Sublingual to Swallowing Levo/T3 - My Grand Experiment n=1 - the results are in!

[FallingInReverse]

I am planning to update on my latest blood test results, but first I’m going to report back on my grand experiment - Switching from sublingual to swallowing my thyroid hormones.

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*****EXPERIMENT SET UP*****

I have been taking sublingual since diagnosed in Aug ‘22 at which time my TSH was 85 and FT4 15% BELOW range.

A way point for context - I was on 50 Levo for 9 months then in July ‘23, I reduced to 25 Levo and added 10 T3. 8 weeks later in Sep ‘23 my TSH was down to 2.274 (.5 - 4.7), FT4 was .76 (.89 - 1.76 still 15% under), and FT3 was 3.1 (2.3 - 4.2 or 42% through range.) Compared to 2 months ago, TSH was <0.008 (0.55-4.78), FT4 1.34 (0.89 – 1.76) 52% (UP from 7% prior period) and FT3 4.3 (2.3 – 4.2) 105%! (up from 68% prior period).

Therefore, the clear progress in my Ts over the past ~year until this experiment started was all sublingual.

Meds consistency/changes:

END JANUARY THROUGH END MARCH '24 (a solid 9 weeks-ish) - In this 9 week period I consistently took 75 levo, 10 T3, D at 7500 (incl a loading period) w/K. and one Three Arrows twice a week (first time supplementing iron. (To underscore the Ts consistency - this reflected only a small 12.5 Levo increase over the last 6-8 week period and stable 10 T3 for ~a year prior.)

END MARCH I started my sublingual-to-swallow experiment which included no Ts changes except swallowing the 75 Levo and 10 T3. (I did reduce D to 2500 due to an overage, and increased iron from twice a week to daily due to my iron numbers not budging.)

Methodology commentary - My husband told me I shouldn’t have wasted 6 weeks on this at all, that I should just keep optimizing my low T4. But I did want to correct this administration issue while I still had room to improve as I didn't want it to later make me go past my sweet spot. Also, with so long sublingual, I was way too curious to let the chance go by. Also as noted above - yes, I did change D and iron. You can make your own conclusions about what impact that might have had.

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*****MY ORIGINAL HYPOTHESIS vs RESULTS*****

I fully expected my Free Ts to increase - just wasn't sure by how much. Instead, they reduced pretty substantially 20-30 points down through range!

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***** DETAILED RESULTS*****

All tests I’ve ever taken to date, including these, have been done under exactly the same scenarios.

Last doses - Levo 24 hours, T3 18 hours. (Now that this experiment has concluded, I will now be dosing T3 as recco’d on this board. But the important thing is that these two blood tests were done the same and so are comparable for this exercise.)

Fasting, and I don’t take any biotin or B.

RANGES

TSH 0.550 - 4.78 mIU/L

FT4 0.89 - 1.76 ng/dL

FT3 2.3 - 4.2 pg/ml

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March 27 vs May 17 2024

TSH --- 0.008 --- NO CHANGE

FT4 --- 1.34 ---TO--- 1.16 (FROM 52% to 31% through range)

FT3 --- 4.3 ---TO--- 3.7 (FROM 105% - 74% through range)

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*****OTHER LINKS TO THE TOPIC*****

There have been periodical posts here asking about whether one can take Levo sublingual, here are a few if interested:

1) From Dec ‘23: Can levothyroxine be taken under the tongue?

healthunlocked.com/thyroidu...

This is where I was made aware that I wasn’t fully informed on the choice I made to keep taking sublingually.

2) From      tattybogle a year ago: Where and How is Levo absorbed .... A collection of information.

healthunlocked.com/thyroidu...

Which includes a link to this:

Levothyroxine Therapy in Gastric Malabsorptive Disorders

ncbi.nlm.nih.gov/pmc/articl...

Which begins with this:

Oral levothyroxine sodium is absorbed in the small intestine, mainly in the jejunum and the ileum being lower the absorption rate at duodenal level. The time interval between the ingestion of oral thyroxine and its appearance in the plasma renders unlike a gastric absorption of the hormone. However, several evidence confirm the key role of the stomach as a prerequisite for an efficient absorption of oral levothyroxine. In the stomach, in fact, occur key steps leading to the dissolution of thyroxine from the solid form, the process bringing the active ingredient from the pharmaceutical preparation to the aqueous solution.

