Intranasal Medications for Neurocognitive Protection

[DrFraser]

I suspect many are on the board in order to live long and well. Neuroprotection is probably a big part of the focus.

The intranasal route is a novel, but probably effective way of getting substances into the brain.

Rifampin/Rifampicin is a fascinating consideration given IN (Intranasally). The following article is about use with Resveratrol..

Here is one on just Rifampin with mice with lewy body dementia.

Here is one on IN Insulin - there are many of these out there with insulin showing promise in Alzheimer’s.

We have some literature on Rapamycin intranasal - actually quite a bit of information.

Here is the AI review on this. Lastly, GLP-1’s intranasal is an up and coming consideration.

Any thoughts? Anyone doing this, and if so can they detail what they are doing?

Intranasal rapamycin delivery, a novel approach, shows promise in bypassing the blood-brain barrier and directly targeting the central nervous system for treating neurological disorders, including Alzheimer’s disease and epilepsy, with potential for improved cognitive function.

Here’s a more detailed explanation:

• What is Intranasal Rapamycin?

Intranasal delivery of rapamycin, an immunosuppressant drug, involves administering it through the nose to bypass the blood-brain barrier and reach the brain directly.

• Why is it being researched?

  • Neurological Disorders: Rapamycin has shown effectiveness in treating various neurological disorders, including epilepsy.
  • Bypassing the Blood-Brain Barrier: Intranasal administration offers a novel route for drug delivery, allowing rapamycin to enter the central nervous system more directly.
  • Alzheimer’s Disease: Studies suggest intranasal rapamycin can improve cognitive function in mouse models of Alzheimer’s disease and Down syndrome.
  • mTOR Inhibition: Rapamycin inhibits mTOR, a protein involved in cellular growth and metabolism, which is dysregulated in certain neurological conditions.
  • Autophagy Induction: Intranasal rapamycin can induce autophagy, a cellular process that clears damaged proteins and debris, potentially beneficial in neurodegenerative diseases.

• How it works:

  • Nose-to-Brain Pathway: The nasal cavity provides a direct route to the brain through the olfactory epithelium.
  • Nanocarrier Delivery: Researchers are developing nanocarriers to enhance the brain entry efficiency of rapamycin and other drugs delivered intranasally.
  • Dual Therapy: Combining rapamycin with other drugs, such as BACE1 siRNA, can target multiple pathways involved in Alzheimer’s disease.

• Benefits:

  • Improved Cognitive Function: Intranasal rapamycin has shown promise in improving cognitive performance in animal models.
  • Reduced Aβ Deposition: It can reduce the accumulation of amyloid-beta (Aβ) plaques, a hallmark of Alzheimer’s disease.
  • Restoration of mTOR Signaling: Intranasal rapamycin can help restore aberrant mTOR signaling, which is dysregulated in conditions like Down syndrome.
  • Reduced Systemic Side Effects: Intranasal delivery can potentially minimize systemic side effects compared to other routes of administration.

• Examples of Research:

  • A study showed that intranasal rapamycin protected mice from lethal shock induced by staphylococcal enterotoxin B (SEB).
  • Another study demonstrated that intranasal rapamycin ameliorates Alzheimer-like cognitive decline in a mouse model of Down syndrome.
  • Researchers are exploring the use of intranasal rapamycin in combination with other drugs to target multiple pathways in Alzheimer’s disease.

[shc]

Here’s a thread with a few comments from a while back: Rapamycin -- alternate/targeted DIY modes of ingestion?

[Tim]

Several people on this site use epitalon intranasally. Said to be anti-aging and epigenetic, it has a number of benefits. I and other posters here have noticed its pronounced effect on sleep. This is not surprising because it stimulates the release of melatonin. Unlike exogenous doses of melatonin, which I can’t tolerate, epitalon promotes a deep, restful sleep.

It has also been shown that intranasal administration of epitalon stimulates neuron activity in the cerebral cortex of white rats. Only half-joking here, but epitalon may act as a mimetic for thinking, like some peptides are touted as a mimetic for exercise.

Effects of intranasal administration of epitalon on neuron activity in the...

[medaura]

I’m glad you did the digging on Rifampicin! A couple of years back there was this user @MAC who claimed to already be doing intranasal rapa with a DIY delivery system. He hasn’t been active for a long time though — maybe worth emailing him? @RapAdmin do you happen to know and if so can you share whether he’s OK? (Asking in case some users are in direct correspondence with you but not active otherwise.)

