Everything we knew about PSSD is wrong. Check out why.
Posted: Tue Jun 29, 2021 6:07 am
Most prevalent hypothesis about PSSD is that SSRIs downregulate 5-HT1A autoreceptor which controls serotonin flow in the brain. In effect there is too much serotonin which is connected via negative feedback with dopamine and thus the result is PSSD.
Now let me tell you why this is wrong:
1. Neither 5-HT1A agonists or antagonists improve PSSD symptoms. Neither decreasing serotonin via depleting serotonin by taking l-tyrosine or l-dopa and 5-HT1A antagonism or increasing serotonin via taking precursor (Tryptophan or 5-HTP) improves PSSD Symptoms.
2. Increasing dopamine does not improve symptoms.
3. 5-HT2B receptors regulate serotonin release via the serotonin transporter, and are important both to normal physiological regulation of serotonin levels in blood plasma, and with the abnormal acute serotonin release produced by drugs such as MDMA.
Callebert J, Esteve JM, Hervé P, Peoc'h K, Tournois C, Drouet L, Launay JM, Maroteaux L (May 2006).
"Evidence for a control of plasma serotonin levels by 5-hydroxytryptamine(2B) receptors in mice" (PDF). The Journal of Pharmacology and Experimental Therapeutics. 317 (2): 724–31. doi:10.1124/jpet.105.098269. PMID 16461587. S2CID 16099098.
Doly S, Valjent E, Setola V, Callebert J, Hervé D, Launay JM, Maroteaux L (Mar 2008). "Serotonin 5-HT2B receptors are required for 3,4-methylenedioxymethamphetamine-induced hyperlocomotion and 5-HT release in vivo and in vitro". The Journal of Neuroscience. 28 (11): 2933–40. doi:10.1523/JNEUROSCI.5723-07.2008. PMC 6670669. PMID 18337424.
3a. 5-HT2B receptor is both necessary and sufficient for SSRI to work.
"We demonstrate for the first time that 5-HT2B receptors are expressed by serotonergic neurons of the raphe nuclei, which is consistent with a positive regulatory role for these receptors in synaptic 5-HT homeostasis.
""Based on the results presented herein, the activation of 5-HT2B receptors is necessary for acute and chronic SSRI actions, and chronic stimulation with a 5-HT2B receptor agonist is sufficient to mimic SSRI effects in wild type mice."
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3381222/
3a1. Agonising 5-HT2B receptor mimics ssri:
"Direct chronic activation of 5-HT2B receptors appears sufficient to induce chronic SSRI-like effects in the NSF test." https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3381222/
3a2. Blocking 5-HT2B receptor block SSRIs effect:
"Altogether, these results confirm that a lack of functional 5-HT2B receptors is sufficient to abolish the chronic actions of SSRIs at the cellular level."
"5-HT2B receptors are required for SSRI antidepressant acute and long-term effects, possibly by presynaptic modulation of extracellular 5-HT levels."
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3381222/
3a3. Every SSRI is 5-HT2B agonist:
"Fluoxetine and all other SSRIs are 5-HT2B Agonists - Importance for their Therapeutic Effects" https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4207076/
3a4. Different polymorphisms of gene SLC6A4 coding serotonin transporter have no effect on SSRI response:
With the results from one study the polymorphism was thought to be related to treatment response so that long-allele patients respond better to antidepressants Another antidepressant treatment response study did, however, rather point to the rs25531 SNP,[20] and a large study by the group of investigators found a "lack of association between response to an SSRI and variation at the SLC6A4 locus".
Kraft JB, Peters EJ, Slager SL, Jenkins GD, Reinalda MS, McGrath PJ, Hamilton SP (March 2007). "Analysis of association between the serotonin transporter and antidepressant response in a large clinical sample". Biological Psychiatry. 61 (6): 734–42. doi:10.1016/j.biopsych.2006.07.017. PMID 17123473.
