Gabapentinoids I've read NOT to mix calcium and or magnesium with GABAPentin and I assume it's cause it will affect the absorption but I haven't found any info?

[Drag2019]

Now when they mention magnesium when I do a quick search on the internet it appears to be from antacids tums if I recall correctly the aluminum magnesium as a inactive ingredient in them can "change" how GABAPentin is absorbed.


I've also read that calcium can effect it's absorption but I'm unclear about how much or how it does it... I'm guessing that since calcium can reduce stomach acidity in the stomach potentially that may be the reason for it's possible effect on its absorption.

At the same time I'm wondering what it does to calcium absorption into the body, specifically blood calcium absorption and I only managed to find this info with a quick internet search: https://www.ehealthme.com/ds/gabapentin/blood-calcium-increased/


I can't find any good links with verified medical literature. But I got this found this mentioning magnesium: https://www.goodrx.com/gabapentin/magnesium-and-gabapentin





If anyone has more info or verified medical literature to help me get to the bottom of this it'd help satisfy my curiosity lol.

 

[WellTram]

My GP once told me to take magnesium or calcium but not both together. Why ?

 

[JackARoe]

If anyone has more info or verified medical literature to help me get to the bottom of this it'd be help satisfy my curiosity lol.

I think you are on to something. I had even read that people in gabapentin withdrawal getting relief from magnesium.. I think when taken together the absorption is affected but I don't know by what mechanism.

Thanks for the links. The big and dandy gabapentin thread has a lot of info on absorption. Awaiting more technical responses.

 

[OceansState]

I recently got a script for Gabapentin and I read something about not taking Magnesium supplements and Gabapentin together. I dont care for the Gabapentin since it makes my head foggy so i only take it at night now if i need to. I take my gummy Magnesium and other various vitamins and minerals in the Morning.

 

[Keif' Richards]

Yes.

A basic (more acidic) environment is better than an alkaline (less acidic) one. This means anything labeled an antacid, like tums or what have you, is likely to lower the absorption/potency of your Gabapentin. This includes substances not necessarily used as antacids like Magnesium, that have an antacid effect on the gut.

I'm not sure to what extent absorption is effected. I can tell you that I've had to take antacids while on Gabapentin and it was never enough to make me stop and say "man this is not as effective" or any thing like that.

I would just try your best to limit the antacids or otherwise take the antacids at more advantageous times (not within two hours of taking your Gabapentin).

 

[OceansState]

I just looked at the pamphlet that came with the Gabapentin and it says "Do not take aluminum or Magnesium antacids within 2 hrs of taking this drug".

 

[Drag2019]

^ Yeah I'm unclear about what the aluminum has to with anything? Also is the calcium and or magnesium truly only effecting GABApentin via the stomach acidity or is it a bit more complicated than that? It wouldn't surprise me with how weird of a drug GABApentin is.

If it's that simple than taking it a few hours apart from each other should solve the problem.

 

[Skorpio]

Gabapentin is a zwitterion, which means that it has both a positive and negative charge at the physiological pH range. Because of this it won't diffuse through cell membranes passively (like the majority of drugs in use). It gets taken into cells due to its similarity to amino acids, hitching a ride on transporters that use energy (either ATP, or the sodium gradient of the cell) to bring amino acids into intestinal cells.

My guess would be that the calcium and magnesium are either forming complexes with gabapentin which prevent it from entering those transporters (think how magnesium is complexed with taurine, glycine, or threonine in supplements). I was thinking that those ions may inhibit those transporters, but that can't be right, as eating calcium and magnesium supplements don't cause amino acid deficiencies due to preventing their uptake.

 

[Jabberwocky]

My GP once told me to take magnesium or calcium but not both together. Why ?

They compete for absorption.

They are both metals and the body will only absorb one or the other at a specific rate limit. If you took both at once, you'd only absorb 50% of each dose. (Guessing the %, just for example). But the rest just passes and gets excreted unused.