3) I also found this via search from 7 years ago called: Sublingual vs Swallow in am w Water

healthunlocked.com/thyroidu...

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*****ORIGINAL EXPLANATION*****

The gist is that Levo is formulated, tested and indicated to be swallowed. That stomach acid plays an essential role to dissociate parts of the Levo molecule (specifically from the sodium ions) a process that is chemically required to aid absorption.

That was compelling, and so that’s why I fully expected more bioavailability when swallowing.

When it didn’t, I actually assumed that although the tablet dissolved in my mouth (importantly, I did NOT brush my teeth after, and so an hour later when I would have my coffee or breakfast, the dissolved pill was 100% still in my mouth through the day), that over the day it was slowly making it’s way down my throat into my stomach - which all of the above says is required for Thyroxine to get where it needs to to work.

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*****NEW HYPOTHESIS/EXPLANATION*****

How can it be true that stomach acid is required for Levo absorption, AND sublingual not only worked so well for me for over 18 months, but actually in my case worked better (ie, more hormones delivered as reflected in test results)?

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     helvella posted this, called Binding of Thyroid Hormones: healthunlocked.com/thyroidu....

It’s a primer video on how hormones work, and as part of it it discusses the fact that T4/T3 are lipid soluble hormones.

Desk research shows these are facts - T4 is a lipid soluble hormone. The small intestines is aqueous. Under the tongue is lipid-rich. (as explained here: ncbi.nlm.nih.gov/pmc/articl...

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Therefore, if I’ve got this right, here’s what explains the effectiveness of my taking T4/T3 sublingual administration:

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* Water soluble things absorb easily through the walls of the small intestines. But lipid soluble things require the dissociation and ionization process before being able to absorb through the walls of the small intestines. So when a lipid soluble Levothyroxine is swallowed it does indeed NEED the stomach acid and other mechanisms to be dissociated and ionized to be absorbed there.

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* T4 is lipid soluble and therefore, can actually be absorbed through the lipid-rich cell membranes under the tongue (ie, no aqueous barrier under the tongue, so no need for stomach or another acid to dissociate and ionize it to be absorbed.) Further, the mucosal layer under the tongue is thin, and also has a rich blood supply, which facilitates direct entry into the bloodstream. Once in the bloodstream, as a lipid soluble thing, it has different requirements… they need to be bound to plasma carrier protein. And for T4/T3 that carrier is thyroxine binding globulins.

You can see that part of the process in the video Helvella shared starting here at 3:11 youtu.be/jbjmfsYRkZ8?featur...(Not working as expected?) ending around 7:10 but the video names the globulins at minute 8:50.

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Look forward to all input, challenges, etc.

[helvella]

That is an interesting study!

Question

If levothyroxine is absorbed somewhere in the mouth, do the entire levothyroxine sodium molecules get absorbed?

And does the presence of levothyroxine sodium molecules in the bloodstream make any difference (as opposed to levothyroxine with the sodium removed)?

Or does the sodium not pass through to the bloodstream?

Question

Let us accept both that some levothyroxine (with or without sodium!) gets absorbed in the mouth. But some is swallowed. Further, let us accept that the absorption in the mouth is different to the absorption in the stomach/intestine. And it appears that mouth absorption could be better.

How can we ensure that all absorption is from the mouth? Otherwise some will be from the mouth, some from stomach/intestine and the balance could change for each and every tablet taken.

Question

How can you be sure that the levothyroxine is actually being absorbed from the mouth? Imagine that the dissolution and disintegration of the tablet in the mouth, followed by swallowing, just enhances the ability of the stomach acid to remove the sodium, and ensures better absorption in the intestine?

After all, we have seen some members seem to absorb better not because they hold the tablets in their mouths, but simply because they crunch the tablets up before swallowing.

Question

Regardless any of the previous answers, do we have any confidence that the effect will be similar across different makes/formulations of levothyroxine?

I'm quite sure you will take these questions in the enquiring way intended!

[FallingInReverse in reply to helvella]

Those are questions that I was pondering while writing... the more I read into this the more interesting it is to understand. Here's what I just desk-researched. I am open to all questions and challenges!

- What DOES happen to the sodium molecules?! This is pure desk research - but I read that when Levo dissolves in the mouth it's in saliva, which actually is slightly acidic (certainly not as acidic as the stomach) so some does dissociate, BUT dissolution is not necessary for sublingual absorption, and also both water and lipid soluble things can be absorbed in the mouth, and so when it all gets absorbed the sodium part joins lots of other sodium ions in the blood with no problems.