4. SSRI block MDMA (which improves symptoms of PSSD) effects, MDMA works trough 5-HT2B receptor.
"acute pharmacological inhibition or genetic ablation of the 5-HT(2B) receptor in mice completely abolishes MDMA-induced hyperlocomotion and 5-HT release in nucleus accumbens and ventral tegmental area" https://pubmed.ncbi.nlm.nih.gov/18337424/
5. Every treatment with succes rate higher than 1 (inositol, st john wort, ssri reinstatement) involves 5-HT2B receptor.
a. SSRI - as i stated before.
b. St John Wort: Sjw releases serotonin and blocks serotonin reuptake without effect on serotonin transporter and cannot be explained purely by free intracellular sodium increase.
b1. St john wort act on releasing serotonin:
"St John’s wort extract and hyperforin induced a marked release of serotonin from synaptosomes preloaded with [3H]serotonin." https://pubmed.ncbi.nlm.nih.gov/12775192/
b2. St John Wort does not work via serotonin transporter:
"Gobbi et al.[47] reported that inhibition of serotonin reuptake by a methanolic St John’s wort extract and hyperforin is not due to a direct interaction with, and blockade of, the serotonin transporter because in both
compounds had no or only a very slight inhibitory effect on [3H]citalopram binding." https://pubmed.ncbi.nlm.nih.gov/12775192/
b3. It does not work purely but partially via increase in free intracellular sodium concentration:
"Calmidazolium (0.5 microM), an antagonist of the intracellular Ca2+-binding protein calmodulin significantly inhibited the hyperforin-induced shift of the IIV curve maximum and the slow-down of the activation kinetics. It did not, however, affect the delayed inhibition of P-current, indicating that the two stages of modulation are mediated by separate mechanisms." https://pubmed.ncbi.nlm.nih.gov/10954328/
c1. Inositol improves depression symptoms, but it does not work in people who did not respond to SSRIs and it does not amplify SSRI response:
"Studies that use inositol in persons who were resistant to SSRIs specifically have failed to find an antidepressant effect of 12g inositol over the course of four weeks and the combination of inositol with SSRIs failed to outperform SSRIs by themselves over the same time period.
https://pubmed.ncbi.nlm.nih.gov/10907738/
https://pubmed.ncbi.nlm.nih.gov/10023500/
It is clear that PSSD is related to 5-HT2B receptor, how however is unknown. From my scientific research i came to conclusion that SSRI somehow affect 5-HT2B so it does not release serotonin properly, because mind you increasing neurotransmitter amount in the synapse and neurotransmitter release are two different things and they both feel very different. So PSSD is not syndrome where you have too much serotonin, but rather its disease where serotonin is not released properly in the brain.
It would explain why modifying serotonin amount does not work, it's not the amount of serotonin that is wrong but the flow of serotonin.
Now let me tell you why this is wrong:
1. Neither 5-HT1A agonists or antagonists improve PSSD symptoms. Neither decreasing serotonin via depleting serotonin by taking l-tyrosine or l-dopa and 5-HT1A antagonism or increasing serotonin via taking precursor (Tryptophan or 5-HTP) improves PSSD Symptoms.
2. Increasing dopamine does not improve symptoms.
3. 5-HT2B receptors regulate serotonin release via the serotonin transporter, and are important both to normal physiological regulation of serotonin levels in blood plasma, and with the abnormal acute serotonin release produced by drugs such as MDMA.
Callebert J, Esteve JM, Hervé P, Peoc'h K, Tournois C, Drouet L, Launay JM, Maroteaux L (May 2006).
"Evidence for a control of plasma serotonin levels by 5-hydroxytryptamine(2B) receptors in mice" (PDF). The Journal of Pharmacology and Experimental Therapeutics. 317 (2): 724–31. doi:10.1124/jpet.105.098269. PMID 16461587. S2CID 16099098.
Doly S, Valjent E, Setola V, Callebert J, Hervé D, Launay JM, Maroteaux L (Mar 2008). "Serotonin 5-HT2B receptors are required for 3,4-methylenedioxymethamphetamine-induced hyperlocomotion and 5-HT release in vivo and in vitro". The Journal of Neuroscience. 28 (11): 2933–40. doi:10.1523/JNEUROSCI.5723-07.2008. PMC 6670669. PMID 18337424.
3a. 5-HT2B receptor is both necessary and sufficient for SSRI to work.
"We demonstrate for the first time that 5-HT2B receptors are expressed by serotonergic neurons of the raphe nuclei, which is consistent with a positive regulatory role for these receptors in synaptic 5-HT homeostasis.
""Based on the results presented herein, the activation of 5-HT2B receptors is necessary for acute and chronic SSRI actions, and chronic stimulation with a 5-HT2B receptor agonist is sufficient to mimic SSRI effects in wild type mice."
