5+x Sleep Supplements that Work: Valerian, Beer, Cherries, Tryptophan, Theanine | Plus: Effects of Fats, Carbs and GI

While milk with honey is better than milk with glucose (Jalilolghadr 2011), it won't improve - if anything mess - with your sleep quality when it's consumed ≤ 1h before bedtime - noteworthy: the same goes for most foods, though.

While I have chosen it as the title image for today's SuppVersity "Sleep Supplement Special", there's actually surprisingly little (not to say "no") evidence that the notorious hot milk with honey will actually improve your sleep significantly.

That's in contrast to a number of supplements that are discussed in a recent review by scientists from the Northwestern University; a review that highlights both, the short-comings of the existing research on dietary supplements for insomnia and encourage health practitioners "to explore existing resources and partner with patients to understand their goals and advise on safe and effective use of dietary supplements" (Ring 2017).

Studies related to sleep and sleep supplements at the SuppVersity:

Sleep Like an Athlete!

Phenibut Addic- tive or Harmless?

All About GABA at SHR

Melatonin = Easy Fat Loss?

Letrozole? Use Melatonin Instead

Bone & Tooth? Melatonin Helps

Now, the question obviously is: What's safe and effective? By expanding on and elaborating their list of supplements, this article may help you - health practitioner or not - to distinguish promises from factual evidence.

• Valerian - The probably most prominent and certainly one of the best-researched natural sleep aid is the root of Valeriana officinalis - a sleep aid that works... for some.
  
  Since "[v]alerian and its constituent valerenic acid have demonstrated adenosine (A1 receptor) interactions, GABAA receptor (β3 subunit) agonism, and 5-HT5a partial agonism" (Ring 2017) it may be surprising that only 6/9 studies in a recent review by Bent et al showed no effect on subjective sleep quality. 
  

  

  Figure 1: Likelihood that valerian improved sleep quality calculated based on Meta-analysis of 6 studies reporting dichotomous outcomes for sleep quality (adapted from Bent et al. 2006).

  In addition, Bent et al (2006) highlight that "[m]ost studies had significant methodologic problems, and the valerian doses, preparations, and length of treatment varied considerably". More recently, a meta-analysis by concluded:

  "The qualitative dichotomous results suggest that valerian would be effective for a subjective improvement of insomnia, although its effectiveness has not been demonstrated with quantitative or objective measurements. Nevertheless, its use can be considered for some patients given its safety" (Fernández-San-Martín 2010).

  Objective evidence for the efficacy of valerian is thus still missing... possibly due to the use of low-dose / low-concentration supplements. Speaking of which... here are the dosage suggestions Ring et al. provide in their previously cited review.
  
  Dosage: It seems as if it took at least 300–900 mg of a standardized extract of 0.8% valerenic acid - the dosage Ring et al. recommend as an alternative for valerian tea (1.5–3 g of root steeped for 5–10 min in 150 mL of boiling water) - to be taken 30–120 min before bedtime. Effects seem to accumulate over time and may not be noticed with the first administration.

High saturated fat intakes linked to less recuperative slow-wave sleep: In their 2016 study, a randomized crossover inpatient study with 2 phases of 5 nights, St Onge et al. observed differential effects of high fiber and high saturated fat intakes on slow-wave sleep While greater fiber intakes predicted less stage 1 (P = 0.0198) and more SWS (P = 0.0286), the percent of energy from saturated fat predicted less SWS (P = 0.0422). 

• Hops - In (non-alcoholic) beer, hops seems to work wonders for some of us... but wait a minute: is that actually the small quantity of 2-methyl-3-buten-2-ol, xanthohumol, and myrcenol from Humulus lupulus and its effect on GABA that's responsible for these effects?
  
  The fact that non-alcoholic beer works (note: the alcohol in regular beer will reduce REM and boost SWS, but it will also mess w/ the nightly growth hormone production | Prinz 1980), as well, would suggest that it's at least not the alcohol that's responsible for the improvements in subjective sleep quality (assessed by questionnaires), decrease in sleep latency (=time it takes you to fall asleep), and improvement of overall global score of sleep quality improved (Franco 2012 & 2014).
  