- What if it was all/mostly being swallowed anyway? Absolutely some made it's way from under my tongue to my stomach. But if that was all that was happening, then the bioavailability impact on my Free Ts would never had dropped by a whopping 20-30 points through range.

Also, after reading, it's biologically accurate that lipid soluble things are well absorbed in the lipid-rich, blood-flow rich, and thin membranes under the tongue. Which my single n=1 experiment strongly supports. Swallowing not only didn't increase my results, wasn't even equal, but swallowing it DROPPED THEM. What a crazy though that by avoiding metabolism, avoiding the GI tract, avoiding whatever has to happen in the liver at that point, that sublingual may result in something that is more consistent. Now that I think about it, that was my original reasoning... right to the blood stream, avoid the long journey through the GI.

Regards to your "how can we be sure" question.... After I wrote the above I think that is the danger/risk in trying to replicate the conditions of my experiment. It relies on consistency and situation that are not going to be possible for everyone.

An essential part of the administration sublingual was that I was conscious of not brushing my teeth or rinsing my mouth after taking it. I would often grab for it as I was just waking up or in that early morning first wake up, and then fall back to sleep or lay in bed while waking up slowly. It stayed under my tongue completely undisturbed consistently and for hours. I am sure that first glass of water hours later washed some down. But all in all, it relied on my being in control of my schedule and not needing to leave the house (!) - so I could be consistent, I didn't need to brush my teeth because I wasn't leaving the house.

Regards to crushing - I too would love a good controlled A/B test on that. That's what I was so excited about for my last 6 weeks that I was sublingual for so long, had been on my Ts doe for 9 weeks before, and so this period was really as good a control as I could hope for, to get this single data point.

Regards other formulations - I have done zero research there, but bet there's something to be learned by examining the mechanism behind liquid levo absorption.

[helvella in reply to FallingInReverse]

There is a patent - I think the first one for levothyroxine oral solutions - that is itself quite interesting.

The process was to dissolve levothyroxine in an alkaline solution, then (more or less) neutralise that with some acid. I'd need to check, but I think that it was when they added glycerol, the levothyroxine remained in solution even when neutralised - approx pH7. Indeed, I think it remained in solution even in acidic environments such as the stomach.

(Yes, that is levothyroxine sodium.)

I've got a feeling the approach now is a modified or enhanced version of that.

The glycerol is not just to make it a bit gloopy but seems to be fundamental to how is works. (One make used at least some propylene glycol - so there was a variant.)

[FallingInReverse in reply to helvella]

Looks like it is all about taking the Levothyroxine, adding salts for stability, and then adding what's needed to make it into either a tablet or liquid form - with the main goal of stability of the active hormone. This is all in service to it getting to the stomach, to dissociate in the acid, aiding in absorption in the intestines.

I will add further to the one big caveat to repeating my experiment - whether tablet or liquid - the biggest risk and hardest thing about it is consistency in hormone bioavailability.

My original idea was that taking under the tongue is a faster and more efficient path to the bloodstream than swallowing through the GI tract. In a controlled or clinical setting I believe is true. But in normal every day settings, most people would not be able to keep the levo under their tongue undisturbed for long enough or consistently enough. Even if we get less hormone when we swallow it, controlling the dosage sublingually is probably impossible in normal practical settings.

[helvella in reply to FallingInReverse]

I think you have made a big contribution at least to the discussion of these issues.

Of course, "officially" it will be dismissed as anecdotal. But everything, every scrap of progress, starts with a thought, maybe trying something, maybe who knows what.

And I wanted to note that papers about Tirosint gel caps indicate very much higher absorption than tablets. (They rather ignore oral solutions!) And there is some evidence that they can approach 100% absorption.

[wellness1 in reply to helvella]

Approaching 100% absorption would be impressive. I am contemplating switching from Tirosint gel caps to Vencamil. Given your extensive knowledge, do you think that would be the closest tablet to Tirosint? I'm not certain I need to be on Tirosint, which is expensive. I haven't yet found out the cost of Vencamil purchased privately. But from your comment, it appears likely that in making a switch from Tirosint, a higher dose of a tablet could be likely and thus could affect cost comparison. Does that sound reasonable?

[helvella in reply to wellness1]

I don't think any tablet can ever be that close to Tirosint. In Tirosint the levothyroxine is already effectively dissolved and that seems to be the critical factor that makes the difference.

