CR-induced elevated cortisol and sleep

[Zeta]

I've suffered from early waking insomnia all my life. Until a few years ago, it was fairly minor, and manageable. But a few years ago, in connection with some other andropause-like changes I went through, I started to wake and not get back to sleep after 4-5 hours of sleep instead of 6-7 (8 hours is optimal for me). I was also losing weight, though I don't think I was eating less. I think I moved into an aged phenotype all at once. (Long story there.)

 

Regardless of the strange changes that took place a few years ago, the early waking, which was always a problem, became worse. I've had my early morning cortisol tested several times over the last few years, and it's always been above the reference range. This is no big surprise for a person on CR: low blood sugar causes an increase in cortisol (which keeps blood sugar from falling "too low").

 

It's not that I'm tense, it's not that I'm hungry (well, I am, but I always am). I'm just awake.

 

Well, my 2:1 diet plan has yielded some interesting results. The night after Feast Day 2, I sleep beautifully! The night after Feast Day 1, I often sleep fairly well. The night after the fasting day (right now around 700 calories/day), I sleep worse than ever. I wake too early, and can't get back to sleep. I'm happy, non-tense, not really hungry even. Just really awake.

 

So now I'm thinking I might take timed-release zolpidem or something on fasting days before going to bed. But I'm wondering if anyone else has tried any cortisol lowering strategies that have helped with sleep. A lot of supplements that supposedly lower cortisol seem to do so (if they work at all...) by lowering stress. I'm not stressed. Phosphatidylserine blunts the post-exercise cortisol spike, but it’s not clear it would help with low glucose-induced cortisol.

 

Suvorexant might be a better choice than timed-release zolpidem (or one of the other Z-drugs), but I haven't studied the relation between orexin and cortisol enough to know whether it would help me.

 

Any CR folks with early morning insomnia have any strategies they'd like to share?

[bdambrosio]

have you tried melatonin? I find 75 mcg (yes, that's an incredibly low dose hard to find, most people massively overdose on the over-the-counter stuff) knocks me out for about 4 hours. I generally take it when I wake at about 3-4am. 

 

I've also had success with various mental "relaxation" practices, but they can be difficult, not for everyone

[Saul]

Well said, bdambrosio.

 

I take melatonin, 300mcg, and sometimes insight meditation.  I learned this practice after attending several sessions at the Kripalu Center for Yoga and Health, and purchasing an inexpensive recommended book.

 

BTW, I'll be at Kripalu, for R&R,  this Tuesday to Friday, Aug 11-14.

 

 -- Saul

 

 --

[Zeta]

I'm a lifelong insomnia sufferer. Believe me, I've tried melatonin (many doses and timings and timed-releasedness). No effect. And I'm relaxed, so relaxation techniques aren't needed. (I've tried them anyway: no effect.)

 

I'm surprised that of all the CR practitioners out there, few seem to have suffered from the specific condition I'm describing: "wakefulness" because of cortisol ramping up too early in the morning (presumably because of hunger -- though see Michael's thoughts on that in a diff. thread; I'll chime in there in a couple days after more reading).

 

Anyone?

 

Phosphatidylserine? Suvorexant?

 

Zeta

[Dean Pomerleau]

I'm surprised that of all the CR practitioners out there, few seem to have suffered from the specific condition I'm describing: "wakefulness" because of cortisol ramping up too early in the morning (presumably because of hunger)

 

Anyone?

 

Hi Zeta,

 

I too suffer on occasion from 'early waking' syndrome. I normally sleep around 6.5h overnight, and about once or twice a week I wake early, and only get 4-5 hours of sleep. I think its pretty common that CR practitioners seem to get/need less sleep. It seems to be correlated with being most severely CR'ed, and/or carbohydrate restricted. When I (rarely) eat a small, carb-rich snack in the evening, it is definitely less likely to happen. 

 

But I've come to live with it, and realize I don't seem to be adversely affected by the lack of sleep. On those days, I don't fret about it, but instead get up and start my date early, grateful to have an extra hour or two in my day. Perhaps surprisingly, I don't find myself feeling more sleepy on those days, in fact they are often my most productive.

 

I'm blessed with the ability to fall asleep quickly, and have gotten into the habit of taking a 25-30min 'power nap' around mid-day, even on days when I get my usual 6.5h of nighttime sleep. I find a short nap like that to be quite refreshing, while longer naps tend to impair my performance via sleep inertia.

 

So two questions:

• Does your early waking interfere with your daytime productivity? If not, see if you can come to just accept it as a side effect of CR, and even view it as a benefit (more hours in the day).
• Have you considered incorporating a short nap into your daytime routine?

One other thing you might try, recommended to me by Paul McGlothin, but which didn't work for me, is Sandalwood scent. Its a commonly recommended aromatherapy sleep aid, which some scientific support:

 

http://www.ncbi.nlm.nih.gov/pubmed/17879595

 

Per Paul's recommendation, I bought a bar of Sandalwood soap, unwrapped it, and put it on my nightstand. It didn't seem to make a difference to my early waking, but your mileage may vary.

 

--Dean

[Saul]

 Hi Dean!

 

I actually wake up many times during the night -- with the need to urinate.  I've gotten used to practically sleepwalking into my nearby bathroom, barely awake, returning, and promptly falling back asleep.  (Unfortunately, this frequently disturbs my lightly sleeping, insomniac wife.)

