How a single dose of antidepressants can trigger PSSD: a hypothesis

[Ghost]

I've developed something like PTSD to sleep, or to the fear of not being able to sleep and having to work the next day. When it was close to sleep time or I was close to my bedroom I started experiencing hot flashes and severe anxiety and obsessive thoughts. It was so severe that it was totally taking over my life in the end. Only benzos helped, sometimes I had to combine them with zolpidem.
It was very hard to believe but only a few pills of mirtazapine was able to completely erase this obsession. Also including general anxiety, OCD, my emotions and sexual function.

What you say totally makes sense regarding my experience.

EDIT:
Does it make sense that if you're already in an overexcited high glutamate state, hence currently having bad anxiety attack episodes, that it also raises your chances to develop long-term or permanent issues when taking different brain altering drugs/medications?

Also the question arise, what are these LTP/LTD changes exactly? Which brain circuits are being altered and how that have such kind of negative effects on sexuality?

I don't want to detract from the neuro talk here, but I used to have this obsession too. For me it was most of my adolescence on and off and then severe at the beginning of college. It can flare up occasionally but once I let my body take control of when I need to sleep, it's gotten a lot better. For example I have learned that my body WILL sleep when it NEEDS it. The biggest fear of mine was having to go face people and places the next day when I knew I'd be tired and anxious - especially bad when I was working in a hospital or helping with surgeries and felt that I NEEDED to be totally aware of my surroundings at all times - it was a control thing for me as well.

I think I finally realized that I had moved past this obsession when I did Ketamine. After Ketamine I wasn't tired as much so often I'd lay awake at night and then the next day still have energy and be ok. This was eye-opening for me, really helped extinguish a life-long obsession. Therein lies the power of psychoactive drugs, in my opinion.

So moving on to Psilocybin (a very big interest of mine) - Mesolimbo may be interested in this. I will actually take some of the recent Psilocybin posts and put them in that thread because I feel I am talking about it in places besides where it is meant to go. HPPD is definitely real, and it's hard to understand if you haven't taken the drugs. I've always been a very imaginative person and one who is sensitive to the environment. Therefore, HPPD really scared me. I noticed myself checking and seeing if I had HPPD in the days after Psilocybin. This was really no more than OCD behavior and I treated it as such. I've been lucky to have an overwhelmingly positive experience with Psilocybin. That being said it does change things. It's interesting to note that in the studies most people with HPPD don't mind it too much, it's just the more severe cases or the OCD people who are really bothered by it. Anyways, you start to pick up on the weird psychedelic nature of life, especially when you are tripping, but also afterwards as well. You realize that there is a fine line between reality and hallucination. For example: if you want to know what I'm talking about stare at a wooden floor someday. After a while the afterimages and halos will start to make the grains glow and they'll appear to wobble or waver. That's basically you standing on the edge of hallucination. It only takes around 0.2g of shrooms for trying this activity to be fairly psychedelic if I'm in meditation. It's a slider and you start here at these basic things and then scale up to seeing hieroglyphics on the bathroom wall as you increase dosage. You don't realize that until after Psilocybin (i didn't at least). I am aware of being able to make my life feel psychedelic for years (as I describe above), but I was never aware of it being so close to hallucination. So I think HPPD is very subjective and confusing topic. I don't think anyone who takes a psychedelic really sees the world the same way again, but an overwhelming percentage of the time that's a good thing. For example it taught me how to fight (or accept) my obsessional thinking (work in progress). The world would be a much better place if they were accepted and treated like medicine/tools. Art would be better, governments would care more about people, etc.

I get visual snow maybe once a month. Happened yesterday. I never knew what it was for decades until I found it when people were talking about it in relation to HPPD. Usually stress induced and may be from migraines also. Usually triggered by bright, cloudy skies on dreary days. Lasts a minute or less, less if I don't think about it. It looks like bright white dots flying across my vision in circles. I don't think it's any worse after Psilocybin than before.