Tirosint is horrifically costly in many markets. In the UK it is a special import product which ramps the cost up.

I find Vencamil is good for me but, as with every single product, some do not find it as good as others.

Adjusting Vencamil dose is currently more difficult because it is only available in 100 micrograms but 25, 50 and 75 should be available sometime (August?).

[FallingInReverse]

Further down the rabbit hole, in looking for an understanding of how liquid levo works (ie, like tirosint), most papers talk about it in context of its absorption in the stomach. I was trying to figure out why no one ever addressed the absorption of liquid levo that would occur in the mouth.

This paper is got close: Levothyroxine: Conventional and Novel Drug Delivery Formulations published May 2023 in Endocrine Reviews

Interesting to see sublingual being researched (as well as transdermal!) There are really good infographics in this one:

abstract: pubmed.ncbi.nlm.nih.gov/364...

full text: ncbi.nlm.nih.gov/pmc/articl...

Although levothyroxine is one of the most prescribed medications in the world, its bioavailability has been reported to be impaired by many factors, including interfering drugs or foods and concomitant diseases...noninterchangeability between formulations and poor compliance. To address...novel formulations (liquid solutions and soft gel capsules)... [help] eliminate malabsorption. Some other delivery routes (injections, suppositories, sprays, and sublingual and transdermal administrations) are aimed at circumventing different difficulties in dosing.

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This lead me to this case review that directly concludes (based on three cases in a hospital setting) that sublingual was an alternative, and in these cases, a superior way to deliver Levo - consistent with my own "case"! (Acknowledging that I was taking a tablet sublingual (not a liquid), but as noted above the difference is not the active ingredient, and the inactive but stabilizing compound/solution it was suspended in. Tablets do dissolve, mildly dissociate and absorb in the mouth.)

* Treatment of refractory and severe hypothyroidism with sublingual levothyroxine in liquid formulation

researchgate.net/profile/Be...

Discussion: Our patients had severe biochemical hypothyroidism despite very high L-T4 dosages in liquid or tablet formulations. However, their cardiovascular and neurological conditions were not severe enough to require injective administration. Consequently, after the hospitalization of these patents, we decided to shift to the sublingual liquid administration of L-T4, which induced a quickly clinical improvement and a rapid recovery of euthyroidism, reducing the negative effects of the thyroid hormone deficiency at tissue levels...

We used the same daily dose of tablet L-T4 for the sublingual administration in liquid formulation in two of the cases; whereas a slightly reduced dose was used in one case (Fig. 1). This provided further evidence for the efficacy of the liquid L-T4 over tablets [18] and demonstrated the good absorption of L-T4 in the oral cavity. Sublingual and buccal administration may be useful for systemic drug delivery [19]. A recent study has reported that 40% of patients with tablet L-T4 malabsorption have a buccal absorption of liquid L-T4 similar to that of the intestinal absorption of the same liquid formulations [20, 21]. However, buccal L-T4 administration involves the mucosal membranes lining the cheek. Variations in L-T4 absorption may be expected due to individual local pH and saliva composition [20].

On the contrary, sublingual drug delivery is an important method of administration in acute and severe clinical conditions. It helps to avoid the enzymatic degradation of the drugs in the gastrointestinal tract and allows it to achieve a rapid delivery, reaching a fast therapeutic level in the bloodstream. Many drugs are designed for sublingual administration, including cardiovascular drugs, steroids, barbiturates, benzodiazepines, and opioid analgesics.

The sublingual mucosa is more permeable than the buccal mucosa because it is thinner (100–200 μm), highly vascularized, and allows a direct access to the systemic circulation via capillaries and venous drainage [19]. These characteristics allow clinicians to bypass the L-T4 gastrointestinal absorption, the pH-related dissolution phase of L-T4 tablets, the necessity of stomach acidic environment, or the consequences of L-T4 malabsorption due to the small intestinal disease... Our patients did not complain any local or systemic adverse event after the sublingual administration of L-T4. They did not report cardiac arrhythmias or any ECG alterations or gastrointestinal adverse effects. Compared to the parental L-T4 administration, the sublingual management with liquid formulation is less expensive and easier to handle.

Liquid L-T4 is marketed for oral administration, and the sublingual route is not yet acknowledged as an alternative to the traditional oral route. However, in our opinion, it may offer several advantages in patients with refractory hypothyroidism who are unresponsive to the conventional oral administration of L-T4 in tablets, liquid formulations, or soft gel capsules.

