In this article, I try to propose an important question: do sigma receptors present a common denominator in CFS spectrum disorders (such as fibromyalgia, ME/CFS, POTS, MCS and bipolar 2)?
Sigma receptor has been on my radar for a while but there was so little information available about it on Wikipedia until this year so I never fully delved into it. I came across a really thorough review article and when I was finished reading it, my inner response has been nothing other than “Wow! I think this is it!”.
It was a realization that this enigmatic and as of yet “unmined” receptor could very well turn out to be the common denominator in all of the CFS spectrum disorders.
As I’ve written before in One Illness, Many Names that there was some underlying similarity between what seemed like disparate conditions that I listed in the beginning. There are, without a doubt, many differences but the commonalities are obvious to those who lived with those conditions long enough or to anyone who has treated patients with those disorders.
Because the main hallmark of all of the conditions listed above is extreme sensitivity.
Every patient has their unique set of sensitivities (which based on my personal experience can change through the lifetime): extreme sensitivity to postural changes in POTS, extreme sensitivity to light and sound in adrenal fatigue, extreme sensitivity to exertion in CFS, to smells in MCS and to pain in fibromyalgia.
There is often a large overlap between those forms of sensitivity, with the sickest patients can become extra sensitive to literally everything – which to those who had the misfortune of being there is known as one hell of a state to be trapped in.
The other distinctive feature is sensitivity to most drugs and hormones, with all of these patients often responding badly to regular prescribed doses but benefiting from a fraction of a normal dose. That is something all of us learn only on after a few early dreadful experiences: we are not cut out for regular doses of most medications that “normals” seem to tolerate without a flinch.
This super-sensitivity often exists even prior to the formal onset of illness many patients with these conditions would identify themselves as HSPs or “highly sensitive person”.
Being more sensitive is not necessarily a bad thing, it can certainly makes your life harder in some ways but it can also enrich it in others. However, in the disease state, this supersensitivity has transformed into a malignant, maladaptive, and fulminant force. Patients have been told that it’s all in their head, and of course, we know that it’s not, but based on my experience of someone who traveled deep down to the bottom and back, I do beleive that the explanation does hide inside the central nervous system.
That explanation might very well be the sigma receptors.
Now that I understand how sigma receptors work I feel like all of these conditions in the near future could be dubbed “Sigma Sensitivity Spectrum.”
But first of all, I must explain to you how sigma receptors work.
Sigma: the chaperone receptor
The first and most important thing to understand about sigmas, is that they are not a receptor at all. They are in fact, a chaperone protein molecule that “escorts” (or “chaperones”) calcium from endoplasmic reticulum stores located near mitochondria to the plasma membrane. (Link)
If your intracellular calcium is depleted, your mitochondrial can’t generate energy because calcium is an essential co-factor of several key mitochondrial enzymes involved in cellular energy production. When this happens in muscle tissue you will develop lactate overproduction because the cells must rely on alternative ways of generating ATP.
(I delve deeper into the subject of intracellular calcium here)
You can think of sigma chaperones receptors as intracellular loudspeakers. Any neural input that comes to the plasma membrane can be amplified through sigmas.
Now, imagine if you put a stadium concert speaker in your bedroom and ramp it up to the full volume – that’s what it feels like when someone has unregulated sigma transduction combined with the increased incoming stimulus (Dysautonomia as Neuronal storm)
While sigmas regulate virtually every neurotransmitter system that exists in the body, they share a particularly close connection with NMDA receptors that regulate glutamate, the main neurotransmitter in our body (see Glutamate Regulation).
In other words, sigma receptors are the intermediate between the extracellular glutamate and the intracellular calcium release that it induces within the neuronal cells. Without proper sigma function, the calcium stores from endoplasmic reticulum will not be utilized properly and the cell will run into issues with calcium toxicity and depletion.
It is possible that viral DNA alters something in our sigma receptors (link).
But here’s the tricky thing about sigma receptors:
Sigma Receptor Agonists Have a Bell Shaped Curve
Many people with CFS are familiar with a strange phenomenon – they seem to discover a wonder drug that’s working almost right off the start. There’s usually a short 2-5 day honeymoon period (where in early stages one tends to proclaim “hurray, they found the cure!) Only to find their symptoms return or even get worse once the honeymoon period wears out.
