modafinil and flecainide low dose

[yaesutom]

Moreover, modafinil has been recently demonstrated to act as a cellular‐coupling enhancer in astrocytes, through the modulation of gap junctions constituted by connexins.18 In particular, astroglial connexins are involved in sleep and homeostasis regulation,18, 19 as sleep deprivation and subsequent sleep rebound modify their expression and their inhibition causes sleep loss,20, 21 and are more largely involved in neuronal modulation.22 In addition, an astroglial connexin modulator, flecainide,23 has been shown to significantly enhance the wake‐promoting and procognitive effects of modafinil in nonclinical models.24 Modafinil effects on astroglial cell coupling mediated by connexin 30 were reversed by flecainide.24 Altogether, these results indicate that low‐dose flecainide improved the wake‐promoting and procognitive functions of modafinil, probably through the changes of connexin‐dependent gap junctional coupling in astroglial networks. Non‐clinical studies in rat indicated that THN102 significantly increased regional brain
glucose metabolism in the cortex, striatum and amygdala compared to control or drugs administered alone.25

The present study aims to evaluate the effect of the combination of modafinil and flecainide low dose, namely THN102, as a clinical proof of concept of its efficacy on vigilance and cognition

I was going down a rabbit hole related to new Orexin agonist clinical trials and came across this… anyone know if it also works on any other stimulant?

 

[Skorpio]

Flecainide is a class I anti-arrhythmic (sodium channel blocker), so I would be wary of mixing it with stimulants to avoid recreating the cardiotoxicity of cocaine.

What dose did they use in that study to potentiate modafinil

 

[SwissChad]

I was going down a rabbit hole related to new Orexin agonist clinical trials and came across this… anyone know if it also works on any other stimulant?

I've tried the combination previously. It is good, but nothing crazy. It enhances the eugeroic effects of modafinil and some of the pro-cognitive effects, but unfortunately it dosen't effect the stimulant and pro-motivational effects that build tolerance.
Im currently working trying something to counteract that and may add flecianide back into the mix in the future once i've established the efficacy of what I am currently trying.

To answer the question about dosage and risk's of cardiotoxicity. Usually for the sodium channel blocking activity in arythmias starting dosages are usually 50mg twice a day for a total of 100mg and often times titrated up to 300mg + a day. The studies that combined modafinil with flecianide used up to 9mg as a maximum dose of flecianide.

This and lower dosages didn't show any ecg abnormalities when tested with modafinil during sleep deprivation in a group of health individuals, suggesting it's safe to use at these dosages in otherwise healthy users. The study found the optimal dose for a balanced boost in pro-cognitive effects at around 2mg of flecianide. Higher dosages didn't seem to augment the eugeroic effects, but benefited some cognitive tests, at the detriment of others. The lower dosages showed a balanced improvement in most markers.

As mentioned i've tried it and as I suggested it makes modafinil more pro-cognitive and slightly more wakefulness promoting, but that is about it as mentioned to my disappointment it didn't feel like it effected the motivation enhancement or rewarding properties of modafinil.

 

[SwissChad]

I was going down a rabbit hole related to new Orexin agonist clinical trials and came across this… anyone know if it also works on any other stimulant?

The same idea which is connexin inhibition is also persued in combination with other medications like donepezil for alzheimers with preliminary results showing that the combination enhances speed of memory and cortical gamma eeg bands, there is a press release from theranexus on it: https://www.theranexus.com/images/pdf/Theranexus_PR_results_THN201_FINAL.pdf . Hinting at a synergistic effect and a mild vigilance enhancing effect of the combination. I will soon publish a paper on this actually.

Other drug combinations afaik have not been tested thus far except mitrazapine and a connexin inhibitor iirc.

To answer your questions: It may enhance other stimulants. However, it has to be said that the ideas between thn102 (modafinil/flecianide) and thn201 (donep/mefloquine) come from 1. that modafinil upregulates connexins specifically Cx30 and flecianide is a specific inhibitor of Cx30 and that 2. Connexins are upregulated in Alzheimer disease.