My sexuality was markedly better when I was microdosing psilocybin, but I was taking between 0.2-0.3g shrooms for my microdoses - which are higher than suggested, I know. I stopped for a few reasons. First of all, I started disliking feeling "active". I went from looking forward to my dosing days to treating it as a mandatory 6 hours when I couldn't do very much else but sit around and wait for it to wear off. My eyes were like saucers and on several occasions it was painful to go outside because I'd want to freak out when I felt on that borderline of tripping in public. Sexuality was better though, and since I've stopped I've now realized how much it was helping. Things were markedly better while on it. It's been a while since my last real trip, and I'm thinking of doing the next one soon. Also would be happy getting back to another Ketamine infusion now that I have some more of this knowledge of drugs.

[Meso]

Why people with PTSD do not have skin numbness?

Yes, that is a very good question indeed...

Because obviously their androgens receptors are not starving from DHT signaling wich probably lead also to our well known skin numbness.
PSSD,PFS,PAS..etc they are all form of iatrogenic insensitivity to androgens the day more people on this board understand this the more we can make step forward.

Just because these conditions look similar doesn't mean they share the same etiology. It just means that the final effect might share a few dysfunctional pathways. It's a simple rule in medicine study.

PSSD also happen in females, for instance, and they also experience genital numbness. SSRIs although downregulate androgen receptors, at least in the prostate, doesn't explain how a single dose can trigger PSSD in some people - which is the main focus of this thread. Also keep in mind that PSSD isn't just sexual dysfunction, the symptoms also include but not limited to: anhedonia, cognitive dysfunction, blunted affect, and depression.

Glutamate is also deeply involved in sexuality. NMDA receptors support sex hormones production whereas AMPA receptors are involved with libido. mGluR are also important:
Effects of Metabotropic Glutamate Receptor Ligands on Male Sexual Behavior in Rats:

In the present study, we used classical copulatory behaviors to evaluate the effects of LY379268 (a selective mGluR2/3 agonist), MPEP (a selective mGluR5 antagonist) and AMN082 (a selective mGluR7 agonist), on male sexual performance in rats. We found that systemic administration of LY379268 (1, 3 mg/kg, i.p.) had no effect, while MPEP (20 mg/kg, but not 10 mg/kg, i.p.) and AMN082 (10, 20 mg/kg, but not 3 mg/kg) produced a significant and dose-dependent reduction in both sex-seeking and sex-performance behaviors, manifested as an increase in mount or intromission latency and time required for ejaculation, and a reduction in mount or intromission frequency. This inhibition lasted for about 30–60 min. These findings suggest that compounds that target mGluR5 or mGluR7, but not mGluR2/3, may have short-term inhibitory effects on male sexual performance.

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3524377/

Pharmacogenetics of SSRIs and Sexual Dysfunction:

The recent study by Perlis et al. provides interesting information about the potential role of the glutamate system with SSRI-associated changes in sexual functioning [14]. These authors describe associations between GRIA3 and GRIK2 and decreased libido, GRIN3A and erectile dysfunction, and GRIA1 and delayed or absent orgasm.

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4034069/

The role of glutamate and nitric oxide in the reproductive neuroendocrine system:

Glutamate is believed to elicit many of these effects by activating the release of the gaseous neurotransmitter, nitric oxide (NO). NO potently stimulates GnRH by activating a heme containing enzyme, guanylate cyclase, which in turn leads to increased production of cGMP and GnRH release. Recent work has focused on identifying anchoring and (or) clustering proteins that target glutamate receptors to the synapse and couple the glutamate-NO neurotransmission system.

https://www.ncbi.nlm.nih.gov/pubmed/10949072

As Ciprofloxaxin pointed out before, NSAIDs can inhibit 3a-HSD. Ibuprofen, indomethacin. And Ibuprofen normalizes the function of the glutamate-NO-cGMP pathway. However, only a few people are helped by ibuprofen. AR downregulation/desensitization plays a role in PSSD, but it isn't enough to trigger PSSD from a single dose of SSRIs and it isn't enough to explain all symptoms.

Why people with PTSD do not have skin numbness?

