T4/T3 combo not found to be better than T4


Pacific Northwest
Back to the topic of this thread, and studies like @debored13 has been posting:

Replacement therapy with levothyroxine plus triiodothyronine (bioavailable molar ratio 14 : 1) is not superior to thyroxine alone to improve well-being and cognitive performance in hypothyroidism.

Severe TSH Elevation and Pituitary Enlargement After Changing Thyroid Replacement to Compounded T4/T3 Therapy.

I've been going through my GeneDX WES and 23andme chip 4 data using Enlis. What I've learned points out the ridiculousness of these studies.

Turns out there are several genes that affect how thyroid hormones are regulated, and various mutations in each, many of which are pretty common, can be implicated in "thyroid dyshormonogenesis," aka disregulated thyroid hormones.

These include genes that give one normal TSH when one is hypothyroid, genes that give you high T4 and low T3 and vice versa, problems with iodine binding, tyrosine metabolism, TSH resistance, problems in the ER and Golgi apparatus, and those implicated in Hashimotos, Graves disease, and papillary thyroid cancer.

In total, I found I have over 200 altered SNPs, deletions, frame shifts, and missense mutations on 14 different genes, with about 15% of these rare or novel mutations.

I am hard pressed to believe that this is that uncommon, that is, it's highly likely that everyone has a different pattern of these mutations, which could lead to a wide variation in how we assimilate and metabolize iodine and tyrosine, produce and metabolize the various pituitary and thyroid hormones, and develop and experience autoimmune thyroid disease, goiters and thyroid cancers.

The takeaway, therefore, is that, while these studies may be interesting reading to contemplate, unless patients in them are grouped by these genetic factors, iodine and tyrosine status, and beginning and historical rT3, FT3, FT4, TSH, and antibody titers, one cannot deduce whether the data is meaningful or useful to make decisions for any given patient. Its a highly personalized set of variables...


Senior Member
United Kingdom
@debored13 Some commented on the RP forums that cortisol is needed for T3 utilization, When I pressed further he provided these 1 2 3 4 studies.

Made me think of your negative experiences with T3. It is known the some CFS have low cortisol, perhaps you do too. Perhaps this was a factor in your negative reaction. Interesting either way.


Breaking Through The Fog
I also have low cortisol and DHEA but adding either one has never worked for me in terms of my bad T3 reaction. Cortisol on occasion could provide a boost but was never a lasting solution.

I will summarize here again what I've written about on my blog since I feel like I'm now able to explain it better.

I'm now inclined to think that it's the 5HT1A/5HT2A receptor densities within different parts of the limbic system that determine how people will respond to thyroid hormone. 5HT1A receptor dimerizes with dopamine and 5HT2A dimerizes with glutamate. So it's all highly complex and intricate stuff that has huge bearing on such subjective variables as "cognitive function and well being" that these studies attempted to evaluate.

In my opinion any short term reaction to hormone is way more likely to be due to receptor super sensitivity (which in turn will affect the receptor density) rather than to the genomic or intracellular effects of the hormone which usually take weeks to manifest.

T3, Cortisol, DHEA, estrogen are all involved in regulating these receptors. T3 up regulates (e.g. increases) both 5HT1A and 5HT2A. However, 5HT2A receptors will desensitize rapidly and if overstimulated daily for prolonged period of time, they will eventually down regulate. This is the time when the initial "T3 honeymoon" usually ends, necessitating an increase in the dose of the thyroid hormone to reproduce the same effect.

Theoretically speaking, in these case scenario, one might be able to get more mileage out of T3 by using it according to microdosing protocols for 5HT2A agonists - e.g. taking micro doses on every third or fourth day rather than consecutively and to gradually discontinue after a period of 6-10 weeks once the desired outcome is achieved. The doses should be low enough to not cause any significant effect on TSH (e.g. Blanchard protocol that I talk about on my blog). Once you mess with TSH, you enter hypothyroid zone and you need steady dosing.

My learning curve over the years led me to a radical shift in the perspective that I've used NDT as a psychotropic medication, or shall we say a neuromodulating agent rather than as a hormone. T4, on other hand, is a hormone. It is also a competitive T3 antagonist when given initially, especially when given to someone who doesn't have true hypothyroidism. I need to be on a low dose of T4 because I have long standing Hashimoto's. I think the only people who really need a little bit of permanent T3 might be certain patients who've had thyroidectomy.

The lucky people who have healthy and robust receptors are able to adopt so well that they don't really seem to notice the difference between different forms of thyroid. I envy those people.

In conclusion, if one wants to up regulate their 5HT they should go with T3. It can work wonders for fatigue and depression - while it lasts. But there's also a good stay can also push you into mildly manic or unpleasantly overstimulated states, amplify pain or cause various forms of dysautonomic reactions (depending on which part of the limbic system is involved and your other neural receptor settings.

P.S. Low hypothalamic hormones - as often seen in the late stage of the disease - are probably the end result of permanent down regulation of 5HT1A and 5HT2A receptors within the hypothalamus.
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