 

The reasons for the need to urinate: 

(1)  Enlarged prostate -- that's been the case since youth.  (But my PS1 is fine; and frequent checking shows nothing abnormal in my prostate (female GP has the unenviable task of pushing a finger you-know-where  :).)

(2) I eat a lot of raw vegetables -- this produces a lot of urine (and bowel movements, during the day). 

 

I frequently "suffer" from 'Dean's syndrome' :)  -- waking up too early -- but I rarely have trouble getting back to sleep (this is a necessity in my case -- it's unreasonable to wake up early, disturbing my insomniac wife).

 

Wake up time in my family is 6AM -- my wife has to be at work (in Rochester General Hospital) at 8AM.

During the school year, I teach (at the University of Rochester) at 9AM.

 

The bottom line in my case:  Necessity has forced me to develop a sleeping cycle, adjusting to returning to sleep after awakening.

 

(But often, when I wake around 4:30 or later, I an fully awake -- sometimes managing to fall asleep again (after urinating), but sometimes remaining silent in bed.  Often insight meditation helps me fall asleep when I'm too awake -- whether at bedtime, or at 4:30AM.)

 

  -- Saul

[Zeta]

Hey guys, thanks for the comments and suggestions. Glad to know I'm not alone in this sleep problem.

 

Dean, you raise some good questions:

 

• Does your early waking interfere with your daytime productivity? If not, see if you can come to just accept it as a side effect of CR, and even view it as a benefit (more hours in the day).
• Have you considered incorporating a short nap into your daytime routine?

 

My sleep and fatigue situation is complicated right now because I'm so anemic. (I'll have answers about the anemia by the end of the month.) Plus, I have reason to believe I'm at great risk of Alzheimer's, and sleep-deprivation seems particularly dangerous for those at risk of Alz.

 

But, in point of fact, I realize the lower amount of sleep after a fasting day often – by no means always, but often – doesn't "feel" so bad. (But the same amount of sleep after a feast day would feel bad, or worse.)

 

And yes, I nap whenever I feel I need to.

 

By the way, I now have enough data points to be pretty certain that the following pattern is robust:

- Night after fasting day: wake early and not be able to get back to sleep. 4.5-5 hours sleep total (not including any afternoon nap).

- Night after feast day #1: wake early (as always -- to pee, or because of neighbors), but get back to sleep. 6-6.5 hours sleep total.

- Night after feast day #2: wake early (as always -- to pee, or because of neighbors), but get back to sleep. 6.3-7 hours sleep total.

(Times plus or minus 20 or so mins.)

 

I will try the Sandalwood scent!

 

Thanks again,

Zeta.

 

[James Cain]

I'm surprised that of all the CR practitioners out there, few seem to have suffered from the specific condition I'm describing: "wakefulness" because of cortisol ramping up too early in the morning (presumably because of hunger -- though see Michael's thoughts on that in a diff. thread; I'll chime in there in a couple days after more reading).

 

Anyone?

 

Hi Zeta. You've gotten some great responses so far, but some of my thoughts:

 

CR is known to phase advance circadian rhythms (leading to earlier wake times) in proportion to the severity of the CR.

You can sift through some of these for more info: https://scholar.google.com/scholar?q=calorie+restriction+circadian+rhythms

 

As suggested by other posters, and especially in our old email list archives, many Cronies suffer from early waking if 1) they restrict calories severely, 2) they eat most of their food earlier in the day or stop eating fairly early, or 3) restrict carbohydrates too excessively (but this varies between individuals). I experience all of these things, as expected. Delaying morning light, physical activity, or breakfast time, and eating later in the evening may help delay your circadian phase. Another option Saul mentioned which I'm about to experiment with myself is to take melatonin upon sleep as well as to take a smaller dose during mid-night waking.

 

 

• Does your early waking interfere with your daytime productivity? If not, see if you can come to just accept it as a side effect of CR, and even view it as a benefit (more hours in the day).
• Have you considered incorporating a short nap into your daytime routine?

 

Plus, I have reason to believe I'm at great risk of Alzheimer's, and sleep-deprivation seems particularly dangerous for those at risk of Alz.

 

But, in point of fact, I realize the lower amount of sleep after a fasting day often – by no means always, but often – doesn't "feel" so bad. (But the same amount of sleep after a feast day would feel bad, or worse.)

 

And yes, I nap whenever I feel I need to.

 

Lack of sleep is a known risk factor for Alzheimer's. I'd speculate that Cronies who experience normal or elevated energy levels and mental clarity while sleeping less are fine, probably indicative of either enhanced sleep efficiency or a reduced need for sleep. Your feeling fine with less sleep probably mean's you're fine, IMO.

[Saul]

Hi ALL!

 

I would strongly suggest attempting Meditation as a method of falling asleep.  I learned Insight Meditation from lectures at Kripalu -- but I found the best sourse from learning to practice this in a small, inexpensive book (that was recommended for a workshop that I didn't take at Kripalu):

 

"Mindfullness in Plain English", by someone with an Indian sounding name (I have the book somewhere).

 

Dean:  I remember that you at least used to do some kind of Bhuddist mediation -- maybe this book might be as useful  to you as it was to me.

