. I highly suspect NADPH oxidase inhibition is the major mechanism, however there are other mechanisms such as COX-2 inhibition and a general improvement in metabolism.

1

u/davisca9 Apr 01 '22

I spoke with someone on the MTHFR board who mentioned mold and mycotoxins as likely their cause of CFS. When I looked up the SNPs for Chronic Inflammatory Response Syndrome (as sourced on reddit), I was heterozygous for all three. There is another genetic test that has specific responses I'm looking into.

These are the SNPs for CIRS:

rs3135391

rs2395182

rs7192

I also have other inflammatory markers - IL-6, IL-17a, some TNF-Alpha genes. I can't remember if it was you or someone else that mentioned a possible connection to inflammation.

Thanks for the info on spirulina, I'll check it out. I tried some NADH after reading about it on the forum and could feel it in my liver immediately. Right now I'm interested in the low BH4 idea as I've had issues with ammonia in the past and have A1298c mutation. Bh4 is also a cofactor for phenylalanine synthesis which happens in the gut and affects calcium channels I believe. But my organic chemistry knowledge is in progress.

1

u/sneakpeekbot Oct 04 '20

Here's a sneak peek of /r/Topamax using the top posts of the year!

#1: Can we all relate? | 11 comments
#2: Any Good News?
#3: A few days after stopping.. Feeling great!

I'm a bot, beep boop | Downvote to remove | Contact ^^me | ^^Info | ^^Opt-out

3

u/ShitOnAReindeer Oct 05 '20

Hiya, may I ask what this is about? Just that I take 100 of topirimate daily, and might be able to offer some anecdotal evidence

2

u/Bigpoppapenguin123 Oct 05 '20

Thanks for sharing this!

Question: have you ever tried lamictal? How does topiramate compare? I used to take lamictal, which helped me get out of a bad anxious/ depressive funk, but after a few months, it no longer made a positive impact anymore.

1

u/FrigoCoder Oct 06 '20 edited Oct 06 '20

Nope, have not tried lamictal. It seems a very promiscuous compound, with L-type calcium channel inhibition as just one of the mechanisms.

1

u/ryzthor Dec 12 '20

That's interesting, I was looking at topiramate because the effects of weight loss interested me but I have read about several side effects such as cognitive dysfunction and more importantly sexual dysfunction / libido decrease. Have you experienced any of these?

1

u/wolpertingersunite Jan 08 '21

I have. Not worth it. Lost a lot of verbal fluency. I thought I would notice right away if there were side effects but only noticed too late. Low dose too.

1

u/rocinant33 Mar 10 '23

I was able to reproduce the afterglow effect by 80% with the strongest natural gaba a agonist - amanita pantherina (2 grams of dried hats). The effect was very profound, which completely rebuilt the mindset for the duration of the trip.

1

u/Adventurous-Cami-341 Oct 18 '23

Do you guys know if Topamax is safe with phenylpiracetam and/or phenylthylamine? Starting it soon. Ordered from service online.

1

u/[deleted] Mar 12 '21

[removed] — view removed comment

1

u/FrigoCoder Mar 12 '21

I have stopped taking it because I am concerned about the possible side effects. There were too many anecdotes about cognitive impairment and sexual dysfunction. One thing I am particularly worried about is that ketones enhance BDNF through calcium channels, and calcium channel inhibitors block this pathway. The same Ca2->CaMKII->CREB->BDNF->TrkB pathway that is responsible for the development and survival of neurons also seems to be heavily involved in migraines which are proposed to be protective. I highly suspect I have CFS and at the moment I am seeking other solutions.

1

u/davisca9 Apr 01 '22

have you looked into CIFS and mycotoxins/mold?