In this episode, sleep scientist Dr. Matthew Walker reviews a recent study published in the journal iScience (2024) that investigates the metabolic effects of Suvorexant (brand name Belsomra), a dual orexin receptor antagonist (DORA) used for insomnia. The study, conducted by researchers at the University of Tsukuba, involved 14 healthy young men in a randomized, double-blind, placebo-controlled crossover trial inside metabolic chambers.
The core thesis is that Suvorexant does more than induce sleep; it fundamentally alters fuel selection during sleep. The study found that a 20mg dose of Suvorexant significantly increased fat oxidation (fat burning) by approximately 35% and increased REM sleep by nearly 20%, while simultaneously suppressing protein catabolism (muscle breakdown). This suggests a potential âdouble winâ for metabolic health: burning fat while preserving lean muscle mass. However, Walker emphasizes extreme caution, noting the studyâs small sample size (N=14), specific demographic (young healthy men), and the fact that Suvorexant is a prescription drug with side effects, not a weight-loss supplement.
B. Bullet Summary
The Mechanism (DORAs)
DORA Definition: Stands for Dual Orexin Receptor Antagonist.
Orexinâs Role: Orexin (or Hypocretin) is a neuropeptide that acts as the brainâs âwakefulness switch.â
Mechanism of Action: Unlike traditional sleeping pills (benzodiazepines) that sedate the whole brain, DORAs specifically block orexin receptors to âturn offâ the wake drive.
Target: Suvorexant blocks both Orexin-1 and Orexin-2 receptors in the hypothalamus.
The Study Design
Source: University of Tsukuba, published in iScience (2024).
Subjects: 14 healthy young men (mean age ~24.5) with good sleep habits.
Measurement: Participants slept in metabolic chambers using indirect calorimetry to measure gas exchange (O2 consumed vs. CO2 produced) to determine fuel source.
Key Findings
Fat Oxidation: Suvorexant increased fat burning during sleep by roughly 35% compared to placebo.
Persistence: The increased fat burning persisted into the first hour of wakefulness the next morning.
Muscle Sparing: Protein catabolism (muscle breakdown) did not increase; in fact, it was suppressed, suggesting the drug shifts the body to burn fat rather than lean tissue.
REM Sleep: The drug increased REM sleep by ~19.4% in these healthy sleepers.
Sleep Architecture: Unlike some older hypnotics, Suvorexant promoted sleep without crushing REM cycles.
Caveats & Warnings
Demographic Limit: Results are currently only verified in young, healthy males; effects on women, the elderly, or the obese are unknown.
Indication: Suvorexant is FDA-approved for insomnia, not weight loss.
Side Effects: DORAs carry risks including daytime drowsiness and complex sleep behaviors.
Lifestyle Foundation: Walker asserts that medication is never a substitute for diet, exercise, and sleep hygiene.
D. Claims & Evidence Table (Adversarial Peer Review)
Role: Longevity Scientist & Peer Reviewer. Context: Evaluating claims based on the specific iScience 2024 paper and broader medical consensus.
Claim from Video
Speakerâs Evidence
Scientific Reality (Best Available Data)
Evidence Grade
Verdict
âSuvorexant increases fat oxidation ~35% during sleep.â
Cites 2024 iScience study (N=14).
Supported by the specific RCT cited (Park et al., 2024). However, this is a single small trial. No large-scale replication yet exists.
B-(Small RCT)
Plausible (Emerging)
âSuvorexant increases REM sleep (~20%).â
Cites 2024 iScience study.
Broadly Supported. Unlike benzodiazepines which suppress REM, DORAs (Suvorexant, Lemborexant) consistently preserve or increase REM in clinical trials (Herring et al., 2013).
A(Meta-analyses)
Strong Support
âSuvorexant spares muscle (decreases protein catabolism).â
Cites 2024 iScience study.
Supported in this specific context (Park et al., 2024). Orexin signaling is known to regulate muscle glucose metabolism in mice, making this mechanically plausible.
B-(Small RCT)
Plausible (Emerging)
âThis drug could be a weight management aid.â
Speculation based on findings.
Unproven. While acute metabolic changes occur, long-term weight loss data for Suvorexant is lacking. FDA trials did not list weight loss as a primary outcome.
D(Mechanistic)
Speculative / Translational Gap
âSafety Profile.â
General warning given.
Side Effects Exist. FDA label warns of daytime somnolence, sleep paralysis, and âcomplex sleep behaviorsâ (sleep-driving/eating).
Side Effects: The FDA label for Belsomra (Suvorexant) includes warnings for âcomplex sleep behaviorsâ (e.g., sleep-driving, sleep-eating) and worsening of depression/suicidal ideation.
Translational Gap: The metabolic study cited was on healthy men. Obese patients often have different orexin sensitivity (or resistance), so efficacy in the target population for weight loss is currently theoretical.