In PTSD, there is an emotional-driven induction of long-term potentiation (LTP) of synaptic plasticity due to cortisol's facilitation of glutamate release, whereas in PSSD there's induction of long-term depression (LTD) due to cortisol's activation of endocannabinoid system. It all comes down to the inductive stimulus and the balance between LTP/LTD. That said, glutamate release is potentiated in PTSD whereas it's inhibited in PSSD. This is my hypothesis.

Regarding glutamate and genital numbness, glutamate is released by the sensory afferents from the genitals (on the level of the spinal cord). If glutamate release or its receptors are affected, you end up with genital numbness and erectile dysfunction:

In anesthetized ats, the combined administration of the glutamatergic agonists NMDA and AMPA elicited ICP rises in the absence of DPN stimulation. In contrast, both agonists moderately decreased the ICP rise elicited by DPN stimulation but did not affect its latency. These results support our hypothesis that glutamate, released on stimulation of the genitals and acting at AMPA and NMDA receptors, is a potent reactivator of the spinal proerectile network.

https://www.ncbi.nlm.nih.gov/pubmed/14684562

[Dryed]

mesolimbo it urges me to say that it can beneficial to you and for our community if you would try to take contact with utent administrator awor of PFS foundation, he can explain better then any other on this board (without offense) why probably we share the exact same pathology with PSSD,PFS,PAS.. sufferer. Yes pssd happen in both male and female yes there's many other symptoms beyond the sexual one and yes PSSD can happen with only single pills if exist enough rapid and strong androgen ablation in supsceptible subject.

[Snake]

So what real drugs should we try to reverse it?

[TalkingAnt]

Some studies related to mGlu5 (sometimes called mGluR5).

Activation of metabotropic glutamate receptors as a novel approach for the treatment of schizophrenia

Unfortunately, efforts to develop highly selective orthosteric agonists of mGluR5 that have properties suitable for use as drugs have failed. The glutamate binding site is highly conserved across mGlu receptor subtypes [34], making it difficult to develop highly selective orthosteric agonists. Also, mGluR5 orthosteric agonists are analogs of glutamate and do not possess suitable pharmacokinetic properties and brain penetration to allow them to be useful as drugs. Finally, there are several problems associated with the use of agonists as drugs, including adverse effects associated with excessive receptor activation and profound receptor desensitization. To circumvent these problems, we and others have now developed highly selective allosteric potentiators or positive allosteric modulators (PAMs) of mGluR5 [3,35]. These mGluR5 PAMs do not activate the receptor directly but act at allosteric sites to potentiate the response of the receptor to activation by glutamate.

Positive Allosteric Modulators of Type 5 Metabotropic Glutamate Receptors (mGluR5) and Their Therapeutic Potential for the Treatment of CNS Disorders

mGluR5 PAMs were hypothesized to be advantageous over orthosteric mGluR5 agonists such as CHPG because the latter compounds: (1) offer poor discrimination between mGluR receptor subtypes due to the high degree of sequence homology of the glutamate binding site; (2) exhibit poor brain penetrance following systemic administration, and (3) cause rapid mGluR5 receptor desensitization. In an effort to circumvent these issues, mGluR5 PAMs were developed to bind to the receptor at a site that is distinct from the orthosteric glutamate binding site, and increase the functioning of the receptor in the presence of binding of its endogenous ligand glutamate.

Effect of novel allosteric modulators of metabotropic glutamate receptors on drug self-administration and relapse

Metabotropic glutamate receptor type 5 in levodopa-induced motor complications

PD patients without motor complications had reduced
mGluR5 binding in putamen and globus pallidus likely to
compensate for glutamate over activity. In contrast, in PD
patients with motor complications, their mGluR5 binding
was not reduced but higher compared to PD patients without
motor complications and even higher than normal controls
demonstrating an absence of compensation

Changes in the expression of metabotropic glutamate receptor 5 (mGluR5) in a ketamine-based animal model of schizophrenia

This suggests that increased expression of mGluR5 receptors
may reflect a long-lasting adaptive mechanism in response to the ketamine-induced hypoactivation of NMDA receptors. Although an
adaptive response at the level of mGluR5 receptor was observed in
rats after subchronic administration of ketamine, it was insufficient
to prevent the cognitive impairments observed in the NOR test. Nevertheless, our results highlight a new potential pro-cognitive therapeutic target at the level of stimulation of mGluR5.