 

:)

 

  -- Sauk

[Dean Pomerleau]

 

Dean:  I remember that you at least used to do some kind of Bhuddist mediation -- maybe this book might be as useful  to you as it was to me.

 

Good memory Saul. You're right - I did, and do, meditate - several times a day in fact, and find it quite beneficial. 

 

--Dean

[Zeta]

CR is known to phase advance circadian rhythms (leading to earlier wake times) in proportion to the severity of the CR.

You can sift through some of these for more info: https://scholar.google.com/scholar?q=calorie+restriction+circadian+rhythms

 

James, thanks for the interesting comments. I hadn't realized how common the effects on sleep of CR (and various patterns of eating) are. Having looked into it more (including following your links), I now have a good tentative plan. I'm going to eat both my two meals during my "fasting" day later than I'd been doing (and I'll continue taking a second dose of melatonin when I wake to pee). So the "survival mode" benefit of (quasi) fasting will be more in the early part of the day, not in the evening. Because of GERD problems (very minor, but I want to keep them in check), I'm still going to stick to the rule of eating my last meal more than 3 hours before bedtime, but it will be later than it was. But maybe I'll experiment with eating even later.

 

Interestingly, the day after a fasting day, after getting 4-4.5 hours of sleep (more data points now: the pattern has become even more robust), I feel weirdly good! I'm so non-sleepy I can't even take a nap late in the afternoon, even with a siesta-inducing stuffed belly, and without and wiredness from cortisol. It's kind of cool.

 

 

 

Lack of sleep is a known risk factor for Alzheimer's. I'd speculate that Cronies who experience normal or elevated energy levels and mental clarity while sleeping less are fine, probably indicative of either enhanced sleep efficiency or a reduced need for sleep. Your feeling fine with less sleep probably mean's you're fine, IMO.

 

The "if it feels good..." concept doesn't work for me, because of my complicated health problems. I never really feel good these days. But I think you're right that ~4 hours of sleep and feeling less like crap (what I call "good") is less of an Alz. worry than ~4 hours of sleep and feeling more like crap.

 

But I'd still like an answer to my main question: what can lower CR-induced (CR-via-low-glucose-induced) elevated cortisol, or block its actions, in order to improve sleep? (Meditation is irrelevant here, of course -- though it's great for other reasons!)

 

Zeta

[Zeta]

Just a quick update. The pattern I noted above - good sleep after my two feast days, less (but not necessarily so bad) after my fast day, has continued, but my sleep has improved overall. I'm not sure why, though I think it's simply because my overall average energy-intake is slightly higher on my feast days. Eating later on my fasting days may be contributing to slightly longer (though still in the neighborhood of 4-4.5 hours) sleep after a fasting day, but I'm not sure.

 

Feast Day 1: ~4050 calories, 67-68% fat. Stop eating 3 or so hours before bedtime.

Feast Day 2: ~3850 calories, 62-65% fat. Stop eating 4 or so hours before bedtime. (4 instead of 3 hours to get a longer period without food.)

Fasting Day: ~500 calories (was ~800), 20% fat. Start eating 7-8 hours before bedtime (will push that back even more), stop eating 2-3 hours before bedtime.

 

I'm also now taking phosphatidylserine at bedtime, to lower cortisol (even though there's not much evidence it would make a difference). Not sure yet what kind of effect that's having.

 

My sense - I need more data points, though - is that eating later (every day, but the biggest change is on my fasting day) isn't responsible for the improvement. Rather, it's the overall increase in energy-intake. I tried a late night carb snack before bed on fasting days, and that didn't seem to affect the early morning cortisol-induced waking. I sense that CR itself was having a "non-temporally local" effect on my sleep that is now improving as I move away from CR towards quasi-IF. But I need much more data to be sure.

 

Zeta

[Zeta]

I'm also now taking phosphatidylserine at bedtime, to lower cortisol (even though there's not much evidence it would make a difference). Not sure yet what kind of effect that's having.

 

I can report that phosphatidylserine has had no noticeable effect.

 

My sleep after a feast day continues to improve (a few times nearly 8 hours!!), and my sleep after the fasting day is actually getting a bit worse.

 

I'm convinced now more than ever that the problem is the cortisol spike. Eating small carb snacks late in the evening hasn't helped. Larger "snacks" would defeat the purpose of the fasting day, so, at least for now, I need something to 1) knock down cortisol, 2) block its action, or 3) make it irrelevant (i.e., just use Z-drugs or the like).

 

I know zopiclone reliably gives me at least 4 hours of sleep after a fasting day, instead of (what now has shrunk down to) 2.5-3-5 hours.

 

Next things I'd like to try:

 

- suvorexant (Approach #3).

- cannabis  (Approach #3, possibly also #1) (it's the cannabidiol that might be most effective, not the THC).

- oxytocin. (Approach #1). (This I really want to get my hands on for many reasons -- fascinating results with some - a minority, but still - CFIDS-sufferers! But I don't have insurance....)

 

Zeta

[Dean Pomerleau]

Zeta,

 

My sleep after a feast day continues to improve (a few times nearly 8 hours!!), and my sleep after the fasting day is actually getting a bit worse.

 

<snip> 

 

I know zopiclone reliably gives me at least 4 hours of sleep after a fasting day, instead of (what now has shrunk down to) 2.5-3-5 hours.