  

  Figure 2: We better stay skeptical about the role of hops in the beneficial effects of non-alcoholic beers as it has been observed by Franco et al. in stressed Hungarian students in 2014. It's well possible that it's just the carb content of the beer that triggered the improvements in sleep latency and quality in Franco et al. (2014).

  On the other hand, the fact that hops extracts didn't yield comparably convincing results would suggest that there's more to beer than hops and/or the brewing process gives rise to metabolites that are driving an efficacy that cannot be achieved with commercial hops extracts - extracts that have, in contrast to the non-alcoholic beer, been tested in people with chronic insomnia. It is thus not clear if it's the preparation or the subject group (or both) that's responsible for the mixed results of hops only preparations (evidence in favor of valerian + hops combinations is more promising - even in insomniacs).
  
  Dosage: Unlike valerian and most of the other agents discussed in this overview, hops is not without side effects. When administered in high(er) dosages (HED ~64mg/kg) to mice in conjunction with ketamine, the mice resulted in a deep narcosis. For me, that's another reason to rather drink 300ml of a (non-alcoholic) beer with dinner (check out other health benefits of beer) than to take 120–400 mg of hop extract (ideally combined with 374–500 mg of valerian root extract) to up your sleep quality. Immediate effects can be expected.

Blindfolds and earplugs can improve your sleep quality significantly and help resynchronize a messed up circadian rhythm, which is important for both average Joes and athletes | learn more about "Sleeping like an athlete" in my article from June 2017!

Understanding the different sleep phases and their importance - focus on athletes: As Damian Davenne explains in a 2009 review, "[s]leep can be divided into two main electrical states which serve different basic functions. Slow wave sleep (SWS) is a state during which the brain reduces its activities and neuronal activity becomes synchronized. [...] This type of sleep is important for athletes because, without its presence at the beginning of the night, growth hormone cannot be released from the pituitary gland" (Davenne 2009). During rapid eye movement sleep (REM), on the other hand, the brain is very active - proposedly consolidating memories, including movement patterns.

It is thus not really surprising that studies have shown that, after REM sleep loss, procedural memory and motor skills can be affected (Stickgold and Walker 2007). Another relevant physiological phenomenon for athletes is the blockade of cortico-spinal pathways at the brain stem and subsequent suppression of motor activity, which induces a state of total muscle relaxation "that allows effective myofibril restoration" (Davenne 2009).

• Cherries (esp. tart cherries) - Cherries are well-known for their l-tryptophan content, if you fast forward to the corresponding section of this article it is thus not surprising that cherries/cherry-juice seems to be a highly promising sleep quality modulator.
  
  Next to the serotonin- and melatonin-precursor l-tryptophan, cherries contain a plethora of anti-oxidants, as well as pre-formed melatonin - a cocktail that may well explain why a randomized, double-blind, crossover study on the effect of tart cherries on older adults (age ≥ 65 years) with insomnia found that the consumption of an 8-oz serving of tart cherry juice twice daily for 2 weeks found a statistically significant reductions in insomnia severity (measured as minutes awake after sleep onset).
  

  

  Figure 3: Plot of the relative changes in selected markers of sleep quality; p-values for time x group effects indicate statistical significance for insomnia index and wake after sleep onset (Pigeon 2017).

  Moreover, another study in 20 healthy men and women (aged 18 to 40), which detected significant elevations in urinary melatonin, confirms that the benefits are not restricted to the elderly population in whom the natural production of melatonin is known to decrease. After all, the increase in melatonin Pigeon et al. detected in the urine of the subjects, who complained of insomnia but were otherwise healthy, came with significant increases in time in bed, total sleep time, and sleep efficiency (Pigeon 2010).
  