The mGluR5 positive allosteric modulator VU0409551 improves synaptic plasticity and memory of a mouse model of Huntington's disease

Estradiol-Induced Potentiation of Dopamine Release in Dorsal Striatum Following Amphetamine Administration Requires Estradiol Receptors and mGlu5

In Vivo Non-radioactive Assessment of mGlu5 Receptor-Activated Polyphosphoinositide Hydrolysis in Response to Systemic Administration of a Positive Allosteric Modulator

systemic treatment with the selective positive allosteric modulator (PAM) of mGlu5 receptors VU0360172 enhanced InsP (inositol phosphates) formation in different brain regions

Chronic Pharmacological mGluR5 Inhibition Prevents Cognitive Impairment and Reduces Pathogenesis in an Alzheimer Disease Mouse Model

Amplification of mGlu5-Endocannabinoid Signaling Rescues Behavioral and Synaptic Deficits in a Mouse Model of Adolescent and Adult Dietary Polyunsaturated Fatty Acid Imbalance

Increased Alcohol-Drinking Induced by Manipulations of mGlu5 Phosphorylation within the Bed Nucleus of the Stria Terminalis

study provides evidence that a history of excessive alcohol drinking increases signaling through the metabotropic glutamate receptor 5 (mGlu5) receptor within the BNST in an adaptive response to limit alcohol consumption. In particular, disruption of mGlu5 phosphorylation by extracellular signal-regulated kinase within this brain region induces excessive alcohol-drinking

N‐acetylcysteine yields sex‐specific efficacy for cue‐induced reinstatement of nicotine seeking

While previous investigations with NAC have demonstrated
success at reducing nicotine‐seeking behavior in male rats, successful
dosing ranges have not been uniform. For example, one study
reported successful reduction of nicotine‐seeking behavior at 60 and
90 mg/kg NAC, ip, but not 30 mg/kg,44 whereas others only report
success at 100 mg/kg NAC and not 30 or 60.45 Furthermore, NAC is
presumed to work in part by upregulating expression of the glial glutamate transporter GLT‐1.37 However, studies have found that E2 regulates glutamate transporter expression and increases glutamate uptake
in primary astrocytes,61,62 possibly limiting the restorative properties
of NAC in female rats

The novel dehydroepiandrosterone (DHEA) derivative BNN27 counteracts behavioural deficits induced by the NMDA receptor antagonist ketamine in rats

the stimulatory action exerted by DHEA on
glutamate neurotransmission may decrease glutamate hypofunction in schizophrenia and
appears to be linked to a potential therapeutic effect of DHEA administration against negative
symptoms in this disorder

Glutamatergic Signaling Along The Microbiota-Gut-Brain Axis

Recently, the administration of probiotics to BALB/c mice induced a long-lasting enhancement of Glu/glutamine brain levels. Since, in physiological conditions, the blood brain barrier impedes the amino acid passage into the CNS, this data suggest that the gut microbiota may control defined biosynthetic enzymatic pathways involved in Glu production in the brain...in a seminal study on GF mice, a mild stress restraint induced elevation of corticosterone and ACTH plasma levels, which were reversed by specific colonization with Bifidobacteria species [213]. These observations have been confirmed by successive preclinical studies showing that probiotic treatment may normalize HPA axis dysfunction induced by stress in early-life [214]. There is however a bidirectional microbial-neuroendocrine relationship, since stress may have long-term effects on the microbiota composition, as demonstrated both in early-life and adulthood [212]. Cortisol secreted after stress-induced HPA activation can affect immune cells and cytokine secretion both systemically and in the gut. This latter local effect may alter gut permeability and barrier function, and, consequently, the gut microbiota homeostasis and composition...colonization of GF mice with fecal matter from SPF mice or probiotic administration, resulted in partial and complete normalization of anxiety-like behavior as well as of the BDNF levels...Interestingly, administration of fructo-oligosaccharide (FOS) and galacto-oligosaccharide (GOS) prebiotics to rats was associated with increased levels of expression BDNF and of the GluN1 subunits in the hippocampus gyrus dentate [238]. Analogously, a combination of FOS and GOS showing a beneficial effect on stress-related behaviors, elevated BDNF mRNA in the mice hippocampus, while administration of B-GOS in rats had pro-cognitive effects, involving upregulation of cortical NMDA receptors

