If you read my previous posts “Thyroid: My friend, my enemy” and “Armour: A Seduction Story” you know by now that I have a conflicted personal relationship with the thyroid hormone.
And if you read my post “Thyroid Camps Overview” or simply spent enough time browsing the internet on the subject of the thyroid hormone, you probably know by now that when it comes to the thyroid hormone there’s truly no “one size fits all” solution.
We are all different.
When I went on NDT in early 2014, I had postpartum thyroiditis (which I now believe is due to EBV viral activation). I also have elevated thyroid antibodies. Before my thyroiditis was diagnosed with ADHD and depression and prescribed SSRI and Vyvanse. I was one of those people who immediately felt “alive again” after a few doses of Armour – but the effects didn’t last and eventually, my insistence on making NDT work for me again by resorting to “alternative methods” have nearly cost me my life.
If you are taking NDT and T3 and it’s working fine for you then please ignore this post. But if you can relate to my inconsistent and tumultuous relationship with this hormone, if you have been misled by popular online blogs on how NDT works than what I’m about to say might really shed new light on your situation. You will realize that the reason you can’t make it work for you is most likely not because you’re deficient in X, Y, or Z as this amateur blogs would want you to believe.
Likewise, if you’re feeling good on NDT or T3/T4 combo, it’s not due to “placebo effect” as some skeptical endocrinologists would insist.
The real reason as to why people respond differently to T3 is because they have excessive serotonin receptor (5HT) sensitivity (R).
Most people do not have this issue and therefore they do not react strongly to fluctuations of thyroid hormone. The can adapt equally well to hypothyroidism and excess of thyroid hormone. But there is also a small portion of people who can’t adapt. Keep in mind that there is nothing natural about thyroid hormone supplementation, especially with T3: thyroid gland secretes mostly just T4 at a low steady dose, and most of T3 is produced within the cells, therefore bypassing effect on the receptors. Therefore, naturally produced T3 thyroid hormone has much less neurotransmitter effect than externally supplied T3.
Studies show that hypothyroidism affects the binding capacity of multiple 5HT receptors (R) (R).
To put my personal story in perspective, I now suspect that I’ve experienced immediate improvement from T3 because it was good for my adrenergic receptors but I think I experienced very unfavorable effects on some of my serotonin receptors. I also believe that excess serotonin receptors can trigger activation of viral infections and autoimmunity. Not only the immune system is under the direct control of the nervous system but some CNS viruses gain entry into the cell through 5HT receptors (R). Excess serotonin has also been linked to mast cell activation (R).
Serotonin receptor supersensitivity is a huge issue because serotonin receptors in the hypothalamus regulate all the other hormones, in particular, cortisol. They also regulate norepinephrine and dopamine levels.
This is why hypothyroidism and “adrenal fatigue” so often go hand in hand.
There are many different subtypes of serotonin receptors and each one affects the body differently. For me personally, the three prime suspects are 5HT1A, 5HT2A and 5HT2C.
Hypothyroidism downregulates these receptors but too much T3 can make them overly sensitive to stimulation by serotonin.
Moreover, the relationship between serotonin and thyroid disease has shown to be reciprocal: people with abnormal serotonin regulation are predisposed to the thyroid disease (R). Although the exact link is not clear, I suspect it is related to immune system dysfunction.
5HT1A Receptors
Excess 5HT1A stimulation can make you feel hyperthyroid without really being metabolically hyperthyroid.
Excess 5HT1A stimulation will result in a picture very similar to hypoadrenergic POTS:
- Decreased prolactin (relative to baseline)
- Increased body temperature
- Decreased blood pressure (relative to baseline)
- Cutaneous (skin) vasoconstriction/Raynaud
- Decreased sympathetic activation/ excess parasympathetic activity
- Decreased GABA production
- Increased ACTH and cortisol
- Decreased sex hormones
- Decreased norepinephrine activity
- Constricted pupils
Deficiency of 5HT1A receptor will result in a clinical picture very similar to high flow POTS or histamine sensitivity:
- Low body temperature
- Increased heart rate
- Nausea and vomiting
- Cutaneous vasodilation/swelling/warmth in hands and feet
- Increased pain sensitivity
- Weak erections (but possibly increased libido)
- Decreased slow wave sleep
- Excess sympathetic activity
- Increased estrogen
- Oxytocin deficiency
- ACTH/cortisol deficiency
- Increased prolactin (relative to baseline)
- Decreased endogenous opioid production
- Sympathetic overdrive
- Dilated pupils
Both types can result in the feeling of anxiety although these are two different types of anxiety.
