Dayvigo® (lemborexant), Eisai’s dual orexin receptor antagonist, was approved in China in recently. I am wondering if it’s the safest drug we can get on the market?
In the past I tried several other sleep drugs and they don’t work very well on me.
I tried a ‘safe’ pill Ramelteon and it halves my deep sleep duration according to the OURA ring.
I also tried low dose of trazodone and it made me drowsy.
I wrote a post about sleeping drugs.
Benzodiazepines is less effective to me since I got insomnia for 3+ years.
I am trying orexin receptor antagonist these days. Orexin is another neurotransmitter that regulates sleep and generally safe to do something to it.
Bryan Johnson is trying similar drugs too.
Personally I think a good sleeping pill at least should have 3 extra characteristic on top of effectiveness:
- moderate drug metabolism rates, likely 8h, to avoid daytime sleepiness
- safe for long-term use, no risk of cognitive impairment, since insomnia is not easy to cure. Diphenhydramine is a negative one.
- not metabolite by CYP450. Many psychiatric drugs need CYP450 to metabolite, which is one of the major reason why these drugs generally have higher risk of drug durg interaction. CYP450, especially CYA3A4 is really easy to inhibit by drug, supplement or even some food, but many substances need it to metabolite.
Lemborexant does not 100% meet my requirements, but I need to try.
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Rika_Qu,
I hope this link will be useful. You should find a table of sleep drugs I created a couple of years ago. Don’t take everything you read in the table as being true because I used ChatGPT to create it.
As a note there are several orexin type sleep drugs. Quviviq has I believe the shortest half-life with possibly less of an extended next day sleepiness effect.
As an insomniac I’ve used things you mentioned and found them basically not useful or intolerable. I’ve tried Quviviq before, but didn’t see great effect. However, I’m trying it again and paying close attention to whether or not I feel rested the next day compared to other sleep aids I’ve tried.
In general, I’ve used diphenhydramine and doxylamine (doxylamine being the more effective one) as mainstays and found both to be useful. But, do they lead to early dementia? It’s a dilemma. As an alternative there is Silenor (6 mg) which I’ve used and found effective. For some, including me, after a few days using Silenore there may be a a next-day sleepiness effect that is irritating. But, getting that restful sleep with Silenor is great when I need it.
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I would say yes so far, have been on it since July and it definitely helps you sleep. But my dosage is inconsistent, skip 2 days, take 5 mg, skip 3 days, take another pill, etc. It seems to last longer than what’s suggested in the info packet, for me it feels like it’s in my system for 2-3 days, I feel more sleepy than before for sure.
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The issue with the DORA (dual orexin receptor antagonists) is interesting. The two common ones Belsomra (suvorexant) and Dayvigo (lemborexant) both have very long half lives. It looks like at low dose ~6% of individuals report daytime sleepiness and at higher dose ~10%.
These agents are not acting on GABA and also do not worsen sleep architecture, which may be one of the big worries with benzodiazepines and other sleeping medications that primary work on GABA.
Additionally, there is growing data that they may delay tau pathology associated with Alzheimer’s Disease.
There is a trial upcoming I believe actually using it in this context.
Unfortunately it is a controlled substance and an Rx will be necessary as importation is a risk of criminal prosecution. Both of these agents in the U.S. are expensive, but are very cheap in India.
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I revisited using some type of Rx sleep aid with my MD. Previously, he gave me some samples of Belsomra which I took one dose of and it gave me waking hallucinations before I fell asleep. This time he prescribed Doxipine to start with 1/2 tab. I found it effective for staying asleep through the night. I do have a concern about potential sexual dysfunction side effects but I don’t plan on taking it every night. It’s an expensive med and not covered by my Medicare plans. I’ve found a gummy equally as effective for sleep but with a slight sluggish effect for a short period after waking. Also, I am reluctant to use it on a constant basis. Gummy: Wyld Elderberry THC/CBN.
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Doxepin is in the group of meds I won’t use for sleep as it has potent anticholinergic effects and increases neurocognitive decline as do GABA agents. THC is a challenge - it modifies sleep architecture often times decreasing REM sleep - you need to individually check and it is dose dependent. We now however increasingly are seeing data that THC increases vascular bad outcomes even when ingested. The DORA agents seem like a good choice for some people - but sleep is a challenging area for sure; I just don’t advocate taking things that have known significant worse health outcomes.
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Sleep, is complex and variable, but extremely important. On the chart Jay provided above, the risk of demential with Doxepin is low at low doses (definitely a question mark on that vague implication). But, I may ask my physician to Rx lemborexant on a trial basis.