But if you took magnesium several hours after the calcium, you'd absorb maximum amounts of both.

 

[snmfmy]

I think you are on to something. I had even read that people in gabapentin withdrawal getting relief from magnesium.. I think when taken together the absorption is affected but I don't know by what mechanism.

Thanks for the links. The big and dandy gabapentin thread has a lot of info on absorption. Awaiting more technical responses.

Magnesium is absorbed through three processes, active transport and it's controlled by vitamin d, passive diffusion, and solvent drag

The literature regarding magnesium supplementation clearly states that unless you're extremely low in magnesium, you can saturate the diffusion and active transport.

Gabapentin also has active saturable transport by some unknown amino acid and passive diffusion.

Although the mechanism is unknown, I'm guessing it's that magnesium blocks the passive diffusion pathway by just being in the way.

Apparently it's approximately 1/3 less bioavailable

https://associationofanaesthetists-publications.onlinelibrary.wiley.com/doi/10.1046/j.0003-2409.2001.02399.x

However, there are other studies that contradict the idea of gabapentin being saturable and bioavailability dropping as dose increases.

"Mean circulating GBP concentrations (mg/l) at each 1200 mg dose level were as follows: 1200 mg-4.1; 2400 mg-8.6; 3600 mg 13.2; 4800 mg 15.5; 6000 mg-17.2. In six patients, including three taking 6000 mg daily, GBP concentrations continued to rise linearly at each dosage increment."

High dose gabapentin in refractory partial epilepsy: clinical observations in 50 patients - PubMed

Fifty patients with refractory partial seizures took part in a prospective, observational study of adjuvant gabapentin (GBP) in increasing doses. Thirty-three were started on 400 mg GBP daily with further weekly increments of 400 mg until seizures came under control for at least 6 months or to...

pubmed.ncbi.nlm.nih.gov

It's clearly linear and doesn't start to drop off until 4,800 mg daily dose.

Hope the info helps

 

[Skorpio]

Magnesium is absorbed through three processes, active transport and it's controlled by vitamin d, passive diffusion, and solvent drag

The literature regarding magnesium supplementation clearly states that unless you're extremely low in magnesium, you can saturate the diffusion and active transport.

Gabapentin also has active saturable transport by some unknown amino acid and passive diffusion.

Although the mechanism is unknown, I'm guessing it's that magnesium blocks the passive diffusion pathway by just being in the way.

Apparently it's approximately 1/3 less bioavailable

https://associationofanaesthetists-publications.onlinelibrary.wiley.com/doi/10.1046/j.0003-2409.2001.02399.x

However, there are other studies that contradict the idea of gabapentin being saturable and bioavailability dropping as dose increases.

"Mean circulating GBP concentrations (mg/l) at each 1200 mg dose level were as follows: 1200 mg-4.1; 2400 mg-8.6; 3600 mg 13.2; 4800 mg 15.5; 6000 mg-17.2. In six patients, including three taking 6000 mg daily, GBP concentrations continued to rise linearly at each dosage increment."

High dose gabapentin in refractory partial epilepsy: clinical observations in 50 patients - PubMed

Fifty patients with refractory partial seizures took part in a prospective, observational study of adjuvant gabapentin (GBP) in increasing doses. Thirty-three were started on 400 mg GBP daily with further weekly increments of 400 mg until seizures came under control for at least 6 months or to...

pubmed.ncbi.nlm.nih.gov

It's clearly linear and doesn't start to drop off until 4,800 mg daily dose.

Hope the info helps

I wouldn't say that either that review or that the case report are high quality enough for conclusions

Both are more than 20 years old and very light on mechanistic stuff. The review for example does not identify a specific target for gabapentin uptake or mechanism of action (beyond mentioning "an unspecified L-amino acid transporter"). The second one has data at least, but the sample size is really small and it lacks mechanistic explanations.

