Donepezil

[Meso]

The Bethanechol thread encouraged me to try Donepezil.

My PSSD is the result of Clomipramine (Anafranil) + Venlafaxine (Effexor). I was on these drugs for depression and to block RBD dysphoric dreams and morning headaches.

I've been suffering from REM sleep behavioral disorder (RBD) prior to any SRI intake. My dreams are extremely violent and always revolve around dysphoric themes (wars, terrorism, abuse, torture, major relationship issues, fights, even failing exams, etc). They are not like typical nightmares, though.

Effexor is known to exacerbate RBD but it helped me have always-dreamless nights, which improved my mood significantly (+ no more morning headache), so much that I no longer needed Clomipramine, so I quit taking that. Fast-forward 2 years, I'm completely emotionally numb and have zero libido, I had to quit taking Venlafaxine. Half a year later, PSSD is still here (to stay).

Current symptoms:
- Flattened affect ("Flattened" in a sense that my best friend died and I felt nothing.
The only emotion I can feel is anger and irritability. Other than that, I'm a total zombie inside).

- Anhedonia (No longer feeling any pleasure from music or doing hobbies).

- Anorgasmia & erectile dysfunction.

- Brainfog from hell, physical and mental fatigue, very poor memory, and inability to focus.

- My baseline heart rate shot up to ~120 BPM and stayed there. My blood pressure went up to 150/95 mmhg.

All blood tests and examinations were normal (Kidney, liver, heart, electrolytes, hormones, ultrasonography, EEG, ECG, etc, etc)

I tried so many drugs and supplements to list them here, but the only thing that helped me was Aspartame, probably through higher phenylalanine:tryptophan uptake ratio causing lower serotonin synthesis in the brain + increasing aspartic acid. But it doesn't always work and sometimes leaves me with intense anxiety, jitteriness, and nausea.

Now, I realize that Donepezil would increase REM sleep and dreams vividness, but if it works for PSSD, then hell I'll just try other things to combat these dysphoric dreams. PSSD is a living-nightmare by its own right!

[jjr81]

I was just prescribed Memantine by my neurologist. I've stopped sleeping and dreaming so I'm hoping for some improvement with those issues. Plus my terrible memory issues. We also discussed Donepezil. May try next depending on what happens with the Memantine. Thanks for sharing.

[Meso]

I took 2.5 mg Donepezil yesterday. An hour later, I regained some emotional reactivity to the point of eyes tearing up when I remembered my late best friend. This is the first time in a year or more that I feel an emotion other than anger.

The derealization I've been experiencing post-Venlafaxine has also improved. I feel more "engaged" in life, probably due to being more emotionally involved and not so "zombified".

I listened to some music as well and since there was some emotions, it sounded nice. It used to sound like noise all this time to the point of not being able to tolerate it.

Cognitive symptoms improved more drastically than on choline sources + nootropics. I guess Meclofenoxate/choline/Piracetam/Ginkgo weren't providing me enough acetylcholine to make up for the dysfunction I've been having. Although, I wonder if adding Piracetam to Donepezil would improve those symptoms further.

Donepezil made me slightly more anhedonic, but combining it with an Aspartame source has ameliorated the anhedonia and provided an even stronger emotional boost (aspartic acid activating NMDA receptors, or maybe less serotonin synthesis from reduced tryptophan uptake, or more dopamine synthesis from phenylalanine, or a combination of all). One could probably use BCAA to have a similar effect, I reckon.

Let's see if other symptoms (i.e. sexual) would improve by time and if I can regain all the lost emotional reactivity.

As for dysphoric dreams, they got significantly worse + non-stop nightmares all night long. As expected, really. Since Donepezil has a very long half-life, I'll probably use an anticholinergic before sleeping, or Prazosin, or both. I'll see what happens.

[Meso]

A bit of history is in order, I guess:

I tried a plethora of drugs to combat blunted affect (whilst on and off Venlafaxine), RBD, anhedonia, and sleep disorder both on my own and with the help of my psychiatrist: Methylphenidate, Buspirione, Amisulpride, Baclofen, Memantine, Pramipexole, Piribedil, Aripiprazole, Bupropion, Pregabalin, Clomiphene+Exemestane, just to name a few. I also tried so many herbs and supplements and even some research chemicals (i.e. Methoxetamine, alpha-Methyltryptamine).

They were all useless, with few exception:
- Dextromethorphan (DXM): At high dose, it would bring back my emotions temporarily. When it wore off, my libido would return for a day or two (NMDA receptor upregulation and rebound activation, I think). It's also a sigma-1 receptor agonist. However, it's a GIRK inhibitor and an SRI. A very dirty drug overall and caused worsened symptoms.

- Aspartame: High doses improved my anhedonia and restored some emotional reactivity, modestly. Breaks down into phenylalanine and aspartic acid. A high dose, in theory, would prevent tryptophan uptake via phenylalanine competition over the transporter, causing more dopamine synthesis and serotonin depletion (especially when combined with NAC since it upregulates tyrosine hydroxylase, and offers some neuroprotection). Aspartic acid might cause more NMDA receptor activation.

