One user's success with microdosing Prosaz/Fluoxetine (for depression, energy, brain fog,motivation, sleep, brain). Via new neurosteroid mechanism?

junkcrap50

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It was interesting to see another drug having unique benefits at microdose levels, considering the microdosing Abilify. The person believes it is due to a different mechanism than the conventional SSRI process. Rather, that the benefits via microdosing this drug are due to a neurosteroid effect.

Could this help ME/CFS, particularly those who's benefits stopped with Abilify?
Could this target neuroinflamation in ME/CFS?

https://www.reddit.com/r/Nootropics/comments/rerdrr
 

junkcrap50

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Posting a reddit link normally reproduces the whole text of the post, but using firefox and maybe other ad blockers prevents that (for me). I've reproduced parts of it for those who use adblock so they don't have to click a link.

Microdosing Prozac/Fluoxetine: Conclusion 3 years later
Three years ago I was scared to try another AD for my depression/dysthimia after a failure and a horrible WD with Effexor/Venlafaxine, so I started with such a small dose of Fluoxetine that was 5 times lower than the smallest dose prescribed. Looks like this occasion led me to find a completely different mechanism of action of this drug that's only prominent at sub-SSRI doses.

The original post: Microdosing Prozac works instantly? Your thoughts?

Over the years I've received a dozen DMs from people wanting to know more about my experience and asking if it still worked for me. In this post I'll try my best to describe what I found out about microdosing Prozac on and off for 3 years.

Background/My Condition
I suffer from dysthymia which is a chronic form of mior depression, from time to time I get episodes of major depression which basically makes it double depression. Depression itself seems to be a secondary issue of my ADHD-PI and probably comes from multiple academic and career failures.I'm from Russia, so pursuing treatment for ADHD is pointless because it's almost non-existent as a diagnosis here. It's not recognized by the majority of doctors and even if you're diagnosed only Straterra, Phenibut and Piracetam can be prescribed. There is no single stimulant on the market and even Modafinil is Schedule 1. However, this post is not about ADHD.

Dosage
The effective dose range for me is 2-6 mg, around 4 being the sweetspot. Anything below that doesn't work, anything above seems to cancel out the positive effects I get from it, likely due to entering into SSRI's mechanism of action threshhold and SSRI's never worked for me at typical doses, usually only made it worse. I tried Prozac at therapeutic doses 20-40 mg but at that dose there are no benefits which I get from microdosing it, let alone side effects.

Subjective Effects
The effects I get from start to show up around 3 hours after taking it with a peak of 2-3 hours and around 5 hours of after-effects. This is the list of effects that I've experienced:
  • Mood elevation - a general mood boost which is nothing like anything I can compare other than MDMA and Phenibut. It's somewhat similar in terms of its clean-headed nature, though of course by no means it's as powerful. Maybe like 15%.
  • Cognitive stimulation - mentally stimulating likely because of alleviating brain fog, though stimulation does not feel forced, it's calm and relaxing at the same time. Like a cup of coffee in terms of it's potency but not it's nature.
  • Motivation enhancement - mundane tasks become a bit easier to do, it's reminiscent of just feeling "OK" to do stuff in terms of attitude that usually comes with microdosing mushrooms.
  • Muscle and cognitive relaxation - stress becomes easier to manage, calm&clean but awake feeling, muscles aren't as tense, RLS relief.
  • Physical comfort - just feeling better in your skin, also increased touch sensitivity along with it's pleasurability.
  • Increased sense of well-being - self-explanatory.
  • Decreased anxiety - social one as well. Not much but still noticeable.
  • Focus enhancement - not like stimulants but it becomes easier to ignore distractions.
  • Increased music appreciation - sounds become a bit more clear and a bit more pleasurable.
  • Increased libido - only Phenibut comes close in terms of potency of this effect for me
  • Increased sex pleasurability - this one is also huge due to antidepressant use in the past that made my sexual life way worse long-term.
  • Improved sleep quality - not much but it's noticeable that your body was more relaxed during the night upon waking up.
So, it helps me primarily with depressive symptoms such as amotivation, anhedonia, lack of energy e.t.c but some of ADHD symptoms are also alleviated, though not as much.The effects on mood, motivation, empathy, focus, removing brain fog and muscle&emotional relaxation are reminiscent of those of Phenibut for me, so I suspect that GABA is somehow involved in the MOA along with serotonin and dopamine. Better stress response.
References:
Possible Mechanism of Action
As a couple of people in the original post have noted, the MOA might be linked to a neurosteroid effect, particularly an increase in allopregnanolone is responsible for improving GABA sensetivity, therefore this might be a reson why some effects similar to Phenibut.The following articles might give a hint in regards of the MOA and related compounds.