Thus in these 2 cases connexin inhibition just makes sense.

Why may it still work. Regardless whether AD or modafinil upregulate connexins and these connexins inhibitors circumvent that. From my research connexin hemichannels are involved in astroglial cell cupling and act sort of as negative feedback to balance excitation of neurons. When they are inhibited it can essentially enhance excitation of the pathways that are already activated and block the negative feedback. That is a very very simplified interpretation it is likely a lot more complex. This is why it may enhance other stimulants too.

 

[yaesutom]

The same idea which is connexin inhibition is also persued in combination with other medications like donepezil for alzheimers with preliminary results showing that the combination enhances speed of memory and cortical gamma eeg bands, there is a press release from theranexus on it: https://www.theranexus.com/images/pdf/Theranexus_PR_results_THN201_FINAL.pdf . Hinting at a synergistic effect and a mild vigilance enhancing effect of the combination. I will soon publish a paper on this actually.

Other drug combinations afaik have not been tested thus far except mitrazapine and a connexin inhibitor iirc.

To answer your questions: It may enhance other stimulants. However, it has to be said that the ideas between thn102 (modafinil/flecianide) and thn201 (donep/mefloquine) come from 1. that modafinil upregulates connexins specifically Cx30 and flecianide is a specific inhibitor of Cx30 and that 2. Connexins are upregulated in Alzheimer disease.

Thus in these 2 cases connexin inhibition just makes sense.

Why may it still work. Regardless whether AD or modafinil upregulate connexins and these connexins inhibitors circumvent that. From my research connexin hemichannels are involved in astroglial cell cupling and act sort of as negative feedback to balance excitation of neurons. When they are inhibited it can essentially enhance excitation of the pathways that are already activated and block the negative feedback. That is a very very simplified interpretation it is likely a lot more complex. This is why it may enhance other stimulants too.

Interesting. Probably not worth me trying then since meth barely works anymore. I seem to have a permanent tolerance to all stimulants BUT.. I did notice something;

If take a benzodiazepine with a stimulant, I bring back a lot of the classic stimulant motivation I used to get in my early 20s… but I cannot deal with the memory destroying side effects and I always start going psychotic. Hallucinations about being hacked always happens and then I screw up all my devices even just a few days on benzos and stims.

Being in my 40s the bad effects from benzos are multiplied, as if my brain really has changed to where benzos make me turn into a psychotic 90 year old.

But I have been curious why only this combo gives me the motivation…and just can’t seem to replicate it with other things. I do not get ANY psychosis at ANY dose of any stim without a benzo. They can barely even allow me to stay awake just one night - I dose off anyways even at megadoses stims. It’s like the melatonin cycle has much more of an effect over it in middle age.

 

[SwissChad]

Interesting. Probably not worth me trying then since meth barely works anymore. I seem to have a permanent tolerance to all stimulants BUT.. I did notice something;

If take a benzodiazepine with a stimulant, I bring back a lot of the classic stimulant motivation I used to get in my early 20s… but I cannot deal with the memory destroying side effects and I always start going psychotic. Hallucinations about being hacked always happens and then I screw up all my devices even just a few days on benzos and stims.

Being in my 40s the bad effects from benzos are multiplied, as if my brain really has changed to where benzos make me turn into a psychotic 90 year old.

But I have been curious why only this combo gives me the motivation…and just can’t seem to replicate it with other things. I do not get ANY psychosis at ANY dose of any stim without a benzo. They can barely even allow me to stay awake just one night - I dose off anyways even at megadoses stims. It’s like the melatonin cycle has much more of an effect over it in middle age.

Crazy, yeah. Unfortunately I haven't found anything useful to reverse any sort of stimulant tolerance. I've tried dxm and memantine with negligable results. Like it certainly is very eugeroic, which i'll gladly take, but unfortunately, dosen't positively effect my motivation or mood by much.