[RapAdmin]

Yes - @Mac initiated his own trial related to injection and intranasal rapamycin. We tried to get some groups interested in supporting this from a small clinical trial perspective but couldn’t get much traction at the time. See this thread: Intramuscular (IM) + Intranasal (IN) Rapamycin - A new paradigm for human longevity translation

it would be great if Mac could provide an update on his views on these delivery methods.

[qBx123Yk]

I have heard wonderful things about the combination of of epithalon and DSIP. I plan to make my own In spray for both. I have no problem falling asleep, but staying asleep is another matter.

[vongehr]

IN is novel??? I sniffed my Rapamycin just yesterday, followed by a drop of DMSO.

[Alpha]

@DrFraser

Intranasal delivery of rapamycin, an immunosuppressant drug, involves administering it through the nose to bypass the blood-brain barrier and reach the brain directly.

From:

Intramuscular (IM) + Intranasal (IN) Rapamycin - A new paradigm for human longevity translation

• Experimentation with Intramuscular (IM) rapamycin (rapamycin powder at 30mg/mL in DSMO) @ 15mg/week
• Experimentation with Intranasal (IN) rapamycin (rapamycin powder at 30mg/mL in DSM) @ 3mg/nasal cavity/week

This seems pretty easy to do.

Rapamycin powder from Science.bio. 100 mg at $99.00
A bit of DMSO.
Nasal spray bottle.

As DMSO will pull almost anything along with it through the surface, purity and as close to sterile conditions seem prudent.

The questions:

• Can anyone suggest a reason not do this?
• Any downside?
• Would one reduce intake of oral Rapamycin with respect to the uptake in the brain?
• Stacking with Melatonin?

Secondarily, what about intranasal Melatonin?
Could one simply dissolve Rapamycin powder into an intranasal Melatonin product.

I’ve started significantly upping my Melatonin intake. Would intranasal Melatonin require less because of more efficient access to the brain?

---

Note, Science.bio sells Agomelatine powder, a synthetic analog of melatonin, 1 g at $39.99

[DrFraser]

I’m chatting with some of the compounding pharmacies on whether they have a standard IN formulation of Rapamycin.

I think the unknowns are - what is the dose - how much goes systemic and how much goes to the brain. For example, if you overdo it, then you have constant mTORC1 and C2 inhibition and likely have risk of worsening of cognitive outcomes - would be the the worry.

I’m trying to see if anyone actually has clear guidance on this.

I’ve been looking into the Rifampin/Rifampacin as that looks very interesting. Thanks @medaura

Here is what I’m seeing here - and will be making it myself, have Rifampin capsules on the way!
• Nasal Rifampin dissolved to 10 mg/mL rifampin in 0.5% low-viscosity carboxymethylcellulose Carboxymethyl Cellulose (CMC) - Modernist Pantry, LLC. These can be made as 1% Rifampin nasal drops with ingredients for 100 grams being:
o Rifampin 1000 mg
o Hydroxypropyl methylcellulose K4M 1.25 grams
o Polysorbate 80 300 mg
o Ascorbic acid 100 mg
o Sodium sulfite 400 mg
o Purified water 100 grams
o Heat 90 mL of the purified water to 70 degrees Celsius, then sprinkle the hydroxypropyl methylcellulose while stirring. After this dissolves, cool the mixture to room temperature and add the remaining ingredients while stirring. Add the additional 10 mL of purified water.
o Note Bayview Pharmacy will make these Rifampin 1% Nasal Drops - Customized Treatment | Bayview Pharmacy
o Reference Rifampin 1% Nasal Drops
o Nasal Rifampicin Improves Cognition in a Mouse Model of Dementia with Lewy Bodies by Reducing α-Synuclein Oligomers - PubMed
o Nasal Rifampicin Improves Cognition in a Mouse Model of Dementia with Lewy Bodies by Reducing α-Synuclein Oligomers - PMC
o Rifampicin and Resveratrol Nasal Spray Prevents Dementia in Preclinical Study
o https://www.mdpi.com/2227-9059/10/2/297
o https://www.sciencedirect.com/science/article/pii/S2352873718300416

[medaura]

That’s awesome! Please report back on any effects of this.

