u/Collationem

I will start a series of reviews of cutting-edge nootropics that have only been used by a small amount of users. First up is Irdabisant (CEP-26401), a H3 inverse agonist. I had Irdabisant customly synthesized because no nootropics vendor has been willing to supply it. The summary is that I am very pleased with the effects. There are subtle increases in working memory and on well-being without any side effects. The higher dose (25mcg) slightly impacted my sleep latency, so now I am using 10mcg daily.

Irdabisant (CEP-26401)

Duration: 4 weeks.
Dosage: 5mcg to 25mcg.
Mechanism: H3 inverse agonist. Releases histamine by autoreceptor inhibition. Downstream release of dopamine, norepinephrine and acetylcholine.
Half-life: 24-60 hours.
Effects: increases aspects of working memory in healthy subjects. I started with a dose of 5mcg, as the preferred range in that study is 5-25mcg. This was barely noticeable apart from maybe a very slight uptick in working memory and well-being. Could easily have been placebo. On the contrary, 25mcg provides a clear increase in working memory and gives a distinct feeling of well-being which can only be compared with high-dose Idebenone or Testosterone injections. Keep in mind that I didn't use any tests to quantify the increase in working memory. Rather, my job is very cognitively demanding, and I can readily feel any differences in cognition. There is a slight disruption of sleep, mainly a slight increase in sleep latency. I reduced the dose to 10mcg and retained most effects while eliminating this side effect. All in all a very good nootropic. Not as good as TAK-653 for example, but absolutely worth keeping in my daily stack. Because the dosing is in extremely small amounts the cost is actually very manageable, around 5 cents (!) per day. I have enough supply for a lifetime, but hopefully a nootropics company will start selling it so that more people can try it.
Conflicting variables: steady dosing for 1 year of Armodafinil, TAK-653, Selegiline/Testosterone injections and transdermal Dihexa.

Next up in a few weeks: BPN14770, PDE4D NAM from Penchant Bio.

The past years I have been experimenting with many (experimental) nootropics, and I want to share with you the most synergistic combinations of positive allosteric modulators and (partial) agonists.

● Galantamine + ABT-089

Galantamine is (most likely) a PAM of the a4b2 nicotinic acetylcholine receptor, while ABT-089 is an agonist of the a4b2 receptor. Good potentiation of ABT-089 is observed, although this may also be (partly) due to acetylcholinesterase inhibition by Galantamine. It does feel slightly stronger (and cleaner) than combining with Donepezil. Galantamine is dosed between 1 and 10mg and ABT-089 at 5mg.

● Ebelin lactone (Cognance) + Sabcomeline

Ebelin lactone is a PAM of the M1 muscarinic acetylcholine receptor, while Sabcomeline is a partial agonist of the M1 receptor. Highly synergistic unexplored combination especially suitable for learning and memory, probably my favourite combination in this list. I had Sabcomeline customly synthesized for this purpose. I resorted to ND's Cognance due to lack of availability of other M1 PAMs. Cognance is dosed at 100-300mg and Sabcomeline at 10-50mcg.

● Nefiracetam + Sunifiram

Nefiracetam is a PAM of the glycine site of the NMDA receptor, while Sunifiram is (presumably) an agonist of the glycine site. Sunifiram should be dosed very low (100-250mcg) to avoid commonly reported side effects and risk of excitotoxicity. Nefiracetam is dosed 100-300mg, I prefer the lower end of that range.

● Nicergoline + microdose 5HT2A agonist

The most recent combination that I tested. Nicergoline is a relatively selective 5HT1A receptor presynaptic antagonist, which potentiates serotonergic neurotransmission mediated by 5HT2A receptors in the dorsal raphe nucleus and prefrontal cortex. Anecdotally, my normal microdose of 0.5mg DMT (IM) was potentiated into psychedelic territory by priming with 1mg Nicergoline injected intramuscularly (roughly equal to 20-40mg oral). Thanks to u/mastermind_genius for pointing me towards this combination.

Future projects:

● Sigma-1 positive allosteric modulation with an agonist. Probably Methylphenylpiracetam as a PAM from Umbrella Labs (if it ever becomes available), and PRE-084 as an agonist. Alternatively Donepezil can be used as an agonist, but sadly I cannot tolerate the long half life mainly due to insomnia.

If you know of any other synergistic combinations please discuss them below!

Review: Irdabisant (CEP-26401)

Highly synergistic combinations of PAMs and (partial) agonists