  Dosage: While pills are available, all promising research has been done using (tart) cherry juice (8 oz consumed 2x per day, chronically). Compared to whole fruits, the juices also have the advantage of being easier to stomach than the significant number of cherries you'd have to consume to get remotely close to the concentration of active ingredients in the currently available proprietary tart cherry drinks. Immediate effects cannot be expected.

Very low-carb and ketogenic diets shift the ratio of SWS to REM sleep in favor of the former: Whether it is a good or bad thing that Afaghi et al. (2008) observed a significant reduction in REM and a corresponding increase in slow-wave sleep (SWS) is still in the open. What is certain, though, is that (a) low-fat high-carb diets have previously been shown to have the opposite effect (Phillips 1975) and that (b) the pro-SWS effects of ketogenic diets can be used in the treatment of abnormal refractory continuous spikes and waves during slow sleep (Nikanorova 2009).

• L-tryptophan - The serotonin and melatonin precursor may actually help you fall asleep and stay asleep, but the # of studies is limited.
  
  Intriguingly, much of the existing evidence of tryptophan's efficacy is >35 years old, with a review by Ernest Hartmann (1982) highlighting three things
  • "the weight of evidence indicates that L-tryptophan in doses of 1 g or more produces an increase in rated subjective sleepiness and a decrease in sleep latency (time to sleep)",
  • "there are less firm data suggesting that L-tryptophan may have additional effects such as decrease in total wakefulness and/or increase in sleep time", and
  • "negative results occur in entirely normal subjects—who are not appropriate subjects since there is 'no room for improvement'"
  Mixed results are also reported in severe insomniacs and in patients with serious medical or psychiatric illness (details are beyond the scope of this SuppVersity article).
  

  

  Figure 4: Graphical illustration of the number (N=y) of studies showing significant, benefits, trends or no change according to a 1982 review in the Journal of Psychiatric Research by Ernest Hartmann (1982)

  As my plot of the number of studies showing significant benefits, trends and no effects highlights, a reduced sleep latency is what appears to be the most certain benefit you can get from 1g+ of l-tryptophan taken ~30 minutes before bed. Potential benefits may be seen from the same regimen (for the # of occasions you wake up and/or toss and turn, as well as the total sleep time.
  
  Dosage: No clear benefits have been observed for higher dosages (even though studies tested boluses of up to 15g), but it seems advisable especially for lower dosages to consume them "on empty", i.e. at least without other protein foods. Effects - at least the sleepiness - may be expected with the first administration.

High GI-carbs significantly speed up (-49%) how long it will take you to fall asleep: While high GI carbs (GI = 109) still have a bad rep, studies indicate that consumed 4h before bed will speed up the sleep latency of healthy individuals by a whopping 49% (9.0 ± 6.2 min vs. 17.5 ± 6.2 min for otherwise identical low-GI meals (GI =50) | Afaghi 2007)... to consume the meal 4h before bed is important, by the way. In the same study, Afaghi et al. observed that the same meal given 1 h before bedtime increased the sleep latency back to 14.6 ± 9.9 minutes. Other studies even suggest detrimental effects with high GI ingestion too close to bedtime (so stick to the 4h) - including milk + glucose (higher GI) vs. the notorious milk + honey mix (lower GI) when consumed ~60 minutes before bed.

General beneficial effects of carbs have been observed, among others, by Porter and Horne (1981) who provided six male subjects with a high-carbohydrate meal (130 g), a low-carbohydrate meal (47 g), or a meal containing no carbohydrate, 45 min before bedtime. The high-carbohydrate meal resulted in increased REM sleep, decreased light sleep, and wakefulness. As Halson et al. (2014) point out in their review, "the caloric content of the meals was [yet] not matched in the study".

• l-theanine - Usually supplements that are so heavily advertised as Just Chill™ and NeuroSleep™ don't work, but for these l-theanine things could be different.
  
