Cure attempt #2 (in-progress / initial findings)
Posted: Fri Oct 25, 2019 12:19 pm
It has come to my attention that people are trying this regimen without taking precautions into consideration despite the several disclaimers and warnings. Others try it despite having symptoms of low serotonin, ending up with more anxiety and/or depression. I've discussed this with site admins and have decided that I would add a section dedicated to probing and harm-reduction. I'm suffering from a concussion due to an accident last Sunday, so will update this thread after I'm mentally able to.
Disclaimer 1: This regimen is still highly experimental - I don't know how other people would react to it. It poses various risks and it's too dysphoric and too "dirty".
Disclaimer 2: Please don't try this regimen until I confirm or deny permanent improvements to baseline in at least a couple of weeks. Although promising, it's still too early - let's not jump to conclusions. In theory, would work for high-serotonin / low glutamate subtype of PSSD only. Even if you are of this subtype, I don't know how you would react to it, it's too dirty with many mechanisms of actions.
Disclaimer 3: This regimen is very risky and should only be attempted under supervision while having sufficient precautionary measures available. It's your own risk.
In this thread, I will discuss my initial findings related to a curative regimen that I have attempted. For the past couple of months, I've been secretly experimenting with a new 2-drug regimen with the potential of being at least a partial cure - setting a new baseline with permanent improvements. I will type all my findings and what I would expect next, so expect this to be a large thread.
The regimen is: Dextromethorphan hydrobromide (250-300 mg) + Naltrexone (25 mg) for 1 week, followed by gradual tapering off and complete withdrawal by the end of the 2nd week. This regimen, in theory, would work for high-serotonin / low glutamate subtype of PSSD only. I'll discuss the science behind this regimen in-depth, but first:
-------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------
A- First of all, why all the secrecy?
First reason is, giving false hope (or placebo report) to this community is the most dangerous thing one can do due to the number of people desperate and suicidal because of PSSD. Let me emphasis the "initial finding" and "in-progress" nature of this thread. It's better to wait for another month or two to truly be certain that benefits are indeed permanent. That said, people were getting very curious so I thought I'd write this thread.
Second reason is, this regimen carries so many risks of permanent worsening and even death. I preferred to try it myself first to see if my cure theory holds true and since I can take precautions as needed.
Here are some of the risks:
- Serotonin syndrome: DXM has SRI and serotonin releasing action. This is especially risky since this regimen is for high-serotonin subtype only. Having Cyproheptadine on hand is a must.
- Psychosis: DXM is psychotomimitic. If you are prone to psychosis or bipolar and/or have family members who suffer from psychotic disorders or bipolar disorders, there's a good chance that DXM would trigger that for you - sometimes permanently so. Having an antipsychotic and a benzo on hand is a must.
- Suicide/suicidal ideation: This regimen is extremely dysphoric! You are blocking mu receptors while being very dissociated on a NMDA antagonist. This combination is very risky if you are prone to depression.
- Severe panic attack: Mu opioid receptor antagonism leads to disinhibition of locus coeruleus' NE firing (norepinephrine nucleus).
- Permanent worsening of PSSD: As with every relief or cure attempt of PSSD, sometimes these drugs would lead to the opposite of the desired effect; namely permanent worsening of PSSD. This regimen carries this risk, especially because of its initial pro-serotonergic nature.
- Bromism: In case you decide to take DXM at high doses chronically for some reason, bromide ions would build up in your body (they have a half-life of 12 days). This would lead to toxic bromism. This risk is non-existent if taken for only 2 weeks, but it's worth knowing.
- Other ingredient toxicity: DXM is often mixed with other substances. These can be antihistamines, phenylephrine/pseudoephedrine, anticholinergic agents, and guaifenesin. This can lead to accidental overdose on those substances, which is especially dangerous in case of anticholinergics (Google anticholinergic poisoning).
-------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------
B- Okay. So what do you mean by saying 'high-serotonin / low glutamate subtype'?
Let me first explain what serotonin negative feedback loop is:
Serotonin firing is tightly controlled by a negative feedback loop involving the main serotonin nucleus in the brain (raphe nuclei).
1- Serotonin transporter (SERT): This makes sure that serotonin is transported from the synaptic space back into the neuron. Low SERT expression would lead to high serotonin symptoms.