So Doxepin has very potent Histamine Type 1 blockade and less potent Anticholinergic effects.
It is a TCA … here is just a small subset of the supportive literature for these concerns:
- The Adult Changes in Thought prospective cohort (n = 3,434; mean follow‑up 7.3 years) found a dose‑response relationship between cumulative anticholinergic exposure (mainly TCAs, first‑generation antihistamines, bladder antimuscarinics) and incident dementia (HR 1.54, 95% CI 1.21–1.96) and Alzheimer’s disease (HR 1.63, 95% CI 1.24–2.14) for the highest exposure group 1 II.
- A nested case‑control study (JAMA Intern Med 2019, n = 58,769 cases; 225,574 controls) confirmed that anticholinergic antidepressants—including TCAs—had a significantly increased adjusted odds of dementia, independent of comorbidities and depression severity 2 II.
- The BMJ 2019 case‑control analysis (n = >280,000) showed that ≥3 years’ cumulative exposure to strong anticholinergic antidepressants increased dementia risk by 49% (adjusted OR 1.49, 95% CI 1.44–1.54) 3 II.
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How much does chronic insomnia increase the risk of dementia?
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I’ve been taking lemborexant nightly for years. About once a year I intentionally take at least a month or more off to ensure no dependance and to give me receptors a break. It causes no withdrawals, maybe a night or two of some rebound insomnia, then back to my usual insomnia / ruminating issues. It’s been a lifesaver for me. I’ve tried the newer daridorexant, and didn’t find that one effective for me personally. I could say a lot, but feel free to ask any specific questions.
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Interesting they make them cheap in India, even with health insurance coverage, they are kinda pricey for me (maybe because it’s a newer drug?) not entirely sure why I’m paying $115 for a 30 day supply.
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I find the biggest side effect of DORA is sleep paralysis 
And the sleep paralysis happens before I fall asleep.
My mind is so clear but I can’t move my body.
A little separate topic - but we are using DSIP peptide … I think it is working well as is inexpensive through the “Research Peptides” path. It has been improving ability to fall back asleep and improves deep sleep % for us N=2.
Sleep paralysis isn’t good. I’ve had a number of individual’s not love the DORA agents. Personally, I’ve had it slightly improve sleep, not hugely, and no side effects.
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That’s been my personal experience as well. It’s worth having on board and no side effects, but it certainly doesn’t guarantee a perfect night’s sleep.
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Ditto at 5mg. I don’t sleep as well without it, but it does not solve my problems by itself. At 10mg, I don’t feel great the next day.
Regarding cost, I have tried 5mg pills and 10mg pills split, with no discernable difference. It has been $10 a month with the commercial insurance savings card. It’s very unfortunate that these programs are not available for Medicare patients.
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DSIP has become one of our standards as well.
It has increased our deep sleep and consolidated it in a tighter grouping earlier in the sleep cycle. Both our DS phases used to be more scattered, even into the later hours 6 to 7, now almost all of that phase is in the first 3 - 5 hours and it has increased our time in that phase, from an average of 1:20 hr to 1:57 hr per night.
And I always thought I was a super sleeper but using a sleep tracker before and after shows that while I did get adequate time sleeping and had no complaints, these improvements are interesting to me.
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Hi Steve,
I’m starting into a protocol with DSIP, Pinealon and Epitalon and seeing what the sleep data looks like. Just waiting for the Pinealon to arrive.
I do think with just DSIP, for me, I’ve moved up >50% on deep sleep, and it seems pretty consistent even when I’m getting poor total length of sleep or longer sleep.
I’ve seen recommendations that this is something that is used shorter term, not indefinitely (the DSIP). So this may be something to try an get into a good pattern of sleep, but seems like long term daily use may not be clearly safe.
There are some issues with it potentially affecting LH, GH, cortisol, somatostatin, serotonin and dopamine.
So as part of a shorter term protocol it seems fine, but I’m doubting we’ll get any detailed data on whether long term use is a problem or not.
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I’ve read that as well but I’ve not noticed any downside so far after 3 months of use.
The first month we used it continuously, second month 5 nights a week and the result seemed to be “sticky” as in our DS did not drop much the 2 nights off. Have gone back to every night this last 30 days. Again have not noticed any downside but I also have not done any measuring of anything related other than the DS score which stays pretty consistent. Because the DS seemed to be sticky, I’d be OK with a 5 night a week schedule and a week off every once in a while. Similar to our Ipamorelin + CJC 1295 noDAC schedule
I personally don’t have much confidence in any of the “Kavinson” developed products, Epitalon did not increase my telomers with our last TruD test so I’ve stopped using it. That’s supposed to be one of the results.
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