  As the authors of the previously cited review in Current Sleep Medicine Reports point out in their review, "[s]everal studies have shown that intake of L-theanine significantly increases α-wave activity in different areas of the cerebral cortex, leading to a relaxed state without drowsiness" (Ring 2017).
  

  

  Figure 5: 200mg/day l-theanine reduce the cortisol release in response to stress (Kimura 2007).

  In conjunction with its ability to increase dopamine and serotonin, and reduce stress-related norepinephrine and cortisol levels, salivary IgA, and heart rate in response to an acute stressor. Plus: L-theanine has been shown in animal studies to partially reverse caffeine-induced reductions in slow wave sleep (Jang 2012) - effects that can occur even with your average morning Joe (i.e. not just with caffeine consumption late in the day | Landolt 1995).
  
  The reason why I still used "could" in the headline of this paragraph is that there is, more or less, only one convincing study to demonstrate beneficial effects on sleep quality in human beings: a 2011 study by Lyon et al. that investigated the effects of Suntheanine® (a branded l-theanine product) on objective sleep quality in boys with attention deficit hyperactivity disorder (ADHD) and showed objective (actigraph) improvements in sleep percentage and sleep efficiency after 6 weeks.
  

  

  Figure 5: . (a) Sleep length, (b) sleep efficiency, and (c) intermittent awakening WASO data interpreted from actigraph measurements in 10 male subjects. The values represent mean § standard error. Statistical significance was measured using Student’s paired t-test (Rao 2015).

  Similar objective improvements in sleep efficiency and intermittent awakening (WAS) are also reported by Rao et al. (2015) for healthy subjects (see Figure 6).
  
  Dosage: While you will see recommendations ranging from 50 to 400 mg of L theanine taken 30–60 min before bedtime, the "proven" dosage is 200mg. That's more than 4 cups of high l-theanine green tea and thus not really achievable by consuming freshly brewed green tea before bed. As Ring et al. point out, you have to be careful, though, because "[l-t]heanine can have an antihypertensive effect, so it should be used with caution when combined with antihypertensive medications" (Ring 2017).
• Melatonin - Your body's own sleep aid is rather a circadian re-aligner than a true sleeping pill - that's why it works mostly for problems with falling asleep.
  The decrease in sleep onset latency can but doesn't necessarily result in increases in total sleep time. That's why many users who expected benzo-esque results are disappointed.
  
  On the other hand, melatonin has none of the nasty side effects of your average BZD-Z drugs: memory and cognition impairment, psychomotor retardation, or next-day hangover effects (if dosed correctly | Wilson 2010). Likewise, an often-heard of physical dependence has never been observed (Zhdanova 1996).
  
  Dosage: Dosing melatonin is difficult because the optimal dosage differs between individuals. Accordingly, Ring et al. (2017) suggest a dosage plan starting with 0.3mg and increasing to 3mg (max. 6mg) if the desired effects don't occur.
  .

Two Hours of Extra-Sleep Before Sleep Deprivation Minimize the Performance Decrements Due to 24h Sleep Deprivation | more

So, what works? Here's a list: (1) standardized valerian extracts (300-900mg) 60 min before bed, (2) non-alcoholic beer (0.3 L) with dinner, (3) tart cherry juice at a dosage of 8 oz consumed twice per day for days or weeks, (4) ca. 1g of l-tryptophan w/out amino acids competing for uptake (e.g. BCAAs) 30 minutes before bed, (5) l-theanine dosed at 100-400mg/d 30-60 minutes before bed, taking it thrice a day may boost the effect (w/out causing drowsiness) all work, are safe, and worth trying out.

Experimentation may be necessary to find out what works for you - one-size-fits-it-all advice is unwarranted!

The above is especially true for melatonin, which didn't make the A-list, because it's more of a circadian re-aligner than a sleep aid. This doesn't make it less useful, though - on the contrary: if used correctly (1-2h before bed at 0.3-6.0 mg depending on your tolerance) it can have far-reaching beneficial effects on both, your sleep latency, quality, and duration as well as your overall health.