2- Presynaptic 5HT-(1A, 1B, 1D) autoreceptors: These put the brakes on serotonin release. 5HT1A is the most prominent.
3- G protein-coupled inwardly-rectifying potassium channels (GIRKs): Simply put, without sensitive GIRK channels, 5HT1A autoreceptors won't work since they depend on GIRK function. Same goes for many other receptors (such as GABA-B receptors which are also GIRK-dependent).
4- Monoamine oxidase A (MAO-A) enzyme: This oxidizes serotonin, rendering it inactive.
If any of these pathways are malfunctioning, you end up with high-serotonin symptoms, which include:
- Blunted affect / flattened affect: Serotonin enhances cortical inhibition of sub-cortical regions, leading to suppressed limbic-cortical feedback.
- Anhedonia/Apathy/Amotivation: Same as above + blunting dopamine and glutamate release.
- Poor cognitive abilities.
- Loss of libido: potentially reducing central AR expression + serotonin in the lateral hypothalamus is very suppressive to the medial preoptic area (mPOA) activity.
- Genital shrinkage: possible effect on peripheral AR expression and vasoconstrictive effects.
- Erectile dysfunction: directly through inhibitory action on spinal reflexes + indirectly through downregulating oxytocin release and NMDA receptors.
- Anogasmia: blunting oxytocin release and sexual excitability.
- Erogenous genital numbness: by affecting brain regions responsible for erogenous sensations (i.e. parietal lobe).
To identify whether your PSSD involves high serotonin, there are several "probing" strategies that can be tried:
- Alcohol hangover: this leads to rebound glutamate firing + transient 5HT1A autoreceptor hypersensitivity. It can give people of this subtype a window of relief.
- MDMA afterglow: MDMA use leads to serotonin depletion, making some people to experience pro-sexual aferglow effect.
- Fenclonine: same as above.
- Baclofen: as a probe, if you don't react to it unless high doses (75+ mg) are taken, this can potentially signal 5HT1A autoreceptors insensitivity and/or desensitized GIRK channel. Both of these are generally caused by high serotonin. Baclofen works on serotonin by indirectly disabling 5HT1A autoreceptor function, causing postsynaptic serotonin release. If autoreceptors or GIRK channels are already desensitized, baclofen won't work.
-------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------
C- Right. How can this regimen potentially cure PSSD, then? get to the science!
Dextromethorphan HBr:
- GIRK channel antagonist restoring GIRK channel sensitivity after subchronic intake of high doses.
- Bromide ions are inhibitory to serotonin release.
- NMDA receptor antagonism leading to AMPA receptors activation + mu opioid receptors upregulation.
- Nicotinic receptors antagonism leading to rapid upregulation and improvement in limbic response.
- Sigma-1 agonism.
As NMDA receptors are present on GABA interneurons, activation of NMDA receptors leads to inhibition of AMPA receptors. AMPAR activation + neurotrophic effect (BDNF/TrkB) is hypothesized to have a rapid antidepressant effect. The opposite is also true - overexpression or over-activation of NMDA receptors leads to reduced AMPAR/neurotrophy, causing pro-depressive effect. Serotonin generally leads to NMDA downregulation, playing a small part in the antidepressant effect (but ruining NMDAR/cGMP/NO pathway responsible for erectile function).
Subchronic intake of DXM HBr would hopefully do the following:
- Restoration of the serotonin negative feedback loop by correcting GIRK sensitivity.
- Reducing serotonin release (due to bromide ion build up).
- Partial neurotrophic effect that can be potentiated by drugs boosting BDNF and/or upregulating TrkB receptors.
- Re-balacing NMDA/AMPA receptor ratio, leading to better erectile function.
Naltrexone:
- Mu and kappa opioid receptor antagonism --> upregulation.
- Gonadal hormones boosting effect, leading to increased central and peripheral AR receptor expression.
- Microglia inactivation.
- TLR2/4 inhibition.
There's is a phenomenon called "absolute refractory period" in rats. After a rat becomes sexually exhausted following multiple orgasms, introducing a new receptive female (novel stimulus) doesn't work any more to stimulate the male rat to participate in sexual intercourse.