I do agree that the saturation of gabapentin dosing is less of a binary thing than is often adhered to. I don't really see where you get the conclusion of both active and passive transport from those papers though; it seems like you are extrapolating quite a bit.

I've got a fairly low bandwidth the next week for researching papers, but i can look for some recent ones with actual experiments after that.

 

[snmfmy]

I wouldn't say that either that review or that the case report are high quality enough for conclusions

Both are more than 20 years old and very light on mechanistic stuff. The review for example does not identify a specific target for gabapentin uptake or mechanism of action (beyond mentioning "an unspecified L-amino acid transporter"). The second one has data at least, but the sample size is really small and it lacks mechanistic explanations.

I do agree that the saturation of gabapentin dosing is less of a binary thing than is often adhered to. I don't really see where you get the conclusion of both active and passive transport from those papers though; it seems like you are extrapolating quite a bit.

I've got a fairly low bandwidth the next week for researching papers, but i can look for some recent ones with actual experiments after that.

https://www.sciencedirect.com/topics/medicine-and-dentistry/magnesium-transport

Active transport for gabapentin:

A Saturable Transport Mechanism in the Intestinal Absorption of Gabapentin Is the Underlying Cause of the Lack of Proportionality Between Increasing Dose and Drug Levels in Plasma - Pharmaceutical Research

Gabapentin (l-(aminomethyl)cyclohexaneacetic acid) is a neuroprotective agent with antiepileptic properties. The structure is small (molecular weight less than 200), is zwitterionic, and resembles an amino acid with the exception that it does not contain a chiral carbon and the amino group is...

link.springer.com

"In contrast to gabapentin, the absorption pathway of gabapentin enacarbil does not become saturated at clinically relevant doses, allowing greater bioavailability of the active drug.13,16 Gabapentin enacarbil is absorbed through the gastrointestinal (GI) tract and has dose-proportional and predictable PK over a wide dose range, resulting in lower variability of gabapentin exposure compared with the administration of other gabapentin formulations."

Interindividual Variability in the Bioavailability of Gabapentin Enacarbil Extended Release in Healthy Adults: An Analysis of Data From 6 Phase I Studies - PMC

The absorption and bioavailability of oral gabapentin are associated with a high degree of interindividual variability. Gabapentin enacarbil, a prodrug of gabapentin, is well absorbed and provides sustained, dose-proportional exposure to gabapentin. ...

www.ncbi.nlm.nih.gov

So some formulations of gabapentin are passively diffused. Gabapentin by itself is actively transported, but since it's lipophilic it will diffuse through the lumen, but it's minor.

 

[Skorpio]

https://www.sciencedirect.com/topics/medicine-and-dentistry/magnesium-transport

Active transport for gabapentin:

A Saturable Transport Mechanism in the Intestinal Absorption of Gabapentin Is the Underlying Cause of the Lack of Proportionality Between Increasing Dose and Drug Levels in Plasma - Pharmaceutical Research

Gabapentin (l-(aminomethyl)cyclohexaneacetic acid) is a neuroprotective agent with antiepileptic properties. The structure is small (molecular weight less than 200), is zwitterionic, and resembles an amino acid with the exception that it does not contain a chiral carbon and the amino group is...

link.springer.com

"In contrast to gabapentin, the absorption pathway of gabapentin enacarbil does not become saturated at clinically relevant doses, allowing greater bioavailability of the active drug.13,16 Gabapentin enacarbil is absorbed through the gastrointestinal (GI) tract and has dose-proportional and predictable PK over a wide dose range, resulting in lower variability of gabapentin exposure compared with the administration of other gabapentin formulations."