Usually, when “normals” take antidepressants they either feel nothing or slightly worse at first and then when receptors downregulate the improvement begins.
This is not how it works for us, atypicals. When we take something it often makes us feel great on the first day or two, maybe three, and then it either peters out or some things get much worse. This was my personal story with many drugs but especially with thyroid hormone (see “Thyroid: My Friend, My Enemy“.)
Unlike regular antidepressants, many sigma agonists have been shown to completely resolve depression within 2 days. However, these effects will often not last because increased sigma agonism will cause too much stimulus and lead to receptor down-regulation after a longer period of time. When it comes to sigma, there is a very fine line between agonist and antagonist. This is where such neurohacking techniques micro-dosing and cycling become really crucial.
Sigma receptors ligands
Almost all of SSRIs with the exception of paroxetine bind to sigma receptors but with different potency.
On the surface, it looks like SSRIs all share the same mechanism but in practice people with depression have very different response to SSRIs. It has been shown that while fluvoxamine and fluoxetine are potent sigma agonist, while sertraline is a sigma antagonist (although that may too be dose dependent).
Sigma receptors bind DMT, the spirit molecule, which is synthesized in trace amounts. Therefore, if other neurotransmitters and receptors align, people with sigma upregulation may be more likely to experience intuitive, spiritual and creative states.
Neurosteroids are the main endogenous regulators of sigma activity.
Progesterone is a sigma antagonist. DHEA and pregnenalone are sigma agonists but only at a low enough dose. At a higher doses they become a competitive antagonists. This is called a biphasic response. The role of testosterone in sigma regulation is still being debated.
The correct balance of DHEA and progesterone is going to determine the degree of neuronal excitability.
The biphasic response could explain very well the phenomena of very different patient experiences that I’ve discussed in my very old article “My Truth about DHEA” and more recent one titled “Thyroid Wars”.
The two hit hypothesis of CFS.
I always thought that complex illness must have at least “two hits”. In genera, human body is so good at adaptation, that one hit is not enough to take one from a high functioning individual to a train wreck.
Therefore, I do not think that sigma sensitivity is not the primary cause of the illness, they are the amplifier of the illness, they can take the problem that would be a minor problem under normal circumstances and amplify it to the degree of great suffering and debility. What could be sadness will become depression. What could be minor stomach discomfort may become full-blown IBS. And so on. The illness itself is related to other receptors but the sigma dysregulation is what puts it on the loud speaker.
So… where do we go from here?
In addition to using sigma agonists/antagonists, there are probably indirect ways to change the expression of sigma chaperones by altering your intracellular calcium channels with drugs such as thyroid, lithium, IVIG, nimodipine or gabapentin.
I have noticed that taking micronized progesterone makes me more “impervious” to the effects of other medications, while DHEA has the opposite effect.
This brings me back to Alice’s Mushroom principle that I’ve intuitively understood and talked about for a while now.
One side makes you grow bigger, the other side makes you grow smaller…
And what was the caterpillar’s advice to Alice? To keep taking small bites from both sides until she finds the size that’s just right for her.
Alleviating sigma sensitivity (or as I referred to it previously ‘bipolarity’) should, therefore, be the first step in the treatment protocol. Once that part is corrected, it becomes much easier to understand and treat the remaining neurological and physical dysfunction.
The knowledge about sigma receptors is rapidly evolving so we will soon learn a lot more about sigma ligands, and will have much better tools to help us use them correctly. For now, carefully micro-dosing DHEA (or pregnenolone) vs progesterone based on symptoms rather than labs might be the best available way to go. The key is to not think of those drugs as fixed daily hormones but instead to use them flexibly and creatively based on the self-awareness of your neural conduction.
If you have any experience with using sigma ligands or balancing DHEA vs progesterone, please leave a comment below, I’d love to hear about it!
REFERENCES:
- https://www.ncbi.nlm.nih.gov/pubmed/28315270
- https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4906365/
- https://www.ncbi.nlm.nih.gov/pubmed/28529139
- https://en.wikipedia.org/wiki/Sigma_receptor
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