I'm starting to have major doubts about the SERT downregulation, presynaptic 5HT1A-GIRK uncoupling, and the serotonin flooding theory. Hear me out on this.
Presynaptic 5HT1A supersensitivity and/or upregulation causes depression, whereas postsynaptic 5HT1A upregulation/sensitivity are involved with anxiety disorders.
Many people, including myself, have experienced terrible reaction to 5HT1A full agonists. I even tried lavender extract recently and had a terrible reaction, after researching it, it turned out to be a presynaptic 5HT1A full agonist. Also, many people never improved on serotonin depleting agents and serotonin antagonists such as cyproheptadine.
Postsynaptic 5HT1A receptors activation is the main reason for MDMA's empathogenic and pro-social effects. Also, orgasms are extremely pleasurable on MDMA, but it's incredibly difficult to reach orgasms on it. MDMA abuse causes a syndrome very similar to PSSD. To recover from this syndrome, people take SJW to restore "MDMA's magic", by upregulating the postsynaptic 5HT1A, but this is a temporary solution and it doesn't upregulate it potently.
Have you ever wondered why TCAs, that have been on the market way longer than SSRIs, are rarely associated with PSSD? and post-TCA sexual dysfunction is easier to fix than post-SSRI sexual dysfunction? here's why:
"Postsynaptic 5-HT1A receptor sensitivity in the hippocampus, measured by the effect of 8-OH-DPAT to increase cAMP levels in the dialysate, was increased after chronic clomipramine."
Clomipramine binds extremely strongly to SERT (0.14–0.28), but despite this, it doesn't cause postsynaptic 5HT1A receptors to downregulate/desensitize, but in fact it upregulates them. Whereas, SSRIs even weak binding ones to SERT can downregulate postsynaptic 5HT1A receptors. This means that SSRIs can also potently disrupt steroidogenesis and sex receptors sensitivity whereas TCAs do less of that."he lack of an effect of clomipramine on the response to 8-OH- DPAT contrasts with results obtained after long-term administration of SSRI drugs (Li et al. 1993Li et al. , 1994Li et al. , 1996Li et al. , 1997) where subsensitivity of hormonal responses was obtained. Therefore, the 5-HT uptake blocking action of a drug per se does not appear to be sufficient to induce subsensitivity of post-synaptic 5-HT 1A receptors in the hypothalamus, and indeed the finding of an increased cAMP response to 8-OH-DPAT in the hippocampus after chronic clomipramine indicates that subsensitivity of postsynaptic 5-HT 1A receptors was not obtained in this tissue either"
Let's review what postsynaptic receptors do:
- Cortisol and ACTH release.
- Prolactin release.
- Beta-endorphin release.
- Oxytocin release.
What if these receptors are malfunctioning? you get these symptoms:
- Near complete absence of anxiety.
- Blunted affect and social anhedonia. (Low oxytocin)
- Consummatory anhedonia and non-pleasurable orgasms. (Low beta-endorphin)
- Low libido. (Blunted HPA axis)
And with the disruption of sex hormones receptor function (and levels, in some people), and the increase in allopregnanolone (causing GABA-glutamate imbalance) you end up with frank sexual dysfunction.
SSRIs cause HPA axis blunting through upregulating the glucocorticoid receptors, and this causes negative feedback inhibition of cortisol and the adrenals. To reverse this, we need to downregulate those receptors again.
I tried Baclofen recently, and it had ameliorated my blunted affect and anhedonia. It turns out Baclofen inhibits presynaptic 5HT1A receptors indirectly, causing postsynaptic serotonin release. It had also improved my orgasms' intensity, and libido (libido via a different mechanism: ACTH release).
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2943331/Baclofen is an indirect presynaptic 5HT1A antagonist (via presynaptic GABAB receptors on non-5-HT neurons in the DRN)
This is a further proof of my theory: we could be suffering from presynaptic supersensitivity (or at least a normal sensitivity) + postsynaptic desensitization, which SSRIs are known to trigger. Cortisol desensitizes the presynaptic 5HT1A receptors, so after you take SSRIs and they blunt the HPA axis, then you withdraw from SSRIs, cortisol is still inhibited, so presynaptic 5HT1A receptors upregulate again and become supersensitive (or normal sensitivity), triggering depression on top of the symptoms of low postsynaptic function.
My "triad of evil" hypothesis:
1- Glutamate release dysregulation leading to mesocorticolimbic pathway dysfunction and cognitive dysfunction. This can also explain why low dose SSRI can cause symptom relief from PSSD.
2- SSRI-induced postsynaptic 5HT1A subsensitivity + presynaptic 5HT1A supersensitivity (or normal sensitivity). Blunting of HPA axis and cortisol release.
3- Androgen (and possibly estrogen) receptor subsensitivity and dysregulation, leading to sex hormone resistance.