- Baclofen: It used to offset PSSD for a while, providing a significant emotional and libido boost, then I got tolerant. It makes RBD much, much worse, but I used to have deeper sleep on it nonetheless.

Back to Donepezil:
Side effects I notice are typical of muscarinic activation: more salivation, easily sweating a ton, more bowel movements (fixed my chronic constipation), reduced appetite, and mild nausea. Positive inotropic effect on heart. Keep in mind that Donepezil is also a sigma-1 agonist.

Music still sounds nice today. Cognitive symptoms have improved a lot, but there's still derealization and some brainfog.

I feel a small but noticeable libido boost, and heat and my groin area with restored penile sensitivity and reduced numbness. But I have erectile dysfunction, I probably need to get my overly active sympathetic system under control for that.

Let me know if you guys want me to provide more details.

[Knifli]

Thanks for the update!

[Charles10]

very nice, i think donepezil is one of the most promising drugs now... betanechol is having good results, and the donepezil is similar with it, acting in acetylcholine, the apparently good difference is that donepezil pass the blood barrier, then goes more to brain... there is another old topic of 2015 about donepezil here in the forum where have some articles saying hypersexual behavior by the donepezil and some improvements of who was taking it, unfortunately seems he didnt post more... keep us reported, i'm ansious to see the results

[healing]

Wow, so glad it’s working out so far! Keep the updates coming!

[Meso]

3rd day on Donepezil @ 2.5 mg.

All my symptoms keep on improving:
- Flattened affect: I'm noticing an increase in sociability. I reached out to a couple of friends and had a chat. I notice a mild increase in empathy and caring. But my emotions are still largely blunted, but at least they are not flattened anymore.

Donepezil boosts BDNF, so I'm hoping it can fully reverse blunted affect in a month or two.

- Anhedonia: My enjoyment of music is returning fast. I listened to Liszt pieces and enjoyed them like I used to before this whole mess started. I feel nostalgia from listening to music, I feel more "human". Other than that, I got some motivation back and enjoyed working out today.

I didn't expect a cholinergic agent to improve my anhedonia, but maybe it does so through nicotinic receptors (since, unlike Bethanecol which is only a muscarinic receptor agonist, Donepezil prevents the breakdown of acetylcholine, allowing it to activate all nicotinic and muscarinic receptors.)

- Sexual dysfunction: My dick is getting less and less numb by the day. I also notice a significant boost in libido today. I feel horny, about 30% of pre-PSSD level, which is significant since ever since PSSD my libido had been completely absent. As for erectile dysfunction, it's still there but I managed to maintain an erection for a minute today.

- Cognitive symptoms: Drastic improvement. Although I still feel derealization and brainfog, it's no where near pre-Donepezil level. I'm hoping to see more improvement in this department.

Side-effects wise, REM sleep behavior disorder (RBD) is getting worse and I'm having more nightmares, but I don't think this would apply to persons who don't have RBD pre-SSRI to begin with.

So far, Donepezil has been superior to anything I've tried for PSSD and emotional numbness (and I've tried a lot of things).

[Jaxx]

i totally missed this topic, very nice initiative! Also very surprizing to see quick effects, please keep us posted!

[Meso]

9th day update:
There's definitely a cholinergic component to PSSD. My libido has been restored to 50% of pre-SNRI.

Although I still don't fantasize about sex or feel horny per-se, with enough stimulation I managed to maintain a throbbing erection. Just 10 days ago, my libido was completely absent + severe erectile dysfunction.

I've had sex yesterday but for the life of me I couldn't reach an orgasm. I tried to analyze my thought pattern and the problem seems to be derealization, detachment, and significant genital numbness.

It's not like I was close to going over but couldn't manage to, no, it was like I was not even close to having an orgasm. Miles away, in fact! But I still enjoyed the experience.

As for sleep quality, my RBD doesn't mix well with Donepezil. I keep needing Dimenhydrinate in order to have semi-refreshing sleep, which is not bad since it would allow my muscarinic receptors to upregulate during sleep so I can enjoy Donepezil's effects without tolerance, in theory.

Current symptoms:
- Flattened affect: I lost my emotions again. I think this is due to having high progesterone + derealization and general dissociation. Maybe involvement of 5HT2A and mu, or kappa opioid receptors. I read that Naltrexone is used for dissociative disorders. Any ideas?

- Low libido: Although it has improved a lot, there's still room for improvement. 50% more to be specific, if I want to be optimitic in having my pre-PSSD libido anyway, with sexual fantasies, morning wood, and spontaneous erections. For this, I could try Clomiphene (+ an aromatase inhibitor if need be).

- Cognitive dysfunction: I still have a moderate amount of brainfog and poor memory. It's strongly related to dissociation and derealization, though. No emotional memory as well.