 

I'm sorry to hear your troubles with insomnia on after your fasting days continue, and may be getting worse. 2.5 - 3.5 hours of sleep is indeed a small amount.

 

Interestingly, I too have been finding that I'm having more trouble sleeping through the night recently, compared to the time of the CR sleep poll conducted a few months ago, when I was regularly getting 6.5 - 7 hours per night. I seem to be down to 5.5 - 6.5, with some nights much less. Last night my Fitbit told me I only got 3.5 hrs, and I (roughly) estimate that to be correct. For me I'm not sure that it is a result of elevated cortisol, as you suspect for yourself. I'm quite calm and relaxed in bed for substantially longer than I'm actually asleep, it is just that my consciousness doesn't seem  to be shutting back down once I've woken up after a few hours of deep, restful and unconscious sleep. 

 

I don't usually feel tired with the reduced sleep I've been getting lately, but this morning (after only 3.5 hr of sleep last night), I was definitely feeling it. I decided to take a longer nap today, rather than my usual 20-30 minute mid-day power nap. I slept for about 80 minutes at mid-day, enough for a complete sleep cycle. I was worried that I'd experience sleep inertia and be groggy all afternoon, but after a few minutes I felt quite refreshed and energized again.

 

Have you tried longish mid-day naps? Some people find biphasic sleep to be pretty natural. Some people even call it the "Getting Shit Done" sleep cycle. I find after I've eaten in the morning and exercised to bring down my glucose, I'm quite easily able to get a restful mid-day nap that seems to greatly mitigate the deleterious effects of getting less sleep that I'd prefer the night before.

 

--Dean

[Zeta]

I'm sorry to hear your troubles with insomnia on after your fasting days continue, and may be getting worse. 2.5 - 3.5 hours of sleep is indeed a small amount.

 

I forgot to add one critical thing: I went off mirtazapine last week (having started tapering ~18 days ago from an already low dose of 7.5 mg.). I'm hoping that's part of the explanation, and that I'll adjust.

 

Anyway, Dean, I'm sorry to hear that you, too, are having some sleep problems.

 

I realize there's been a misunderstanding (which I tried to fend off earlier, I believe, but failed):

 

 

For me I'm not sure that it is a result of elevated cortisol, as you suspect for yourself. I'm quite calm and relaxed in bed for substantially longer than I'm actually asleep, it is just that my consciousness doesn't seem  to be shutting back down once I've woken up after a few hours of deep, restful and unconscious sleep.

 

I've been puzzled by something, and now I think I know the answer: why has tthere appeared not to be much resonance here among other CR practitioners with this sleep problem I'm describing? Surely it's not a rare problem, thought I. Part of the explanation is of course that our community here is still small. But a more important explanation, I now see, is likely that people are reacting, once they see the word "cortisol", in something like the following way: "Poor Zeta, wakes up after a few hours feeling stressed out and can't get back to sleep."

 

Very much needed clarification: I am completely relaxed, and, above, all, mentally calm - to the best of my self-awareness - when I wake up too early! Cortisol released because of low blood glucose does not (at least not in me) produce a feeling of stress or lack of calm or anything like that!! I'm just awake. (Well, sometimes, I'm tired, but not sleepy, or, main point: just can't fall asleep!) When people tell me to breathe deeply or meditate for five minutes (and many have...), they're missing the point.

 

So, Dean, and others reading this who might have sleep problems: feeling calm and not being able to get back to sleep despite not having slept enough is not an indication that elevated cortisol isn't causing the problem. (Double-negative isn't the same as a positive here: it might still not be the problem. Or it might be. I think it probably is for many of us.)

 

So, join me in finding a way of dealing with this!!! (Strategies #1, #2, or #3 mentioned earlier - or other strategies you might come up with)

 

Forgot to mention Relora, which I just got and will be trying tomorrow.

 

 

About napping: that's been a key part of my sleep strategy for years, but I no longer can nap longer than 20-30 minutes.

 

Amazingly, though, yesterday, after my 22-minute nap, I felt nearly fine. Really weird! I had a normal day, despite a total of 170 minutes of sleep. But I can't nap early enough to save more than half or so of the day (interestingly: I used to need a nap 3 or so hours after waking -- that, starting in the late 1990s; but now my first meal is later, and is low-carb on feast days, which might have eliminated the postprandial fatigue from all the grains I used to eat that made me want to nap).

 

Fingers crossed for Relora.

 

- Zeta

[Dean Pomerleau]

Thanks Zeta,

 

Very much needed clarification: I am completely relaxed, and, above, all, mentally calm - to the best of my self-awareness - when I wake up too early! Cortisol released because of low blood glucose does not (at least not in me) produce a feeling of stress or lack of calm or anything like that!! I'm just awake. (Well, sometimes, I'm tired, but not sleepy, or, main point: just can't fall asleep!) When people tell me to breathe deeply or meditate for five minutes (and many have...), they're missing the point.

 

I have definitely misunderstood, at least in terms of your symptoms, and quite possibly the cause as well. I've always associated high cortisol levels with feeling 'wired'. But I realize now this could be totally mistaken. Maybe cortisol just makes you feel alert, and its other endocrine changes (e.g. noradrenaline or adrenaline) that are also associated with the 'fight or flight' reflex that creates the feeling of being 'wired'. 