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3381222/
3a1. Agonising 5-HT2B receptor mimics ssri:
"Direct chronic activation of 5-HT2B receptors appears sufficient to induce chronic SSRI-like effects in the NSF test." https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3381222/
3a2. Blocking 5-HT2B receptor block SSRIs effect:
"Altogether, these results confirm that a lack of functional 5-HT2B receptors is sufficient to abolish the chronic actions of SSRIs at the cellular level."
"5-HT2B receptors are required for SSRI antidepressant acute and long-term effects, possibly by presynaptic modulation of extracellular 5-HT levels."
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3381222/
3a3. Every SSRI is 5-HT2B agonist:
"Fluoxetine and all other SSRIs are 5-HT2B Agonists - Importance for their Therapeutic Effects" https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4207076/
3a4. Different polymorphisms of gene SLC6A4 coding serotonin transporter have no effect on SSRI response:
With the results from one study the polymorphism was thought to be related to treatment response so that long-allele patients respond better to antidepressants Another antidepressant treatment response study did, however, rather point to the rs25531 SNP,[20] and a large study by the group of investigators found a "lack of association between response to an SSRI and variation at the SLC6A4 locus".
Kraft JB, Peters EJ, Slager SL, Jenkins GD, Reinalda MS, McGrath PJ, Hamilton SP (March 2007). "Analysis of association between the serotonin transporter and antidepressant response in a large clinical sample". Biological Psychiatry. 61 (6): 734–42. doi:10.1016/j.biopsych.2006.07.017. PMID 17123473.
4. SSRI block MDMA (which improves symptoms of PSSD) effects, MDMA works trough 5-HT2B receptor.
"acute pharmacological inhibition or genetic ablation of the 5-HT(2B) receptor in mice completely abolishes MDMA-induced hyperlocomotion and 5-HT release in nucleus accumbens and ventral tegmental area" https://pubmed.ncbi.nlm.nih.gov/18337424/
5. Every treatment with succes rate higher than 1 (inositol, st john wort, ssri reinstatement) involves 5-HT2B receptor.
a. SSRI - as i stated before.
b. St John Wort: Sjw releases serotonin and blocks serotonin reuptake without effect on serotonin transporter and cannot be explained purely by free intracellular sodium increase.
b1. St john wort act on releasing serotonin:
"St John’s wort extract and hyperforin induced a marked release of serotonin from synaptosomes preloaded with [3H]serotonin." https://pubmed.ncbi.nlm.nih.gov/12775192/
b2. St John Wort does not work via serotonin transporter:
"Gobbi et al.[47] reported that inhibition of serotonin reuptake by a methanolic St John’s wort extract and hyperforin is not due to a direct interaction with, and blockade of, the serotonin transporter because in both
compounds had no or only a very slight inhibitory effect on [3H]citalopram binding." https://pubmed.ncbi.nlm.nih.gov/12775192/
b3. It does not work purely but partially via increase in free intracellular sodium concentration:
"Calmidazolium (0.5 microM), an antagonist of the intracellular Ca2+-binding protein calmodulin significantly inhibited the hyperforin-induced shift of the IIV curve maximum and the slow-down of the activation kinetics. It did not, however, affect the delayed inhibition of P-current, indicating that the two stages of modulation are mediated by separate mechanisms." https://pubmed.ncbi.nlm.nih.gov/10954328/
c1. Inositol improves depression symptoms, but it does not work in people who did not respond to SSRIs and it does not amplify SSRI response:
"Studies that use inositol in persons who were resistant to SSRIs specifically have failed to find an antidepressant effect of 12g inositol over the course of four weeks and the combination of inositol with SSRIs failed to outperform SSRIs by themselves over the same time period.
https://pubmed.ncbi.nlm.nih.gov/10907738/
https://pubmed.ncbi.nlm.nih.gov/10023500/
It is clear that PSSD is related to 5-HT2B receptor, how however is unknown. From my scientific research i came to conclusion that SSRI somehow affect 5-HT2B so it does not release serotonin properly, because mind you increasing neurotransmitter amount in the synapse and neurotransmitter release are two different things and they both feel very different. So PSSD is not syndrome where you have too much serotonin, but rather its disease where serotonin is not released properly in the brain.
It would explain why modifying serotonin amount does not work, it's not the amount of serotonin that is wrong but the flow of serotonin.