It was found that this transient-but-complete insensitivity to sexual stimuli occur rapidly after multiple orgasms. Upon further investigation, it was found that orgasms downregulate AR expression in the mPOA - which is the main cause for this phenomenon.
Why use Naltrexone, then?
So, I had the idea "what if we block mu receptors instead? could that potentiatlly lead to downstream upregulation of mPOA AR expression?" which lead to testing of Naltrexone in this regimen in a bid to reverse serotonin's effect on central AR expression - at least partially.
Second reason is re-sensitization of the limbic pathways to the hedonistic response and pleasure by restoring mu receptors' reactivity to transient, phasic endorphine release.
Third reason is restoring both positive and negative emotional spectrum and reactivity. Mu and kappa opioid receptors play a crucial role in emotional sensation. Kappa is more involved in negative emotions - which makes Naltrexone for restoring both positive and negative emotions through sensitization.
-------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------
D- Interesting. However, what makes you sure that these benefits would "stick" permanently if achieved?
Do not understimate long-term potentiation (LTP). With NMDA receptors inhibited, AMPA receptors activity would be drastically enhanced through increased glutamate release. This can be enough to trigger the "what fires together wires together, as long as there's a burst of dopamine" mechanism. NMDA receptors are also important for LTP and erectile function, so we get a 'during' and 'after' drug effects.
"During" phase: Improved AMPAR, neurotrophic effect and LTP.
"After" phase: Upregulated NMDAR expression, further facilitated LTP, and pro-erectile function.
I already suspect that PSSD is caused in part by the lowered glutamate and blunted HPA reactivity --> leading to long-term depression (LTD) affecting several pathways. It's more plausible to my brain than a frank methylation issue - and can maybe explain why some people get windows of full relief lasting a couple of days occasionally.
I think brain areas responsible for PSSD symptoms are permanently or at least semi-permanently "sleeping" due to LTD. With some AMPAR and neurotophic enhancement, maybe we can trigger potent enough LTP to waken them up and restore the circuits. This requires lowering serotonin + sensitizing GIRK during the extra glutamate phase.
I suspect that the pro-glutamatergic effects of DXM aren't sufficient for LTP and a glutamatergic agent (i.e. Semax) is better added to the regimen. But I wanted to try the 2-drug on their own first to see what benefits stick.
Thread is continued on the following post.
Disclaimer 1: This regimen is still highly experimental - I don't know how other people would react to it. It poses various risks and it's too dysphoric and too "dirty".
Disclaimer 2: Please don't try this regimen until I confirm or deny permanent improvements to baseline in at least a couple of weeks. Although promising, it's still too early - let's not jump to conclusions. In theory, would work for high-serotonin / low glutamate subtype of PSSD only. Even if you are of this subtype, I don't know how you would react to it, it's too dirty with many mechanisms of actions.
Disclaimer 3: This regimen is very risky and should only be attempted under supervision while having sufficient precautionary measures available. It's your own risk.
In this thread, I will discuss my initial findings related to a curative regimen that I have attempted. For the past couple of months, I've been secretly experimenting with a new 2-drug regimen with the potential of being at least a partial cure - setting a new baseline with permanent improvements. I will type all my findings and what I would expect next, so expect this to be a large thread.
The regimen is: Dextromethorphan hydrobromide (250-300 mg) + Naltrexone (25 mg) for 1 week, followed by gradual tapering off and complete withdrawal by the end of the 2nd week. This regimen, in theory, would work for high-serotonin / low glutamate subtype of PSSD only. I'll discuss the science behind this regimen in-depth, but first:
-------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------
A- First of all, why all the secrecy?
First reason is, giving false hope (or placebo report) to this community is the most dangerous thing one can do due to the number of people desperate and suicidal because of PSSD. Let me emphasis the "initial finding" and "in-progress" nature of this thread. It's better to wait for another month or two to truly be certain that benefits are indeed permanent. That said, people were getting very curious so I thought I'd write this thread.
Second reason is, this regimen carries so many risks of permanent worsening and even death. I preferred to try it myself first to see if my cure theory holds true and since I can take precautions as needed.