E. Actionable Insights (Pragmatic & Prioritized)
Top Tier (High Confidence)
Prioritize REM Sleep: REM sleep is metabolically active. Avoid alcohol and traditional sedatives (benzodiazepines/Z-drugs) as they suppress REM sleep, potentially impairing overnight metabolic regulation.
Standard Sleep Hygiene: Continue 10-minute pre-bed meditation (as mentioned in the transcript) and maintain a cool, dark sleep environment to maximize natural orexin suppression at night.
Experimental (High Risk / Doctor Supervision Required)
DORA Protocol for Insomnia: If you already suffer from insomnia and are considering medication, discuss Suvorexant (Belsomra) or Lemborexant (Dayvigo) with your physician.
Rationale: Unlike older drugs, these may offer a metabolic âbonusâ (fat oxidation) rather than a penalty, while preserving sleep architecture.
Note: Do not request this solely for weight loss. It is a Schedule IV controlled substance.
Avoid
Off-Label use for Weight Loss: Do not use Suvorexant strictly as a âdiet pill.â The safety risks (somnolence, parasomnias) outweigh the potential ~35% increase in overnight fat oxidation without further long-term weight loss data.
Narcolepsy: If you have narcolepsy or suspected narcolepsy, you must strictly avoid DORAs, as they will exacerbate symptoms (cataplexy).
H. Technical Deep-Dive
The Orexin/Hypocretin System
The findings in this video hinge on the unique mechanism of the Orexin (Hypocretin) system. Orexin A and B are neuropeptides produced in the lateral hypothalamus. They bind to two receptors:
OX1R: Involved in reward seeking and emotional regulation.
OX2R: The primary driver of sleep/wake stability.
Why the Metabolic Shift?
The study suggests that the Orexin system is a master regulator of the sleep-feeding cross-talk.
Wakefulness: High Orexin promotes wakefulness and carbohydrate preference/seeking.
Sleep: Low Orexin allows sleep and shifts the body toward lipid mobilization (fat burning).
The Drug: By artificially blocking Orexin receptors with Suvorexant, the drug mimics a state of âdeep physiological night,â forcing the metabolic switch from glycolytic (carb) mode to lipolytic (fat) mode more aggressively than natural sleep might in a stressed individual.
Comparison to Other Hypnotics
GABAergics (Ambien/Xanax): Increase global inhibition. Often suppress REM and Slow Wave Sleep (SWS). Do not inherently promote fat oxidation.
DORAs (Belsomra): Targeted inhibition of âwakeâ only. Preserve REM/SWS cycling. Appear to favor fat oxidation (lipolysis) over proteolysis (muscle breakdown).
I. Bibliographic Verification
Primary Study:
Title:Orexin receptor antagonist increases fat oxidation and suppresses protein catabolism during sleep in humans
Matt seems to have a positive view of Dual Orexin Receptor Antagonists (DORAs) which includes suvorexant (Belsomra), the drug studied in this RCT, and doxepin, because he believes they do not disrupt and may in fact improve sleep architecture. He likes trazodone for the same reason, although it seems to act through a different unknown mechanism. I have found trazodone helpful but have not tried any of the DORAs.
Iâm just learning about DORAâs for the first time.
My husband takes ambien, so I just asked our doc to get him on one of these, asap. After watching Matt, I was under the impression these were new, so Iâm shocked to see theyâve been available for a while and no one has talked to him about them!! Grrrrr.
FYI, on goodrx, I see one is over $400 per month, but two of them are $135, cash pay.
Unfortunately, suxvorexant is a controlled substance in the US. It is not available from India in tablet form, at least as far as I can find
You can buy it by the kilo, though.
IMO: For many of the elderly, sleep aids are necessary. No amount of sleep hygiene, CBT, is going to cure the problem. The problem is old age and loss of function. Many people, including me, will require long-term sleep supplements and/or medication. No amount of psycho BS, " cure the root cause," is going to cure it. The root cause is old age, and while rapamycin is very beneficial, it has had no effect one way or another on my sleep.
There are many reasons not to take doxylamine. IMO: Doxepin is a safer alternative, possibly peptides, but there are no long-term studies on sleep-inducing peptides that I could find.
Anticholinergic & central nervous system effects
First-generation antihistamines like doxylamine have strong anticholinergic activity. In older adults, this is linked to:
Confusion, delirium, and worsening cognition
Hallucinations or agitation in vulnerable patients
Daytime sedation, slowed reaction time, and impaired balance
Large observational studies of chronic anticholinergic use (including first-gen antihistamines) show an increased risk of dementia that can persist many years after exposure
Participants 40 770 patients aged 65-99 with a diagnosis of dementia between April 2006 and July 2015, and 283 933 controls without dementia.