Please note that because these receptors affect energy, body temperature, and heart rate, it is very easy to mistake them for symptoms of hypothyroidism.
The tricky thing about 5HT1A receptors is that they function differently depending on whether they are located pre-synaptically (inhibit serotonin) or post-synaptically (release serotonin). Therefore depending on the dose of T3, you can get a very different effect. The effect on pre-synaptic receptors is probably the basis for why Ken Blanchard’s micro- T3 method works the best for some people and the effect on post-synaptic receptors is why Wilson’s method works better for others. (The same will be true for other meds that work on 5HT1A receptors. Unfortunately, almost all the drugs that act on 5HT1A will initially act on autoreceptors and lower serotonin before they act on postsynaptic receptors to improve serotonergic transmission. Lithium appears to be the only exception to that rule although it comes with its own bad set of side effects during initiation stage).
But that’s not all. Thyroid hormone also affects 5HT2A and 5HT2C levels which complicates the picture even further.
5HT2A Receptors
Excess 5HT2A receptor stimulation will result in:
- Increased depression
- Increased intracellular calcium release
- Increased neuronal excitation
- Increased smooth muscle contraction
- Increased vascular reactivity
- Increased platelet aggregation
- Increased pain sensitivity
- Decreased heart rate and low blood pressure (via vagus nerve activation)
- Low blood pressure
- Increase in dopamine levels
- Increased skin vasoconstriction
- Decreased intraocular pressure
- Decreased ACTH and corticosterone
- Decreased renin
5HT2A deficiency will produce the opposite picture:
- Hypomania or psychosis
- Decreased intracellular calcium
- Decreased neuronal excitability
- Decreased smooth muscle contraction
- Low dopamine
- Increased heart rate and blood pressure
- Increased cutaneous vasodilation
- Decreased oxytocin (social anxiety, loss of ability for emotional connection)
- Increased renin
- Increased ACTH and corticosterone
- Increased intraocular pressure
All of these serotonergic receptor fluctuations are much more pronounced in women because these receptors are also affected by the sex hormones estrogen and progesterone. Women who deal with severe PMS often have a malfunction in one of these receptors. The monthly fluctuations in sex hormones also make it difficult for receptors to find a steady state and adapt to a constant level of thyroid hormone. Most women I know have developed either CFS or POTS or psych issues during after a major hormonal perturbation of pregnancy and/or menopause.
5HT2A receptors are also unique and especially challenging to understand because they downregulate in response to both agonists and antagonists. And to make things worse, they continue to work even when they are not stimulated by serotonin.
The way I fixed my permanent 5HT2A upregulation after T3 (Or my “T3 crazies” as I call it) was lithium orotate, despite the fact that I did not initially use it for this indication (see my older post “Recovering with Lithium Orotate“). In theory, an inverse 5HT2A agonist
5HT2C receptors
The main function of 5HT2C receptors is to block the release of catecholamines dopamine and norepinephrine. They are the most likely explanation behind the atypical cases of what’s been described as “apathetic hyperthyroidism”. While in normal people, excess thyroid hormone will usually result in increased catecholamine levels, in people with supersensitive 5TH2C it can actually result in shut down of NE and DA, causing anhedonia, fatigue, loss of motivation and trouble with concentration.
People change.
Some people spent a lot of time trying to figure out their receptors through genetic analysis. I suspect that it’s often misleading, especially in the second half of life because genetics do not account for environmental factors, such as viral infections, toxins. They do not account for the imprint of drugs that we’ve taken, stress levels we endured, etc. Throughout our life, we acquire viral DNA which can lead to altered intracellular calcium release and neural receptor expression. The only proven way to figure out your 5HT receptor profile is by looking at the clinical presentation and response to various drugs, hormones, and supplements. Supersensitive serotonin receptors shift easily both ways, making one fluctuate between depression and hypomania and between POTS and CFS.
My 5HT, as well as other receptor settings today, are probably completely different than they were twenty years ago. This is how people change. Everybody changes chemically throughout their lifetime but the more sudden the change, the more jarring the experience.
To conclude this post on a more philosophical note, sudden changes in serotonergic receptor expression are probably responsible for many of the midlife personality changes, divorces, sudden spiritual awakening stories (5HT1A receptor is also thought to be responsible for transcendent experiences), or change political party affiliations (which has also been scientifically linked to brain circuitry).
Interesting article, thank you