Here are some of the risks:
- Serotonin syndrome: DXM has SRI and serotonin releasing action. This is especially risky since this regimen is for high-serotonin subtype only. Having Cyproheptadine on hand is a must.
- Psychosis: DXM is psychotomimitic. If you are prone to psychosis or bipolar and/or have family members who suffer from psychotic disorders or bipolar disorders, there's a good chance that DXM would trigger that for you - sometimes permanently so. Having an antipsychotic and a benzo on hand is a must.
- Suicide/suicidal ideation: This regimen is extremely dysphoric! You are blocking mu receptors while being very dissociated on a NMDA antagonist. This combination is very risky if you are prone to depression.
- Severe panic attack: Mu opioid receptor antagonism leads to disinhibition of locus coeruleus' NE firing (norepinephrine nucleus).
- Permanent worsening of PSSD: As with every relief or cure attempt of PSSD, sometimes these drugs would lead to the opposite of the desired effect; namely permanent worsening of PSSD. This regimen carries this risk, especially because of its initial pro-serotonergic nature.
- Bromism: In case you decide to take DXM at high doses chronically for some reason, bromide ions would build up in your body (they have a half-life of 12 days). This would lead to toxic bromism. This risk is non-existent if taken for only 2 weeks, but it's worth knowing.
- Other ingredient toxicity: DXM is often mixed with other substances. These can be antihistamines, phenylephrine/pseudoephedrine, anticholinergic agents, and guaifenesin. This can lead to accidental overdose on those substances, which is especially dangerous in case of anticholinergics (Google anticholinergic poisoning).
-------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------
B- Okay. So what do you mean by saying 'high-serotonin / low glutamate subtype'?
Let me first explain what serotonin negative feedback loop is:
Serotonin firing is tightly controlled by a negative feedback loop involving the main serotonin nucleus in the brain (raphe nuclei).
1- Serotonin transporter (SERT): This makes sure that serotonin is transported from the synaptic space back into the neuron. Low SERT expression would lead to high serotonin symptoms.
2- Presynaptic 5HT-(1A, 1B, 1D) autoreceptors: These put the brakes on serotonin release. 5HT1A is the most prominent.
3- G protein-coupled inwardly-rectifying potassium channels (GIRKs): Simply put, without sensitive GIRK channels, 5HT1A autoreceptors won't work since they depend on GIRK function. Same goes for many other receptors (such as GABA-B receptors which are also GIRK-dependent).
4- Monoamine oxidase A (MAO-A) enzyme: This oxidizes serotonin, rendering it inactive.
If any of these pathways are malfunctioning, you end up with high-serotonin symptoms, which include:
- Blunted affect / flattened affect: Serotonin enhances cortical inhibition of sub-cortical regions, leading to suppressed limbic-cortical feedback.
- Anhedonia/Apathy/Amotivation: Same as above + blunting dopamine and glutamate release.
- Poor cognitive abilities.
- Loss of libido: potentially reducing central AR expression + serotonin in the lateral hypothalamus is very suppressive to the medial preoptic area (mPOA) activity.
- Genital shrinkage: possible effect on peripheral AR expression and vasoconstrictive effects.
- Erectile dysfunction: directly through inhibitory action on spinal reflexes + indirectly through downregulating oxytocin release and NMDA receptors.
- Anogasmia: blunting oxytocin release and sexual excitability.
- Erogenous genital numbness: by affecting brain regions responsible for erogenous sensations (i.e. parietal lobe).
To identify whether your PSSD involves high serotonin, there are several "probing" strategies that can be tried:
- Alcohol hangover: this leads to rebound glutamate firing + transient 5HT1A autoreceptor hypersensitivity. It can give people of this subtype a window of relief.
- MDMA afterglow: MDMA use leads to serotonin depletion, making some people to experience pro-sexual aferglow effect.
- Fenclonine: same as above.
- Baclofen: as a probe, if you don't react to it unless high doses (75+ mg) are taken, this can potentially signal 5HT1A autoreceptors insensitivity and/or desensitized GIRK channel. Both of these are generally caused by high serotonin. Baclofen works on serotonin by indirectly disabling 5HT1A autoreceptor function, causing postsynaptic serotonin release. If autoreceptors or GIRK channels are already desensitized, baclofen won't work.