As a sleep medication, DORAs are terrible â at least daridorexant. I used it for a few months and the effect eventually stopped completely, like hitting a wall. My body had gotten used to the medication, and without it I was left with strong hyperarousal for a long time. There are lots of bad experiences on Reddit. The drug isnât very popular. Itâs certainly a better option than benzos or Ambien, if it happens to work for you. The medication has to be taken on an empty stomach, otherwise you wonât notice any effect. Sometimes you donât notice any effect even when you take it on an empty stomach. A strange medication.
Thatâs a great heads up, so thanks for sharing your experience.
My husband canât take trazadone (itâs contraindicated with something else he takes), so Iâll hope this works for him.
Doc just called in Quviviq (daridorexant) for him to try. He only rxâd 10 because he said most patients donât like how they feel on them. Also, he said he does not have one patient that likes bellsomra.
If this doesnât work, I imagine heâll try the other 2 options just to be sure.
The main problem for most people is that lemborexant is a controlled substance and expensive for most people.
"Lemborexant and controlled substance classification
Federal scheduling: The Drug Enforcement Administration (DEA) officially placed lemborexant in Schedule IV of the Controlled Substances Act through a final rule that became effective on March 3, 2021. Schedules of Controlled Substances: Placement of Lemborexant in Schedule IV
âFederal Register :: Request Accessâ
Abuse potential: While a clinical study found that lemborexant has an abuse potential similar to other Schedule IV sedatives like suvorexant and zolpidem, the risk of developing dependence and misuse is considered low. Some studies also suggest it may have a lower potential for abuse than benzodiazepines.
Prescription restrictions: As a controlled substance, lemborexant is subject to certain federal and state restrictions. These may include limits on the number of pills per prescription and restrictions on refills
Doxepin is also one of the worst sleep medications I know; I donât understand how it can help anyone sleep at all. In general, I would leave sleep medications as the very last option. The body gets used to them and their effect wears off sooner or later, and once youâve learned to sleep with medication, sleeping without them becomes impossible. Maybe not everyone ends up like this, but I did, and getting out of that mess took a long time â Iâm still trying to recover. Iâve tried practically every âsleep medicationâ available in Europe. In the end, the only path to improvement has been meditation, though you shouldnât expect any quick results; it requires regular practice.
If your husband is used to taking Ambien, switching directly to daridorexant wonât work. Iâd recommend starting with, for example, half an Ambien plus daridorexant, and then gradually tapering off the Ambien. If dependence has already developed, itâs impossible to sleep without it. Daridorexant works in a very different way. It has to be taken on an empty stomach, and you need to be in bed on time; falling asleep happens naturally, if it happens. If you miss the right time window, for example by watching TV or something similar, the medication wonât have any effect later. At least thatâs how it is for me, and many others have reported the same. But at its best, the medication allows you to sleep in a very natural way and wake up feeling refreshed.â
I took ambien for aprox 15 years⌠then switched to edibles⌠then switched to trazadoneâŚthen got off trazadone, too.
And to your point, yes, I went through a few months where I had many nights with less than 4 hours of sleep to break the cycle. I was a zombie.
In the meantime, for the husband, almost anything is worth a shot to get him off ambien⌠so DORAs it shall be!
@desertshores they are crazy expensive! At least we can get lemborexant and daridorexant for $135 per month, vs over $400 for belllsomra. Once we know which, if any, of these work for him, then Iâll try ordering from KnippeRX as David shared
Sorry for your sleep problems. Since meditation works for you, it is possibly just a psychological problem, not the problems old age and loss of function create.
When it comes to psych meds for sleep, they donât work for everyone, just as particular antidepressants donât work for everyone.
Both doxepin and quetiapine work for me. But doxepin is the safer of the two. Doxepin is a tricyclic antidepressant drug used to treat depression, anxiety, and insomnia.
Have you tried quetiapine? It is not an antidepressant. A 50 mg tablet, which I obtained from India, knocks me out all night. 50 mg of quetiapine is considered a low dose. It is a dose used for sleep. This dose is smaller than the doses used for therapeutic purposes.
âatypical antipsychotic medication used primarily to treat schizophrenia and bipolar disorder. It is available in both immediate-release and extended-release forms and works by rebalancing levels of dopamine and serotonin in the brain to improve mood, thinking, and behavior.â
They are expensive. For me, daridorexant cost âŹ300 per month. When the effect wore off, I first spent a few weeks getting about 2 hours of sleep per night, and eventually I went three days with 0 hours of sleep. I was close to psychosis and had to start diazepam, because nothing else, less harmful, had worked. I then tapered it off slowly once I got my mental state stabilized.
Of course, I have tried quetiapine, it messes with my head, but for sleep it does absolutely nothing. Itâs not really a sleep medication to begin with, just like most of the drugs that are used arenât. Also, it makes my nose so blocked that itâs already hard to sleep because of that. The same thing happens with trazodone, it makes my nose congested.
Just incase itâs helpful, Iâve shared this previously, but in addition to many things turning my sleep around, including rapa, the addition of LDN last year was a game changer. It doesnât work for everyone but youâll take this stuff out of my cold dead hands.