We can conclude that the sublingual administration of L-T4 may be a safe alternative method for acute treatment of severe hypothyroidism, compared to the parenteral L-T4 administration.

[Bertwills]

I’m going to try sublingual. My digestion is very disturbed & I think I might benefit. Which brands do you take? I know that my Accord T4 dissolves very quickly, my Thybon Henning is much slower.

Thank you for reporting on your research. Fascinating

[FallingInReverse in reply to Bertwills]

I’m in the US. I have brands Synthroid for T4 and Cytomel for T3.

I’m not sure I’d “recommend “ this necessarily … I started doing it unknowingly from day 1 and really not knowing any better. But if you do - definitely be careful, and treat it like a dose change, and monitor as soon as 6 weeks. You won’t know how much active hormone is being absorbed unless you test. Will be interested to see how it goes!

: )

[tattybogle]

Are you going to go back to sublingual to see if results go back up ?

my T4/T3 levels bounce around a lot (on same dose Levo ) so for me one point of reference wouldn't be very reliable evidence.

[FallingInReverse in reply to tattybogle]

Nah… I did the switch because at the end of the day - Levo tablets are designed, studied and indicated to be taken swallowed, on an empty stomach.

This “study” and desk research illuminated some of the “why”s for me.

I thought the reason was more to do with less efficient absorption through sublingual or buccal mucosa… or that stomach acid was chemically required for absorption.

But what I read shows it’s not those things.

As much as Synthroid and Cytomel actually taste pleasantly sweet … I did have to avoid brushing my teeth or rinsing my mouth through at least lunchtime or later… and that’s kinda yuck : )

Bioavailability may be less BUT swallowing is ultimately more consistent is my guess.

I welcome all corrections!!!

And also caution anyone who tries it to take it seriously like a titration… changing nothing else for a full 6 weeks and monitoring their levels.

A single data point is just that. And as my husband said - I should focus on getting better : ) I did indeed take a precious 6 weeks to satisfy my curiosity on this. But you’ll see I was only 50% through range for T4 and that’s my next priority to tackle. Not to mention upper range for t3 which I need to refine next. I’ll do it the intended way of swallowing from here on out.

It was certainly fun, educational and very satisfying to do this tho!

[tattybogle in reply to FallingInReverse]

yes .. brushing teeth/ leaving house etc ... i see your point .

re. hubby.... i disagree, it wasn't a waste of time ... it's a good idea to take a few weeks (at times that suit us) to learn how various changes affect us . We are taking this for life ,and have to be our own regulating system (via dose changes etc) to respond to other changes as we go through life .. so learning how our individual system responds will come in very handy.

[FoggyThinker in reply to tattybogle]

Yes exactly, and it might very well have worked better (and FallingInReverse that was your hypothesis if I'm understanding correctly)

[montieth]

Do you have to buy it as sublingual or can you do this with any of the levo as long as it isn't coated?

[FallingInReverse in reply to montieth]

I was using my regular basic Synthroid brand Levothyroxine and Cytomel brand liothyronine tablets - both formulated for swallowing.

They are not in any way designed to dissolve, although of course they do.

There is no Levo or T3 available that is formulated to be administered under the tongue. Even liquid Levo is designed to be swallowed and absorbed the same way a swallowed tablet is.

That’s the flaw in this whole sublingual thing : ) It is not necessarily hard to understand, but the journey exogenous Levo takes through our bodies has many many many steps. And each step has its biological mechanisms and challenges.

Although it is factual to point out the important differences of lipid vs aqueous absorption, and how this likely impacts bioavailability and consistency whether you take levo sublingual or swallowed…

And it certainly interesting to think about how it might hold the key for “novel drug delivery” formulas as noted in the article above… for example, there is potential to bypass common Levo absorption blockers - ie, “interfering drugs or foods and concomitant diseases... noninterchangeability between formulations and poor compliance”…

That being said - in a real life practical setting I don’t think there is any value to taking it sublingually. And creating conditions where there is consistency is not easy if you are not completely in control of your schedule and create some inconvenience (Notably teeth brushing!). If I’m looking for more bioavailability, then I’ll titrate my dose and take as indicated - swallowed, empty stomach, no food/drink/coffee etc for a solid hour or more.

My two cents.