 

Since I haven't looked into it, I'm not sure about the answer this this question - how does cortisol make a person feel when it (and it alone) is elevated? Question 2: Zeta, do you have evidence that it is elevated cortisol that is causing your sleep problem?

 

Perhaps it doesn't matter - all this talk of cortisol is secondary to the fact that you (and sometimes I), have trouble sleeping (specifically getting back to sleep once awakened), and perhaps more importantly for you, what you can do to eliminate it.

 

Forgot to mention Relora, which I just got and will be trying tomorrow.

 

 I hope Relora does the trick. That first study you pointed to [1] appears to have observed some pretty impressive results for people suffering from high cortisol. Strange they didn't measure sleep parameters. Unfortunately the earlier study [2] that did measure sleep found no benefit from Relora among the anxious, healthy women who took it in a double blind trial. I'll be curious how it works for you.

 

If you ever want to do an experiment on yourself with compounds like Relora in a single-blind, crossover fashion, let me know. If the pills in question have a similar appearance, or even just similar shape to some other pill or tablet you're willing to take (to serve as the placebo), I can explain the procedure I've used in the past to hide from myself which supplement I'm taking first vs. second during an "N-of-1" self experimentation crossover trial.

 

But in this case, perhaps a placebo-induced improvement in your sleep quantity would be just as good as a 'real' cure!

 

As for me, I mentioned earlier that with a short (or sometime long-ish) nap at mid-day, I don't seem to be negatively impacted after a night of (apparently) little sleep. I'm not even sure which if any of the restorative benefits of sleep I'm missing on a night when it feels like I'm awake and alert (i.e. conscious) but nevertheless relaxed and still, for much of the night. Empirically such a night seems pretty restorative, based on the fact that the following day I don't seem to experience ill effects. So I've come to just accept them when they occur.

 

--Dean

 

-------------

[1] J Int Soc Sports Nutr. 2013 Aug 7;10(1):37. doi: 10.1186/1550-2783-10-37.

Effect of Magnolia officinalis and Phellodendron amurense (Relora®) on cortisol
and psychological mood state in moderately stressed subjects.

Talbott SM(1), Talbott JA, Pugh M.

Author information:
(1)SupplementWatch, 648 Rocky Knoll, Draper, UT 84020, USA.
smtalbott@supplementwatch.com.

BACKGROUND: Magnolia (Magnolia officinalis) and Phellodendron (Phellodendron
amurense) barks are medicinal plants commonly used as traditional remedies for
reducing stress and anxiety. Modern dietary supplements are intended to induce
relaxation and reduce stress as well as stress-related eating. Previous studies
have shown the combination of Magnolia/Phellodendron (MP) to reduce both cortisol
exposure and the perception of stress/anxiety, while improving weight loss in
subjects with stress-related eating. Competitive athletes are "stressed" by their
intense exercise regimens in addition to their normal activities of daily living
and thus may benefit from a natural therapy intended to modulate baseline
perceptions of stress and stress hormone exposure.
METHODS: We assessed salivary cortisol exposure and psychological mood state in
56 subjects (35 men and 21 women) screened for moderate stress and supplemented
with a standardized/patented MP combination (Relora®, Next Pharmaceuticals) or
Placebo for 4 weeks.
RESULTS: After 4 weeks of supplementation, salivary cortisol exposure was
significantly (p<0.05) lower (-18%) in the Relora group compared to Placebo.
Compared to Placebo, the Relora group had significantly better (p<0.05) mood
state parameters, including lower indices of Overall Stress (-11%), Tension
(-13%), Depression (-20%), Anger (-42%), Fatigue (-31%), and Confusion (-27%),
and higher indices of Global Mood State (+11%) and Vigor (+18%).
CONCLUSION: These results indicate that daily supplementation with a combination
of Magnolia bark extract and Phellodendron bark extract (Relora®) reduces
cortisol exposure and perceived daily stress, while improving a variety of mood
state parameters, including lower fatigue and higher vigor. These results suggest
an effective natural approach to modulating the detrimental health effects of
chronic stress in moderately stressed adults. Future studies should examine the
possible performance and recovery benefits of Relora supplementation in athletes
overstressed by the physical and psychological demands of training and
competition.

PMCID: PMC3750820
PMID: 23924268 

 

--------------

[2] Nutr J. 2008 Apr 21;7:11. doi: 10.1186/1475-2891-7-11.

Effect of a proprietary Magnolia and Phellodendron extract on stress levels in
healthy women: a pilot, double-blind, placebo-controlled clinical trial.

Kalman DS(1), Feldman S, Feldman R, Schwartz HI, Krieger DR, Garrison R.