What neither melatonin nor any other sleep aid can make up for, though, is sleep hygiene.

One supplement that has evidence to support its effect, which I still won't recommend, though, is (*) Kava Kava (Piper methysticum), which messes w/ the cytochrome enzyme cascade (CYP450), will affect the metabolism of both meds and other dietary supplements, and has been linked to liver failure (albeit outside of RCTs lasting up to 6 months | Clouatre 2004), as well as the following concoctions that are often recommended but don't have convincing scientific backup: (i) chamomile, despite proven interactions of apigenin in chamomille w/ the GABA receptor, (ii) passion flower, (iii) California poppy, (iv) skullcap, (v) lemon balm, (vi) St. John’s wort, (vii) lavender, and (viii) magnolia bark | Comment on Facebook!

References:

• Afaghi, A., O'connor, H., & Chow, C. M. (2007). High-glycemic-index carbohydrate meals shorten sleep onset. The American journal of clinical nutrition, 85(2), 426-430.
• Afaghi, A., O'Connor, H., & Chow, C. M. (2008). Acute effects of the very low carbohydrate diet on sleep indices. Nutritional neuroscience, 11(4), 146-154.
• Bent, S., Padula, A., Moore, D., Patterson, M., & Mehling, W. (2006). Valerian for sleep: a systematic review and meta-analysis. The American journal of medicine, 119(12), 1005-1012.
• Clouatre, D. L. (2004). Kava kava: examining new reports of toxicity. Toxicology letters, 150(1), 85-96.
• Davenne, Damien. (2009) "Sleep of athletes–problems and possible solutions." Biological Rhythm Research 40.1: 45-52.
• Dement, W C. (2005). "Sleep extension: getting as much extra sleep as possible." Clinics in Sports Med, 24: 251–268.
• Fernández-San-Martín, M. I., Masa-Font, R., Palacios-Soler, L., Sancho-Gómez, P., Calbó-Caldentey, C., & Flores-Mateo, G. (2010). Effectiveness of Valerian on insomnia: a meta-analysis of randomized placebo-controlled trials. Sleep medicine, 11(6), 505-511.
• Franco, L., Sánchez, C., Bravo, R., Rodríguez, A. B., Barriga, C., Romero, E., & Cubero, J. (2012). The sedative effect of non-alcoholic beer in healthy female nurses. PloS one, 7(7), e37290.
• Franco, L., Bravo, R., Galán, C., Rodríguez, A. B., Barriga, C., & Cubero, J. (2014). Effect of non-alcoholic beer on Subjective Sleep Quality in a university stressed population. Acta Physiologica Hungarica, 101(3), 353-361.
• Halson, S. L. (2014). Sleep in elite athletes and nutritional interventions to enhance sleep. Sports Medicine, 44(1), 13-23.
• Hartmann, Ernest. "Effects of L-tryptophan on sleepiness and on sleep." Journal of psychiatric research 17.2 (1982): 107-113.
• Jalilolghadr, S., Afaghi, A., O'Connor, H., & Chow, C. M. (2011). Effect of low and high glycaemic index drink on sleep pattern in children. JPMA-Journal of the Pakistan Medical Association, 61(6), 533.