Interindividual Variability in the Bioavailability of Gabapentin Enacarbil Extended Release in Healthy Adults: An Analysis of Data From 6 Phase I Studies - PMC

The absorption and bioavailability of oral gabapentin are associated with a high degree of interindividual variability. Gabapentin enacarbil, a prodrug of gabapentin, is well absorbed and provides sustained, dose-proportional exposure to gabapentin. ...

www.ncbi.nlm.nih.gov

So some formulations of gabapentin are passively diffused. Gabapentin by itself is actively transported, but since it's lipophilic it will diffuse through the lumen, but it's minor.

Gabapentin encarbil is not gabapentin, it is a completely different compound. It has a protecting group on the amine to prevent charge, and is a prodrug. Gabapentin itself isn't lipophillic at all.

Also I'm not disputing that it is actively transported, it is. I am disputing that gabapentin is passively transported. That paper supports that conclusion.

I'm not sure what that magnesium science direct article is for. I was only talking about magnesium for its role as an inhibitor of gabapentin uptake.

Studies aren't all made equal. In general studies with experiments rather than case studies or reviews are the most credible, with additional layers of abstraction being less reliable. Reviews are really only good for knowing the current state of the field, so they need to be as current as possible to have value.

I appreciate your willingness to find papers, I just think that you can become more effective by citing high quality science.

 

[snmfmy]

Gabapentin encarbil is not gabapentin, it is a completely different compound. It has a protecting group on the amine to prevent charge, and is a prodrug. Gabapentin itself isn't lipophillic at all.

Also I'm not disputing that it is actively transported, it is. I am disputing that gabapentin is passively transported. That paper supports that conclusion.

I'm not sure what that magnesium science direct article is for. I was only talking about magnesium for its role as an inhibitor of gabapentin uptake.

Studies aren't all made equal. In general studies with experiments rather than case studies or reviews are the most credible, with additional layers of abstraction being less reliable. Reviews are really only good for knowing the current state of the field, so they need to be as current as possible to have value.

I appreciate your willingness to find papers, I just think that you can become more effective by citing high quality science.

Well I posted the actual experimental data from the epileptics getting escalating doses from 1200 to 6000 mg in a day. But I'll link again.

It stays linear from 1200 to 4800 mg and only slightly dropped off at 6000 mg, meaning the intestinal transport appears to be unsaturable,

"Alternatively, the proportionally increased absorption might reflect the recruitment of an another absorption mechanism, e.g. passive diffusion."

https://www.sciencedirect.com/science/article/pii/S1059131102001425

It's a very good study with rigor.

10 subjects vs the 37 used for the cannonical bioavailability studies are essentially identical with respect to statistical significance and representation.

https://www.sciencedirect.com/science/article/pii/S1059131102001425

Furthermore, other studies show that area under the curve for the same dose increases when the dose is split into every six hours instead of every eight.

The data shows that at least in some humans it is not a saturable transport mechanism or has a passive mechanism as well. That's not my conclusion. That's the conclusion of the study authors.

 

[Skorpio]

I read the study you presented. I don't comment on studies without reading them and their results. I just don't think it has any conclusive evidence for mechanisms of uptake being passive or active.

It is neat to see that the dose doesn't saturate, but that isnt really germane to the question asked regarding magnesium. I'd like to see something where specific transporters are blocked or knocked out to prove passive transport, or something with that level of speficity. Either that or a coherent explanation of how those results relate to the effects of magnesium on gabapentin uptake.

I'm probably done here for the time being, it feels like we are running in circles.

 

[OceansState]

I have a question. What about if you take Loperamide and then take Gabapentin. I ask because I thought loperamide slows down the intestines.

Im not really smart enough to read those cited articles/papers and understand them.

 

[LucidSDreamr]

I think you are on to something. I had even read that people in gabapentin withdrawal getting relief from magnesium.. I think when taken together the absorption is affected but I don't know by what mechanism.

Thanks for the links. The big and dandy gabapentin thread has a lot of info on absorption. Awaiting more technical responses.

Magnesium is a muscle relaxant. Just throwing that out there.

That’s why they say to take Heavy mg doses for mdma bruxism