Author information:
(1)Director, Nutrition, Miami Research Associates, Miami, FL, USA.
dkalman@miamiresearch.com

BACKGROUND: Recent research has established correlations between stress, anxiety,
insomnia and excess body weight and these correlations have significant
implications for health. This study measured the effects of a proprietary blend
of extracts of Magnolia officinalis and Phellodendron amurense (Relora) on
anxiety, stress and sleep in healthy premenopausal women.
METHODS: This randomized, parallel, placebo controlled clinical study was
conducted with healthy, overweight (BMI 25 to 34.9), premenopausal female adults,
between the ages of 20 and 50 years, who typically eat more in response to
stressful situations and scores above the national mean for women on
self-reporting anxiety. The intervention was Relora (250 mg capsules) or
identical placebo 3 times daily for 6 weeks. Anxiety as measured by the
Spielberger STATE-TRAIT questionnaires, salivary amylase and cortisol levels,
Likert Scales/Visual Analog Scores for sleep quality and latency, appetite, and
clinical markers of safety. The study was conducted by Miami Research Associates,
a clinical research organization in Miami, FL.
RESULTS: The intent-to-treat population consisted of 40 subjects with 26
participants completing the study. There were no significant adverse events.
Relora was effective, in comparison to placebo, in reducing temporary, transitory
anxiety as measured by the Spielberger STATE anxiety questionnaire. It was not
effective in reducing long-standing feelings of anxiety or depression as measured
using the Spielberger TRAIT questionnaire. Other assessments conducted in this
study including salivary cortisol and amylase levels, appetite, body morphology
and sleep quality/latency were not significantly changed by Relora in comparison
to placebo.
CONCLUSION: This pilot study indicates that Relora may offer some relief for
premenopausal women experiencing mild transitory anxiety. There were no safety
concerns or significant adverse events observed in this study.

PMCID: PMC2359758
PMID: 18426577

[Brett Black]

I forgot to add one critical thing: I went off mirtazapine last week (having started tapering ~18 days ago from an already low dose of 7.5 mg.).

I'd be concerned about mirtazapine, it has shown to be carcinogenic in both mice and rats. I was under the impression that, toxicologically, seeing carcinogenic effects in two species is often considered a potentially serious sign. The fact that both species also developed the same type of cancer and the dose may not have been sufficiently high in mice just adds to that concern. Yet it still obviously got FDA approval... 

 

Carcinogenicity studies were conducted with mirtazapine given in the diet at doses of 2, 20, and 200 mg/kg/day to mice and 2, 20, and 60 mg/kg/day to rats. The highest doses used are approximately 20 and 12 times the maximum recommended human dose (MRHD) of 45 mg/day on a mg/m2 basis in mice and rats, respectively. There was an increased incidence of hepatocellular adenoma and carcinoma in male mice at the high dose. In rats, there was an increase in hepatocellular adenoma in females at the mid and high doses and in hepatocellular tumors and thyroid follicular adenoma/cystadenoma and carcinoma in males at the high dose. The data suggest that the above effects could possibly be mediated by non-genotoxic mechanisms, the relevance of which to humans is not known.

The doses used in the mouse study may not have been high enough to fully characterize the carcinogenic potential of mirtazapine tablets.

http://dailymed.nlm.nih.gov/dailymed/archives/fdaDrugInfo.cfm?archiveid=20642

[Zeta]

First, Brett: like, wow! Thank you! I'm stunned and surprised at myself for not having looked into mirtazapine closely enough to have uncovered the cancer risk. Very unlike me. It's a sign of my desperation about sleep. For other reasons, I'd been planning not to go back on mirtazapine, but you've given me another reason (even though at 7.5 mg., the risk is probably very low).

 

 

Since I haven't looked into it, I'm not sure about the answer this this question - how does cortisol make a person feel when it (and it alone) is elevated? Question 2: Zeta, do you have evidence that it is elevated cortisol that is causing your sleep problem?

 

Perhaps it doesn't matter - all this talk of cortisol is secondary to the fact that you (and sometimes I), have trouble sleeping (specifically getting back to sleep once awakened), and perhaps more importantly for you, what you can do to eliminate it.

 

#1. I'm not sure, to be honest. But I think it would generally create a feeling of being alert.

 

#2. My evidence is: A) It's a very plausible mechanism, and B) the two times I've had morning cortisol tested in the last few years it's been really, really high - well above the reference range. (Doctor: "Did you sprint to the lab that morning???" - No, my girlfriend drove me and I sat peacefully waiting for my turn with the phlebotomist.)

 

Not convincing evidence at all, of course. But enough that it's the best hypothesis I have.

 

 

Your idea about helping with an experiment is excellent and much appreciated! We should start doing more of that. (We all need to live together in some sort of co-housing arrangement!) In this case, though, it won't be practical because of my travel plans, and because I only plan to take Relora after a fasting day, so it would take a long time to generate meaningful data.

 

 

As for me, I mentioned earlier that with a short (or sometime long-ish) nap at mid-day, I don't seem to be negatively impacted after a night of (apparently) little sleep. I'm not even sure which if any of the restorative benefits of sleep I'm missing on a night when it feels like I'm awake and alert (i.e. conscious) but nevertheless relaxed and still, for much of the night. Empirically such a night seems pretty restorative, based on the fact that the following day I don't seem to experience ill effects. So I've come to just accept them when they occur.

 

I may end up with the same attitude. Last post-fasting day, like I said, I got very little sleep, but I got by pretty much fine.

 

Zeta

 

[Dean Pomerleau]

#2. My evidence [that my cortisol is likely elevated and causing my insomnia] is: A) It's a very plausible mechanism, and B) the two times I've had morning cortisol tested in the last few years it's been really, really high - well above the reference range. (Doctor: "Did you sprint to the lab that morning???" - No, my girlfriend drove me and I sat peacefully waiting for my turn with the phlebotomist.)