• Jang, H. S., Jung, J. Y., Jang, I. S., Jang, K. H., Kim, S. H., Ha, J. H., ... & Lee, M. G. (2012). L-theanine partially counteracts caffeine-induced sleep disturbances in rats. Pharmacology Biochemistry and Behavior, 101(2), 217-221.
• Kimura, K., Ozeki, M., Juneja, L. R., & Ohira, H. (2007). L-Theanine reduces psychological and physiological stress responses. Biological psychology, 74(1), 39-45.9
• Landolt, H. P., Werth, E., Borbély, A. A., & Dijk, D. J. (1995). Caffeine intake (200 mg) in the morning affects human sleep and EEG power spectra at night. Brain research, 675(1), 67-74.
• Lyon, M. R., Kapoor, M. P., & Juneja, L. R. (2011). The effects of L-theanine (Suntheanine®) on objective sleep quality in boys with attention deficit hyperactivity disorder (ADHD): a randomized, double-blind, placebo-controlled clinical trial. Alternative medicine review, 16(4), 348.
• Ozeki, Makoto, Lekh Raj Juneja, And Shuichiro Shirakawa. "The Effects Of L-Theanine On Sleep Using The Actigaph." Japanese Journal Of Physiological Anthropology 9.4 (2004): 143-150.
• Nikanorova, M., Miranda, M. J., Atkins, M., & Sahlholdt, L. (2009). Ketogenic diet in the treatment of refractory continuous spikes and waves during slow sleep. Epilepsia, 50(5), 1127-1131.
• Phillips, F., Crisp, A. H., McGuinness, B., Kalucy, E. C., Chen, C. N., Koval, J., ... & Lacey, J. H. (1975). Isocaloric diet changes and electroencephalographic sleep. The Lancet, 306(7938), 723-725.
• Pigeon, W. R., Carr, M., Gorman, C., & Perlis, M. L. (2010). Effects of a tart cherry juice beverage on the sleep of older adults with insomnia: a pilot study. Journal of medicinal food, 13(3), 579-583.
• Porter, J. M., & Horne, J. A. (1981). Bed-time food supplements and sleep: effects of different carbohydrate levels. Electroencephalography and clinical neurophysiology, 51(4), 426-433.
• Prinz, P. N., Roehrs, T. A., Vitaliano, P. P., Linnoila, M., & Weitzman, E. D. (1980). Effect of alcohol on sleep and nighttime plasma growth hormone and cortisol concentrations. The Journal of Clinical Endocrinology & Metabolism, 51(4), 759-764.
• St-Onge, M. P., Roberts, A., Shechter, A., & Choudhury, A. R. (2016). Fiber and saturated fat are associated with sleep arousals and slow wave sleep. Journal of clinical sleep medicine: JCSM: official publication of the American Academy of Sleep Medicine, 12(1), 19.
• Stickgold, R and Walker, M P. (2007). "Sleep-dependent memory consolidation and reconsolidation." Sleep Med, 8: 331–343.
• Wilson, S. J., Nutt, D. J., Alford, C., Argyropoulos, S. V., Baldwin, D. S., Bateson, A. N., ... & Gringras, P. (2010). British Association for Psychopharmacology consensus statement on evidence-based treatment of insomnia, parasomnias and circadian rhythm disorders. Journal of Psychopharmacology, 24(11), 1577-1601.
• Zhdanova, I. V., Wurtman, R. J., Morabito, C., Piotrovska, V. R., & Lynch, H. J. (1996). Effects of low oral doses of melatonin, given 2–4 hours before habitual bedtime, on sleep in normal young humans. Sleep, 19(5), 423-431.

