This is beautiful. Thank you.
freemany
Karma: 45
Hi! It’s time to convert my lurking into an active account. I’m interested in all things related to making the long-term future go well, and I currently run Future Forum.
This is amazing, thank you!
This is beautiful. Thank you.
Hi! It’s time to convert my lurking into an active account. I’m interested in all things related to making the long-term future go well, and I currently run Future Forum.
This is amazing, thank you!
This is an awesome self-experiment. Sadly the 100ug dose used might be too low by at least an order of magnitude. How was it chosen?
We’ve been doing extensive placebo-controlled preclinical mouse trials with orexins and stabilized orexins in the last 6 months. Typically, we use 1 − 1000 ug per mouse per dose. We’ve found that 100ug intranasally is our common effective dose in mice, to achieve measurable behavioral effects such as improved wakefulness or increased locomotion.
Happy to share more preclinical research data here privately.
Scaling drug dosing from mice to humans would via conventional allometric scaling done in reseach would suggest at least a 100x higher dose in humans, if not more.
(Though this is complicated in this case by intranasal dosing, peptides, etc).
Another interesting recent data point for needing higher doses: In narcoleptic humans, the potent small-molecule orexin agonist oveporexton when dosed in milligrams achieves “improved attention, memory, and executive function over 8 weeks.”
“Least-squares (LS) mean placebo-adjusted changes [in attention, memory, executive function] from baseline were −10.77 (95% CI, −16.74 to −4.79), −9.45 (95% CI, −15.66 to −3.24), −8.60 (95% CI, −14.84 to −2.36), and −8.69 (95% CI, −14.90 to −2.47) PVT lapses with 0.5/0.5 mg, 2⁄2 mg, 2⁄5 mg, and 7 mg/placebo doses, respectively.” (Ref) Note that this is in narcoleptics, who have less orexin signalling, hence complicating these otherwise very impressive results.
Key point: Oveporexton is dosed in a 0.5 to 7mg range with good systemic absorption, while also being as potent or more potent than natural orexins and being much more stable with a multi-hour half-life than orexin A’s rapid degradation. Interesting for you to consider that 100ug of natural orexin might be underdosed.
Lastly, published human intranasal orexin-A studies were already in the 1.55-1.78 mg range (435-500 nmol), whereas this experiment used 0.10 mg (100 µg, about 28 nmol). Human intranasal orexin-A references with explicit doses:
Baier et al. 2011, Sleep Medicine
https://pubmed.ncbi.nlm.nih.gov/22036605/
Dose: 1.55 mg (435 nmol) in narcolepsy with cataplexy
Finding: reduced REM sleep quantity and reduced direct wake-to-REM transitions.
Weinhold et al. 2014, Behavioral Brain Research
https://pubmed.ncbi.nlm.nih.gov/24406723/
Dose: 1.55 mg (435 nmol) in narcolepsy with cataplexy
Finding: fewer false reactions on divided-attention testing, plus REM-stabilizing effects.
Meusel et al. 2022, Journal of Neurophysiology
https://pubmed.ncbi.nlm.nih.gov/35044844/
Dose: 1.78 mg (500 nmol) in healthy lean males
Finding: increased resting muscle sympathetic nerve activity after intranasal orexin-A (meh?)
Sayk et al. 2015, Exp Clin Endocrinol Diabetes abstract
https://www.thieme-connect.com/products/ejournals/abstract/10.1055/s-0035-1549071
Dose: 1.78 mg (500 nmol) in healthy normotensive males
Finding: null on sympathetic baroreflex
In other words, this trial dose was only about 1⁄15 to 1⁄18 of doses already used in prior human intranasal orexin-A studies. That likely matters even more because orexin-A is a fragile peptide with rapid degradation and uncertain intranasal CNS delivery, so effective brain exposure is probably well below nominal administered dose.
The 2.5 mL intranasal volume also seems large enough to increase runoff and swallowing, which could further reduce effective exposure. For our human phase I we’re planning to keep volume to 500ul or less.
That makes me consider if this is a too conservative peptide dose and formulation, not strong evidence against the target.
I’m very impressed by the self-experimentation and rigor, and would be excited to see and fund more of this work on Manifund.