 

Not convincing evidence at all, of course. But enough that it's the best hypothesis I have.

 

That (particularly B) sound like pretty reasonable evidence to me. As whether its cortisol or something else that's keeping you awake probably doesn't matter anyway.

 

 

Your idea about helping with an experiment is excellent and much appreciated! We should start doing more of that. (We all need to live together in some sort of co-housing arrangement!) In this case, though, it won't be practical because of my travel plans, and because I only plan to take Relora after a fasting day, so it would take a long time to generate meaningful data.

 

It doesn't require colocation. In fact, while its easier to do it with a partner, it can be done alone with a little more effort. Why does that sound rather salacious? Seriously, if you (or anyone else) ever wants to try a single-blind experiment on themselves (e.g. testing the effectiveness of a supplement vs. a placebo control), let me know. I've done it in the past without anyone's help, and have a protocol for it. But it sounds like this is not such a time for you.

 

Good luck and let us know how the Relora works for you.

 

--Dean

[Zeta]

Well, one can't expect miracles, but Relora Attempt #1: fail. Total sleep last night: 125 minutes. Argh....

 

Took 125 mg. (half a pill) around 20:00, then 300 mg. at 01:20 (bedtime last night). Actually didn't even fall asleep within 5-8 or so minutes -- took 25 or so mins. (unusual for me), though I doubt that was a consequence of the Relora. Woke up an hour or so later to pee, then an hour or so later again, and that was it.

 

This is irritating. I may just end up using a Z-drug (zopiclone is what I have on hand) every 3rd day. 200-270 mins. of sleep every third day was working fine. But now it's down to two hours....

 

It also occurs to me that I could push my meals -- actually it's down to one meal, pretty much -- on the fasting day way, way back so that I'm eating from 22:00-23:00 or even later. I ruled that out initially for various reasons, but getting better sleep without drugs might be worth whatever GERD, etc. concerns I might have about late night eating.

 

- Zeta

[Dean Pomerleau]

In light of the discussion in this thread about just how much contribution elevated cortisol has in CR-related sleep difficulties, the results of this new meta-analysis [1] just posted by Al Pater on the relation between CR and cortisol in humans seem quite relevant.

 

Two findings from the analysis seem particularly relevant to these discussions:

1. Fasting (for what appears to be 3-6 days based on graph below) resulted in elevated cortisol, but a low calorie diet (LCD, defined as > 800kcal/day) or very low calorie diets (VLCD defined as < 800kcal/day) did not, especially if extended in duration (see #2).  The http://www.tandfonline.com.sci-hub.io/doi/abs/10.3109/10253890.2015.1121984hasforest plots for the three conditions - I haven't included them here. 
2. It appeared that subjects' cortisol level returned to baseline after they've been following a LCD or VLCD for an extended duration. The details are illustrated in the graph from the paper included below, showing that at least by three weeks (and perhaps earlier), subjects in studies for LCD or VLCD has cortisol levels indistinguishable from baseline.

So it is curious Zeta that you continue to exhibit symptoms (and measurements it sounds as well) of elevated cortisol, given that your overall calorie intake is not particularly restricted, and even on your "fasting" days you're still consuming 500 kcal, which would qualify as a VLCD (rather than fasting) by these authors' definition.

 

Of course the subjects in the studies included in this analysis were almost certain to be overweight/obese (as most adults in the developed world are, and as you would expect participants in most diet studies to be) or at least normal weight - and hence possessed more metabolic reserves than we CR folks. It seems reasonable to think that eating few(er) calories may have more of an impact on cortisol levels when someone has less fat to burn, particularly in the early morning when the body has gone without food for many hours, resulting in early waking as you Zeta, and quite a few of us other CR folks as well, experience.

 

--Dean

 

------------

[1] Systematic review and meta-analysis reveals acutely elevated plasma cortisol following fasting but not less severe calorie restriction.

 

Nakamura Y, Walker BR, Ikuta T.

Stress. 2015 Nov 19:1-21. [Epub ahead of print]

PMID: 26586092

 

http://www.tandfonline.com.sci-hub.io/doi/abs/10.3109/10253890.2015.1121984

 

Abstract

 

Elevated plasma cortisol has been reported following caloric restriction, and may contribute to adverse effects including stress-induced overeating, but results from published studies are inconsistent. To clarify the effects of caloric restriction on plasma cortisol, and to assess cortisol as an indicator of stress during caloric restriction, we conducted a systematic review and meta-analysis of published studies in which cortisol was measured following caloric restriction without other manipulations in humans. We further compared effects of fasting, very low calorie diet (VLCD), and other less intense low calorie diet (LCD), as well as the duration of caloric restriction by meta-regression. Overall, caloric restriction significantly increased serum cortisol level in thirteen studies (357 total participants). Fasting showed a very strong effect in increasing serum cortisol, while VLCD and LCD did not show significant increases. The meta-regression analysis showed a negative association between the serum cortisol level and the duration of caloric restriction, indicating serum cortisol is increased in the initial period of caloric restriction but decreased to the baseline level after several weeks. These results suggest that severe caloric restriction causes activation of the hypothalamic-pituitary-adrenal axis, which may be transient, but results in elevated cortisol which could mediate effects of starvation on brain and metabolic function as well as ameliorate weight loss.