PubMed: Selective brain steroidogenic stimulants (SBSSs) - Main clue
SSRIs act as selective brain steroidogenic stimulants (SBSSs) at low doses that are inactive on 5-HT reuptake
Brain principal glutamatergic neurons synthesize AlloP, a neurosteroid that potently, positively, and allosterically modulates GABA action at GABAA receptors. Cerebrospinal fluid (CSF) Allo levels are decreased in patients with posttraumatic stress disorder (PTSD) and major depression. This decrease is corrected by fluoxetine in doses that improve depressive symptoms. Depression-like behavioral dysfunctions (aggression, fear, and anxiety) associated with a decrease of corticolimbic AlloP content can be induced in mice by social isolation. In socially isolated mice, fluoxetine and analogs stereospecifically normalize the decrease of Allo biosynthesis and improve behavioral dysfunctions by a mechanism independent from 5-HT reuptake inhibition. Thus, fluoxetine and related congeners facilitate GABAA receptor neurotransmission and effectively ameliorate emotional and anxiety disorders and depression by acting as selective brain steroidogenic stimulants (SBSSs).​

Wikipedia:Etifoxine - Another compound
Etifoxine stimulates the biosynthesis of endogenous neurosteroids, for example: allopregnanolone, a nanomolar potentiator of GABA activity.​

Wikipedia:Neurosteroid -Main clue
These neurosteroids exert inhibitory actions on neurotransmission. They act as positive allosteric modulators of the GABAA receptor (especially δ subunit-containing isoforms), and possess, in no particular order, antidepressant, anxiolytic, stress-reducing, rewarding, prosocial, antiaggressive, prosexual, sedative, pro-sleep, cognitive and memory-impairing, analgesic, anesthetic, anticonvulsant, neuroprotective, and neurogenic effects.​
Certain antidepressant drugs such as fluoxetine and fluvoxamine, which are generally thought to affect depression by acting as selective serotonin reuptake inhibitors (SSRIs), have also been found to normalize the levels of certain neurosteroids (which are frequently deficient in depressed patients) at doses that are inactive in affecting the reuptake of serotonin. This suggests that other actions involving neurosteroids may also be at play in the effectiveness of these drugs against depression.​

PubMed: AlloP increase in DA response - Might explain alleviating anhedonia
The neurosteroid allopregnanolone increases dopamine release and dopaminergic response to morphine in the rat nucleus accumbens
AlloP dose-dependently increased the release of DA in the nucleus accumbens. Furthermore, this hormone doubled the DA response to morphine. These effects were observed for AlloP doses of 50 and 100 pmol injected intracerebroventricularly. These results suggest that the stimulatory effect of AlloP on DA could mediate some of the behavioural effects of neurosteroids and, in particular, the interaction of these hormones with mood and motivation.​
 

xebex

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Interesting! I have just been prescribed fluoxetine for PMDD and I read an (old) article in The Guardian talking about how low dose Prozac could potentially help severe PMS - i'm not saying ME is PMS but maybe there's some links - maybe this is why more women get it?

https://www.theguardian.com/science...oses of the anti,end of their menstrual cycle.

I really believe that’s ALLOP plays a part in my ME. Every month my ME improves until the progesterone drops and I’m back at square one again (along with horrendous PMDD symptoms), this cycle has been going on for years! Accompanied by worse and worse moods swings until I finally realised I had PMDD and asked doc for a prescription.

I really wonder what would happen if I was able to cut out that huge hormone drop - would I just keep improving?!

I have been observing over time that it almost seems like my body is allergic to its own natural rises and drops of hormones. It might explain why we crash from doing nice things that don't seem to be too exertive - the dopamine rises from doing the nice thing but then the body/brain freaks out to that rise just as it does to the Allop in PMDD.

I also had some small improvements using ritalin in a similar way to the OP just 1/4 of a pill every 3 days but eventually it stopped being effective.

I think I am going to try taking Prozac at a very low dose. I'll take it as if treating PMDD first and see how that goes and report back in a month or so.

really interesting info, thanks.