Also question, in case I try to replicate your protocol—how much can you scale up this recipe? Does it need to be made in tiny batches for shelf life or fridge life purposes? My concern other than the pain in the ass of having to cook it up often would be to ensure my scale is sensitive enough to the tiny mass increments used.

Second question, are you adding resveratrol as in the recipe that was tested with very positive results? I don’t think of that much as an ingredient but can’t rule out its having synergistic effects with rifampicin. It’s what the study suggested at any rate.

And just making sure you saw, during your deep dive on this subject, that the researchers’ preferred protocol for using the intranasal spray was to shoot it up nostril A, inhale, and then immediately block nostril A with a finger in order to blow it out of nostril B. This was supposed to maximize its delivery across the nasal route and I wanted to make sure you saw that detail.

[DrFraser]

I think the drops are good per the pharmacy documentation for ~84 days. So a batch of 100 mL would make sense - or maybe even half that.

When using a nasal atomizer, you’ll put no more than 0.25 mL up each nostril at a time (use a 1 mL syringe), then wait a few minutes and repeat - so that 1 mL is utilized.

Blow one’s nose beforehand.

What is good with this formulation is that it adheres to the nasal mucus membranes.

I’m going to do a similar recipe with rapamycin, I think.

Yes, I’ll be formulating mine with resveratrol and have the powder and all the other ingredients arriving this week.

Just saying what I’m doing, not giving anyone medical advice to anyone - make sure that before doing anything completely wild like this, consult with your doctor (good luck on getting a stamp of approval on this one!)

[medaura]

Ha, you’re giving us the Fraseresque version of Attia’s disclaimer at the end of his podcast.

Assuming no adverse effects yourself, will you be offering this to any of your patients with measurable tau levels in their blood? I mean, if you have any…

This isn’t all that wild really, since there’s already been a trial with preliminary results so it’s not completely untested.

How much resveratrol will you be using in the recipe, if I may ask, and in which step will you incorporate it? I don’t have the equipment or the patience to DIY this right now but it’s definitely on my radar for over the next 2-5 years. My mind has been feeling quite a bit sharper lately with the only change I can think of being boatloads of creatine, and possibly most of that pregnancy related brain shrink reversing itself. But apoe3/4 is a tough nut to crack and takes planning decades in advance.

[DrFraser]

Rifampin nasal spray is made by several compounding pharmacies, usually for eradication of MRSA from the nasal passage.

So in this study with mice the rifampin and resveratrol where in a 1:1 ratio, with dose being 0.02 mg/day. An average mouse is 0.02 kg. So this looks like 1 mg/kg dosing.

According to this it would appear as though we should reduce the mg/kg by 12.3 fold.

So for a human, we’d be looking at 0.08 mg/kg x 80 kg = 6.4 mg to be equivalent to what was given to the mice. I see another source that claims a ratio of 22 fold change in this scenario, rather than 12.3. This would come in at 3.6 mg.

The mice were given this daily M-F each week for 1 month.

At the concentration of 1 mg/mL it would be not be feasible to put this volume nasally, and I doubt that much is needed. It might be worth seeing if it’ll make a decent compound at 4 mg/mL of each resveratrol and rifampin. Of note, for reference, the oral dose of rifampin is typically 300-600 mg twice daily, so this is a tiny dose.

It is feasible to do 1 mL intranasally.

[dicarlo2]

You are probably aware of this, but I think it’s worth stating for others that Rifampin is the most powerful known inducer of various CYP450 enzymes. This means many drugs will have less effect or possibly even become ineffective. I don’t know how intranasal doses compare to oral for CYP450, but I would generally advise caution to anyone seeking to replicate this that they carefully check all of their medications and supplements for interactions.

Aside from drug interactions, Rifampin is also known to be hepatotoxic and one should check their liver enzymes for any elevations.

Most medications and supplements discussed on this forum are broadly safe for people to try without too much thought, and Rifampin is not one of them.

[DrFraser]

@dicarlo2 Good point on this, but it is dose related - 600 mg/day long term orally with first pass metabolism in the liver … sure. Those points would be valid. The dose makes the poison. I’ve prescribed rifampin many times, and never had any significant adverse outcome for 7-10 days of treatment, or for TB much longer (more of an issue there).

Intranasal 4 mg (so less than 1% of oral dose, delivered to the nose), which doesn’t get first pass metabolism - and even if it did - it will never be of any significance for the concerns one would have with full dose rifampin.