-------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------
C- Right. How can this regimen potentially cure PSSD, then? get to the science!
Dextromethorphan HBr:
- GIRK channel antagonist restoring GIRK channel sensitivity after subchronic intake of high doses.
- Bromide ions are inhibitory to serotonin release.
- NMDA receptor antagonism leading to AMPA receptors activation + mu opioid receptors upregulation.
- Nicotinic receptors antagonism leading to rapid upregulation and improvement in limbic response.
- Sigma-1 agonism.
As NMDA receptors are present on GABA interneurons, activation of NMDA receptors leads to inhibition of AMPA receptors. AMPAR activation + neurotrophic effect (BDNF/TrkB) is hypothesized to have a rapid antidepressant effect. The opposite is also true - overexpression or over-activation of NMDA receptors leads to reduced AMPAR/neurotrophy, causing pro-depressive effect. Serotonin generally leads to NMDA downregulation, playing a small part in the antidepressant effect (but ruining NMDAR/cGMP/NO pathway responsible for erectile function).
Subchronic intake of DXM HBr would hopefully do the following:
- Restoration of the serotonin negative feedback loop by correcting GIRK sensitivity.
- Reducing serotonin release (due to bromide ion build up).
- Partial neurotrophic effect that can be potentiated by drugs boosting BDNF and/or upregulating TrkB receptors.
- Re-balacing NMDA/AMPA receptor ratio, leading to better erectile function.
Naltrexone:
- Mu and kappa opioid receptor antagonism --> upregulation.
- Gonadal hormones boosting effect, leading to increased central and peripheral AR receptor expression.
- Microglia inactivation.
- TLR2/4 inhibition.
There's is a phenomenon called "absolute refractory period" in rats. After a rat becomes sexually exhausted following multiple orgasms, introducing a new receptive female (novel stimulus) doesn't work any more to stimulate the male rat to participate in sexual intercourse.
It was found that this transient-but-complete insensitivity to sexual stimuli occur rapidly after multiple orgasms. Upon further investigation, it was found that orgasms downregulate AR expression in the mPOA - which is the main cause for this phenomenon.
Why use Naltrexone, then?
So, I had the idea "what if we block mu receptors instead? could that potentiatlly lead to downstream upregulation of mPOA AR expression?" which lead to testing of Naltrexone in this regimen in a bid to reverse serotonin's effect on central AR expression - at least partially.
Second reason is re-sensitization of the limbic pathways to the hedonistic response and pleasure by restoring mu receptors' reactivity to transient, phasic endorphine release.
Third reason is restoring both positive and negative emotional spectrum and reactivity. Mu and kappa opioid receptors play a crucial role in emotional sensation. Kappa is more involved in negative emotions - which makes Naltrexone for restoring both positive and negative emotions through sensitization.
-------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------
D- Interesting. However, what makes you sure that these benefits would "stick" permanently if achieved?
Do not understimate long-term potentiation (LTP). With NMDA receptors inhibited, AMPA receptors activity would be drastically enhanced through increased glutamate release. This can be enough to trigger the "what fires together wires together, as long as there's a burst of dopamine" mechanism. NMDA receptors are also important for LTP and erectile function, so we get a 'during' and 'after' drug effects.
"During" phase: Improved AMPAR, neurotrophic effect and LTP.
"After" phase: Upregulated NMDAR expression, further facilitated LTP, and pro-erectile function.
I already suspect that PSSD is caused in part by the lowered glutamate and blunted HPA reactivity --> leading to long-term depression (LTD) affecting several pathways. It's more plausible to my brain than a frank methylation issue - and can maybe explain why some people get windows of full relief lasting a couple of days occasionally.
I think brain areas responsible for PSSD symptoms are permanently or at least semi-permanently "sleeping" due to LTD. With some AMPAR and neurotophic enhancement, maybe we can trigger potent enough LTP to waken them up and restore the circuits. This requires lowering serotonin + sensitizing GIRK during the extra glutamate phase.
I suspect that the pro-glutamatergic effects of DXM aren't sufficient for LTP and a glutamatergic agent (i.e. Semax) is better added to the regimen. But I wanted to try the 2-drug on their own first to see what benefits stick.
Thread is continued on the following post.