10mg Melatonin Increase Diet-Induced Weight Loss in 30-D Study from 4% to 7% + Have Profound Antioxidant Effects

If you want to take melatonin, take it before bed and thus in sync with your circadian rhythm| learn more

If that's not your first visit at the SuppVersity, the fact that the sleep hormone melatonin is a powerful antioxidant won't be news for you. The fact that it may facilitate weight loss has been discussed in a previous SuppVersity article from September 2015 (read it), too. In the corresponding study, taking 1-3 mg melatonin helped women lose 7% body fat, and gain 3.5% lean mass ... albeit over a time of 12 months.

A new study does now suggest that melatonin can help you manage your body weight in the short run, too.

Learn more about the effects of Melatonin & co. at the SuppVersity

GABA Diabesity Treatment

Phenibut Addic- tive or Harmless?

All About GABA (+ SHR podcast)

Melatonin = Easy Fat Loss?

Letrozole? Use Melatonin Instead

Bone & Tooth? Melatonin Helps

That's partly due to its anti-inflammatory effects, but it's also because melatonin has been shown to increase the energy expenditure by activating brown adipose tissue (Jiménez‐Aranda 2013), to preserve mitochondrial function (Reiter 2016).

Figure 1: This figure summarizes the multiple actions of melatonin in reducing oxidative stress (Reiter 2016).

As the overview in Figure 1 tells you, melatonin also exerts immunomodulatory actions and beneficially affects the expression and secretion of some adipokines from fat cells. Furthermore, Szewczyk–Golec et al. (2017) highlight that ...

"[o]besity has been related to the chronic sleep disruption, another epidemic of the industrialized world and [a subsequent] deficiency of melatonin [which] may well contribute to obesity and its complications" (Szewczyk–Golec 2017).

Yet, while there's plenty of evidence of its weight loss benefits in rodents, its effects on the weight loss efforts of overweight/obese humans is missing... or it has been missing before  Szewczyk–Golec et al. decided to study if melatonin would affect the antioxidant level and concentration of circulating adipokines in obese human subjects on a calorie–restricted diet.

30 days of dieting with either melatonin or placebo 

To assess whether their hypothesis is accurate, the scientists recruited thirty volunteers with BMI ≥ 30 kg/m² (obesity class I or class II) who were then randomly and double-blindedly allocated to a melatonin (MEL) or a placebo (PL) group.

• During the experimental period, 10 mg melatonin (LE–KAM, Zakroczym, Poland) or placebo (equivalent amount of lactose) were supplied in identical sachets to be taken orally in a single dose for 30 days, 1 hr before bedtime (learn why timing's important). 
• All participants used a calorie–restricted diet (1000–1200 kcal/day for women and 1400–1600 kcal/day for men).

Before and after the 30-day intervention period, a standardized set of anthropometric measurements was performed. DXA scans, however, were not conducted.Accordingly, it is difficult to judge how much of the ~3.1kg extra-weight the subjects in the melatonin group lost was body fat.

In the Rasmussen study (1999), the testosterone levels of middle-aged male rats were not changed by boosting melatonin to 15-fold higher levels than you'd observe in young rats. What the administration of melatonin did, however, was to inhibit the age-related increases in visceral fat, leptin and insulin.

Will this work for men, too? In view of the antioxidant prowess of melatonin, this seems to be a stupid question, right? Well, the Internet is a place where rumors turn into truths when if they're just repeated often enough and one of those rumors/truths is: "Melatonin will reduce your testosterone levels". Now, we all know that this is bad news for any dieter, as low testosterone levels will favor the loss of muscle over fat mass. So, is that actually a relevant concern? This question is difficult to answer, because - as usually - there's conflicting evidence. In long-term studies like Rasmussen et al., scientists didn't observe negative effects of skyrocketing middle-aged male rats' melatonin levels to values that were 15-fold higher than those of young rats (Rasmussen 1999), though. What the melatonin did, however, was to ameliorate the age-related accumulation of visceral fat, as well as the increases in leptin and insulin (see Figure on the left).

In humans, ramping up the melatonin amplitude by a factor 6 (by administering 2mg of melatonin intranasally every day for 2 months) of young men (23-32 years), Terzolo et al. (1990) had previously observed no changes in the testosterone AUC over 24h. What the scientists did observe, though was a significant change in the 24-hour patterns of cortisol and testosterone, which displayed an anticipation of the morning acrophase of about 1.5 hours (not significant) for cortisol and three hours (P < 0.05) for testosterone. Why's that important? Well, the answer is easy: If you measure testosterone levels only once before and after melatonin supplementation at a given time of the day, you will observe changes in testosterone - significant reductions, because testosterone will then peak at 4 AM, not 7 AM and will thus have begun to decline again when you draw blood in the AM. So, while further studies would be highly appreciated, but the current evidence seems to refute the notion that there's a significant reduction in testosterone and the way melatonin affects the circadian rhythm may well explain why studies that measured testosterone only once in 24h may produce the misleading impression that melatonin would sign. reduce your testosterone levels.

