(updated and rewritten 3/2019)

Summary

One study suggests that lamotrigine and folate in the form of folic acid may interact somehow, blocking lamotrigine’s benefits.  A small controversy has developed around this. Here are a few conclusions I hope may dampen some of that controversy.

  1. Be humble. Don’t believe to know more than we know.
  2. Relax. There’s a temporary solution that’s pretty simple.

(If you need some help understanding the different forms of folate, my page on that may help.)

Be humble

We don’t know the mechanism of the interaction between lamotrigine and folic acid.  So we don’t know which forms of folate might avoid this interaction. We shouldn’t pretend — to ourselves or others — to know enough to make pronouncements about how to use folate in the context of lamotrigine. Or, as attributed to Mark Twain but apparently of uncertain origin, “It ain’t what you don’t know that gets you into trouble. It’s what you know for sure that just ain’t so.”

Specifically, that means we should not assume that some other form of folate (e.g. the one that goes around the enzyme some people are missing, L-methlyfolate) avoids the problem. Even if someone puts forth a very good theory about how it might avoid the problem. More on this below in the L-methlyfolate section.

Relax: a temporary solution

A) If you’re going to take lamotrigine, discontinue folic acid. If lamotrigine doesn’t work, maybe try it again after you’ve been off folic acid a while. How long? Don’t know. Maybe a month or two?

B) if you’re on lamotrigine and it’s working, be careful about adding folate in any form. (If your benefit seems to fluctuate, if you eat much wheat flour, maybe even cut that back some if flour is enriched with folic acid in your country, as it is in the U.S.)

C) If you’re taking L-methylfolate, e.g. Deplin, and all is well, continue. If while on it, lamotrigine is started and doesn’t work, maybe try lamotrigine again later when haven’t been taking L-methlyfolate. (For how long? Again, don’t know).

D) Finally, if you’re taking neither, then don’t start them together. Try one and then the other. In bipolar depressions, it would make sense to try lamotrigine first (L-methylfolate is supposed to be an antidepressant, not a mood stabilizer; but don’t assume we know very much here either!).

Which folate are we talking about?

Folate is the compound found in broccoli, spinach, peas and other foods. Folic acid comes in pills. It is converted through your liver to several forms of folate in your blood. Finally, there’s a different pill version called l-methylfolate which is more costly but works around a genetic barrier that about 15% of the U.S. population carries. If you’re one of those 15%, you’d need the spendy version if for some reason you want to take folate.

How are you supposed to find out?  What is special about folate, anyway?  Why would you want to get extra folate?  For these questions, see my page on Folate.  Short answer: some very limited evidence suggests that extra folate might help treat depression. That’s why the research team used it in the study described below; then they stumbled on this possibility that folic acid supplements might interfere with lamotrigine.

Folic acid supplement interferes with lamotrigine?

Here’s the study on which that concern is based. Geddes  In patients with bipolar depression, who all were taking quetiapine/Seroquel, the investigators added either lamotrigine or folic acid or both.  The main purpose of the study was to see if lamotrigine, added to quetiapine, was better than adding a placebo, so there was a placebo group as well.   So there are four different groups of patients in this study, whose outcomes were compared to one another, in blue below:

folic acid no folic acid
lamotrigine A: lamotrigine and folic acid B: lamotrigine alone
placebo C: placebo and folic acid D: placebo, no folic acid

Remember, everyone is getting quetiapine as well, and many patients were also taking other stuff — moderately complex and sometimes very complex soup. Despite that, several signals were clear in this study.

What did they find?  Their depression measure used is called a QIDS-SR (exactly what that is, if you don’t know it, doesn’t matter much here). A reduction of 4 points, on this 16 point scale, is a pretty big drop. That’s what lamotrigine alone produced, compared to placebo: 4 points more reduction than a placebo (comparing groups B and D above). In this business, that is a very solid signal of effectiveness.

But the group that got lamotrigine and folic acid (Group A above) — well you might expect them to do maybe even a little better, with a second potential antidepressant on board? Nope, they didn’t do better than Group C, folic acid plus placebo.  The benefit that lamotrigine provided in Group B was lost when lamotrigine was combined with folic acid (Group A).

Huh? What’s going on here? The study authors speculate that folate and lamotrigine might both be trying to bind to the same spot on neurons (there is some old evidence to suggest this might be so). Or that maybe folic acid interferes with the absorption of lamotrigine.  In any case, they are clearly concluding that this apparent interaction between lamotrigine and folic acid is real, and substantial.

Indeed,  their study shows:

  1. adding lamotrigine to quetiapine really works, clearly better than a placebo (for up to 52 weeks in this long study; Group B versus Group D); and
  2. “if a patient with bipolar disorder needs folic acid therapy, then lamotrigine should be avoided and vice versa”  (their quote, emphasis mine).

They also note: “The result raises an intriguing question about the likely efficacy of lamotrigine in countries which fortify wheat flower with folic acid: the US programme has been estimated to provide 100–200 μg of folic acid per day in women of childbearing age.  It is unclear if this amount is sufficient to reduce the treatment effect.”

L-methylfolate/Deplin

Might this popular form of folate get around the apparent interference of folate and lamotrigine? This has been strongly suggested, e.g. in a published response to the original study:

As noted on its FDA package insert, lamotrigine inhibits dihydrofolate reductase, the enzyme that catalyses the reduction of dihydrofolate to tetrahydrofolate, thereby reducing the formation of the bioactive form methyltetrahydrofolate (5-MTHF). Prescription 5-MTHF (Deplin), with its direct passage across the blood–brain barrier and no need for several enzymatic interconversions, could be an optimum augmentation for patients with mood disorders who take lamotrigine…

But note the explanation offered by the authors of the original study:

“Lamotrigine was originally synthesised as one of a series of folate antagonists on the grounds that folate was thought to be pro-convulsant.   Hence, it is possible that lamotrigine and folate both bind to a common receptor or enzyme site. Alternatively, it could be a pharmacokinetic effect whereby folic acid reduces absorption of lamotrigine from the gastrointestinal tract.”

To my ear, they are emphasizing the principle with which I began above: be humble. Don’t presume to know more than we know.