 

KEYWORDS:

 

Caloric restriction; Cortisol; Hypothalamic-pituitary-adrenal axis; Meta-analysis; Stress; diet; endocrinology; weight control

[Zeta]

Dean and Al: thanks for this! Very interesting.

 

So it is curious Zeta that you continue to exhibit symptoms (and measurements it sounds as well) of elevated cortisol, given that your overall calorie intake is not particularly restricted, and even on your "fasting" days you're still consuming 500 kcal, which would qualify as a VLCD (rather than fasting) by these authors' definition.

 

Of course the subjects in the studies included in this analysis were almost certain to be overweight/obese (as most adults in the developed world are, and as you would expect participants in most diet studies to be) or at least normal weight - and hence possessed more metabolic reserves than we CR folks.

 

I think that's exactly it: although my weight has gone up, I'm still well below my pre-CR weight, so by the end of my 450-calorie day (I've now gone down to 450 calories; not going to go lower), I'm at a significant calorie deficit.

 

Reading through the paper (and a few related papers), I see that one solution to the sleep problem might be leptin. But, of course, based on what we know about leptin, this could easily negate the effects of CR (though maybe only some of them).

 

What we -- or I -- need is some way to block the effects of cortisol on sleep only. That may simply not be possible with today's medicine.

 

I'm still waiting to try suvorexant (which affects orexin receptors). Other than that, I see little hope. But I'm adjusting. If I really need to be rested the next day (and won't be in a position to take naps), I pop 7.5 mg zopiclone, and get 180-240 mins. of sleep instead of 120-150 or so. And, interestingly, more than a few hours of sleep after a fasting day is fine! But zopiclone doesn't meet the criterion of blocking the effects of cortisol on sleep only. It's a relatively powerful drug that is probably not good for long-term brain health (though I'm guessing, hoping, that a few times a month is safe).

 

Zeta

[mikeccolella]

Zeta, It certainly resembles advanced sleep phase disorder. Had it all my life and it tends to get worse with age. In my case it appears to be genetic. My mom has it and so do two of my bros. Lighting may also be a factor as it is a circadian disorder. I always have several led lights on in the evening and avoid bright light in the morning, if outdoors before noon I use polaroid lenses. My symptoms are much like yours. I wake up at 2:30 or 3 and the brain is kickin ass, it just wants to get going! It is not anxiety, on the contrary it is a life force. A desiire to take on the world. The problem is two hours later I get very sleepy and feel a funk the rest of the day.

Some things i have tried:

1. Melatonin kinda helps but it depresses me for the rest of the day even though I only took 100-300 mcg

2. Valerian-really sucks

3. Lavender was useless

4. Trazedone was worthless

5. Clonazepam or lorazepam. Well these really work, but I really hate takeing them because they mess with the brain and I am paranoid about long term effects even though my mom has taken loraz for decades and her mind at 87 is virtually normal.

7. Chammoile was worthless

6. Benadryl works but the side effect for me is a hangover worse than the sleep deprivation.

 

For me quitting alchohol and doing the lighting thing-avoid it in the morning and get plenty later in the day and right up to bedtime helps considerable so that generally I feel pretty darn good. Of course i also engage in good sleep hygeine. My last meal is at 430 and i go to bed at 9. Usually sleep until about 4 with one piss call in between.

 

Well I hope something here might help.

 

Mike C.

[AlPater]

I was surprised to see that sleep deprivation is an osteoporosis risk.  Also, the discussion of heredity and sleep loss/twins studies were of note.

 

Nearly a decade later, an independent group at Penn conducted a similar experiment on identical and fraternal twins, finding that resiliency and vulnerability to sleep loss are highly heritable (Sleep, 35:1223-33, 2012 http://www.journalsleep.org/ViewAbstract.aspx?pid=28635 PMID:22942500).

 

http://www.the-scientist.com/?articles.view/articleNo/45375/title/Go-To-Bed-/&utm_campaign=NEWSLETTER_TS_The-Scientist-Daily_2016&utm_source=hs_email&utm_medium=email&utm_content=26793607&_hsenc=p2ANqtz--EOUZDEPgmAfWio74GPxOOIW2n_novB3dgXvacc0MtJVzo4ugzUVVBxtC1qV1gdgoZy0LpM3FfBRfisx1Ms59EUhP49A&_hsmi=26793607

 

 

 

 

 

LASTING EFFECTS OF SLEEP LOSS: The short-term consequences of sleep loss are numerous, but whether they leave a lasting scar is unknown. So Carol Everson and Aniko Szabo of the Medical College of Wisconsin subjected rats to a 10-month regime of sleep restriction and then allowed the animals to sleep as they pleased for several months. Compared to control animals, the sleep-deprived rats suffered a variety of physical effects, with some problems persisting even after the recovery period (PLOS ONE, doi:10.1371/journal.pone.0022987, 2011). In another study by Everson and colleagues, bone and bone marrow abnormalities persisted throughout sleep restriction and recovery periods (Exp Biol Med, 237:1101-09, 2012).

[Saul]

Hi ALL!

 

Whenever I have a little trouble getting to sleep at night, I relax any tensed muscles, and use the breath (if needed) to enter a meditative state.  Sleep comes easily and naturally.

 

My wife has much more trouble, with insomnia .

 

  --  Saul