Buspirone, Cyproheptadine, Pindolol, the autoreceptor and PSSD

full explanation of what I know about these drugs and how they work I been asked and deliberately avoided naming drugs that may work for PSSD. My knowledge was still evolving as I learned about the condition forming a hypothesis. Also I'm not a clinician. There is laws around drugs, I can't say take this or that. That is the doctors responsibility. But I can give you what you need to know. I get a lot of emails begging for help. So use this to your advantage. Everything you need is in the substack and the video posted at the bottom. The following is based on the concept that people with PSSD may have to much serotonin in the extracellular brain fluid. When you take a SSRI it blocking the SERT is the fuse. The explosion is the 5-HT1A autoreceptor desensitizing. This creates a positive feedback loop that keeps it desensitized. The hypothesis is that if the 5-HT1A is pushed to hard and instead of it recovering when you stop the SSRI it weakens further and serotonin in the extracellular fluid increases making your anhedonia and sexual dysfunction worse. There is science to back this thinking up. Here is a quote of the math: “−26.03 ± 1.82 mV, n = 8” and the 14-day fluoxetine result is “−8.7 ± 0.9 mV, n = 8,” source paper What that paper is saying is, the signal serotonin transmitted to the coupling through the autoreceptor is reduced to about 33% of normal on day 14 from taking Prozac. The SSRI trick the brain into thinking the serotonin is low so it fires more of it faster. The SSRI forces the 5-HT1A autoreceptor to operate in a maladaptive way. This creates a positive feedback loop where increasing serotonin in the extracellular brain fluid promotes the neuron to fire more serotonin. The more serotonin you add the weaker the signal becomes, making the brain think there isn't enough serotonin when there is to much. When you quit the SSRI, the amount of serotonin in the brain fluid increases further. This is called Serotonin Rebound. It happens because the brain lowers it's production of serotonin to compensate for the 5-HT1A autoreceptor firing to fast. The amount available to fire with increases thereby raising the levels in the brain fluid further. It's been measured in animal studies. Generally the levels come back down in about a week after the SSRI is gone. There is a problem. Klomp et al. (2014) demonstrated that when you restart Prozac after a week. The level of serotonin in the previously treated rats went up 293% in the brain fluid and the rats that were given Prozac for the first time went up 197% Klomp et al. wrote: “may be indicative of the continuing presence of 5-HT receptor desensitization, at least until one week after drug discontinuation,” My hypothesis is that this 5-ht1a autoreceptor may not have recovered. Buspirone and Cyproheptadine provides some evidence. If there is to much serotonin or it is cycling to fast due to weaken 5-HT1A autoreceptor. We can understand these popular PSSD community drugs better. Buspirone (Antagonist and partial agonist, half-life 2-3 hours) The agonist quality is hard to measure. Pfizer puts it at 58% in one assay, and there is others stating as low as 20% and as high as 93%. The antagonist potential is related to concentration and affinity. Serotonin wins out on affinity with a Ki of about 1–5 nM, versus about 15–30 nM for buspirone. Also if the concentration of serotonin is greater it will win again. This doesn't mean Buspirone won't occupy the receptors, it takes more of the drug to be successful. Cyproheptadine (Antagonist of 5-HT1A/2A/2B/2C, D2, H1, M1-M5, half-life 8.6 hours) On paper it looks a lot like the antipsychotic, Olanzapine. Here is approximate values for the important receptors for both drugs. Cyproheptadine 5-HT2A: 0.5–3 nM, antagonist 5-HT2C: 2–18 nM, antagonist D2: 74–112 nM, antagonist 5-HT1A: 50–70 nM, antagonist H1: 0.06–2 nM, antagonist Olanzapine 5-HT2A: ~3 nM, antagonist 5-HT2C: ~10 nM, antagonist D2: 20 nM: antagonist 5-HT1A: 2100 nM H1: 3 nM When we look at the values, They both block the 5-HT2A/2C the same, Cyproheptadine doesn't do much on the D2 or 5-HT1A receptors, and it's very sedating due to the H1 block. While reports of Cyproheptadine is community lead and anecdotal, they are favoured towards improvement of emotional range. This tells me that the drug is easing serotonin activity on the 5-HT2A/2C receptors. Now lets look at the last drug. Pindolol (Beta blocker β1/β2/β3 and 5-HT1A/1B antagonist, 20% agonist, half-life 3-4 hours) 5-HT1A: Ki 6–15 nM 5-HT1B: Ki 8 nM The ability for Pindolol to block the 5-HT1A is 2-fold better than Buspirone. It's activation of the 5-HT1A is significantly lower and the half-life is about twice as long. As for the 5-HT1B block, that's a brake that sits on the serotonin axon terminal. It has a similar role as the 5-HT1A. If it is also uncoupled, then blocking that one would promote recoupling and also help to bring the serotonin level down in the extracellular brain fluid. There is something you should know. How these drug work in the brain relies on he state of the receptors that transmit the signal the neurotransmitter sends. If the receptors are healthy taking an 5-HT antagonist once would raise the serotonin levels in the brain. If the receptors are uncoupled, you need to recouple them so they work again to lower neurotransmitters in the brain. This is why you see so much confusion in the online withdrawal community. There is expected effects, but the drug can also have abnormal effects if the receptor is sufficiently desensitized. I never see this detail being accounted for in withdrawal circles. I still can't tell you what to take, dosing or if it will work or not. It's all theoretical at this time. I do suggest understanding this information then if you want to try it, at least you will be well informed and heck maybe even have a shot at getting your doctor on board. 7 Minute Video explaining PSSD Evidence list matching your Symptoms to high serotonin enviroment