[lookingforacure]

Mesolimbo- I just wanted to let you know that I too was extremely emotional prior to the onset of PSSD.

[Ghost]

@Meso, if you think it would be helpful - I would be able to run a list of SNPs from the PSSD genome database for a few of these genes. Anything I have from the genome project is yours as well if you think it may aid you.

Just get me a list and I'll start updating the database and running it.

[Meso]

Does it make sense that if you're already in an overexcited high glutamate state, hence currently having bad anxiety attack episodes, that it also raises your chances to develop long-term or permanent issues when taking different brain altering drugs/medications?

Also the question arise, what are these LTP/LTD changes exactly? Which brain circuits are being altered and how that have such kind of negative effects on sexuality?

I nearly missed this edit. Regarding your questions, yes it could alter your brain if it causes a sharp rise in cortisol, but only if these drugs aren't GABAergic or indirectly inhibitory. But still, it takes a massive rise in cortisol to induce enough glutamate release for a change to happen within a single dose. Chronic dosing during that state would be required generally, unless you have several genetic predisposition, especially FKBP5 polymorphism.

The brain circuits that are of importance to us are within: prefrontal cortex, amygdala, hippocampus (and the limbic system in general). We seem to be experiencing LTD, mediated through cortisol's activation of the endocannabinoid system. Whereas PTSD are experiencing LTP, especially in the amygdala and hippocampus.

The mesocorticolimbic pathway long-term depression is the most involved with sexual dysfunction. Androgens' libido-boosting and mood-boosting effects are partially mediated via their ability to potentiate this pathway. So, if SSRI-induced alteration of androgen receptors is significant, then we would end up with double-inhibition of this pathway.

Mesocorticolimbic dysfunction also causes blunted affect, anhedonia, cognitive dysfunction, and apathy commonly found in PSSD.

So what real drugs should we try to reverse it?

Hmm.. psychedelics are hit-or-miss, they can either cure you if you are lucky, or just have a temporary effect like alcohol hangover.

I'd be more interested in restoring the HPA axis reactivity. SSRIs blunt the HPA axis through glucocorticoid receptor upregulation, causing negative feedback mechanism to kick in and reducing cortisol release. The only thing that would restore the HPA axis would be downregulating the GR receptors, so adaptogens won't be useful here.

Licorice extract won't work since it's a potent phytoestrogen, so it would make you worse. I think maybe chronic Prednisolone is needed here to bring them down, but I'm not sure yet, I have to research this.

@Meso, if you think it would be helpful - I would be able to run a list of SNPs from the PSSD genome database for a few of these genes. Anything I have from the genome project is yours as well if you think it may aid you.

Just get me a list and I'll start updating the database and running it.

That would be helpful, thanks.

5HTTPLR allele, COMT-Met, and FKBP5 rs1360780 T allele

[Knifli]

I had pssd symptoms after one pill and stopped for a few days after (numb genitals was my first symptom, didn't went away in the days ofd) but i took the ssri for 5 months (thought it was a side effect that would go away). The emotional blunting, confusion and dissociation started later on the drug (still have all those symptoms)

[Ciprofloxacin]

So, everything that downregulates glucocorticoid receptors and/or inhibits 5ht1a presynaptic will improve the symptoms.?

Is it possible that my gut problems are just because of malfunctioning hpa axis?