With respect to the oxidative status of their subjects, the authors observed a melatonin-exclusive statistically significant increase in adiponectin (+22.6% | p = 0.029) and omentin-1 (+23.4% | p = 0.0044) and the significant reduction of the lipid oxidation marker MDA (-28.6% | p = 0.042), as well as like-wise melatonin-exclusive increases in glutathione peroxidase (GPX | +44.3% | P =  0.0049).

Figure 2: Changes in the anthropometric parameter from day 0 to day 30 (Szewczyk–Golec 2017).

Now, those changes are expected in overweight/obese subjects who lose weight, anyway. With melatonin being able to significantly augment them, the study at hand does, however, suggest that these benefits are more pronounced with melatonin.

Women Lose 7% Body Fat, Gain 3.5% Lean Mass in 12 Months-Long RCT | learn more

Against that background, it is a bit surprising (not to say disappointing) that Szewcyk-Golec et al. did not observe a difference in the diet's effects on the subjects' waist circumference, which would be expected with a concomitant 43% increase in weight loss and an augmented reduction in markers of oxidation and obesity-related adipokine levels. In the absence of reliable DXA data, the jury is thus still out there when it comes to what really counts when it comes to weight loss: the loss of body fat (not muscle).

Luckily, this is not the first "melatonin for weight loss" study. In fact, I've written about an even more exciting study in older women (56-73), in which the provision of 1-3 mg of melatonin (which is by the way rather the dosing I would recommend) helped them "Lose 7% Body Fat, Gain 3.5% Lean Mass in a 12 Months-Long RCT" (read the older article about melatonin and fat loss).

Melatonin is not the only supplement that may facilitate restorative sleep. Learn more in "Sleep Like an Athlete: Supplement Smart to Complement, not Replace Periodization & Basic Rules of Sleep Hygiene" | read more)

So, what's the verdict? While it appears to be likely and is supported by the previously cited 2015 study that melatonin facilitates weight and, more importantly, fat loss, the study at hand must still be considered preliminary evidence "that administration of this agent may be a useful adjunct in obesity treatment" that will also "facilitate the health improve-ment during obesity management" (Szewczyk–Golec 2017).

Future studies will have to be conducted with more participants, male participants and lean participants to know potential differences in the effects/efficacy of high and low doses of melatonin in different subject groups | Comment!

References:

• Jiménez‐Aranda, Aroa, et al. "Melatonin induces browning of inguinal white adipose tissue in Zucker diabetic fatty rats." Journal of pineal research 55.4 (2013): 416-423.
• Szewczyk–Golec, et al. "Melatonin supplementation lowers oxidative stress and regulates adipokines in obese patients on a calorie–restricted diet." Oxidative Medicine and Cellular Longevity (2017): ahead of print.
• Rasmussen, Dennis D., et al. "Daily melatonin administration at middle age suppresses male rate visceral fat, plasma leptin, and plasma insulin to youthful levels." Endocrinology 140.2 (1999): 1009-1012.
• Reiter, Russel J., et al. "Melatonin as an antioxidant: under promises but over delivers." Journal of pineal research (2016).

Sleeping Like an Athlete: Supplement Smart to Complement Your Diet, Periodize Your Training, Practice Sleep Hygiene

Blindfolds and earplugs can improve your sleep quality significantly. The special beauty of blindfolds is: unlike earplugs, blindfolds may also be used to refresh 'other things' you may be doing beneath or on top of your sheets, which in turn will help those who are struggling with getting restorative sleep (learn more)

While every idiot will tell you that ZMA is "the shit" (it indeed is, literally) its purported benefits are either insufficiently proven or even disproven, as it is the case for the alleged  anabolic effect of ZMA, which clearly don't exist (Wilborn 2004) outside of the "alternative facts" supplement companies use in pamphlets people call "write ups". Obviously, this won't stop the bros at the gym from telling you: "Dat ZMA gives me an amazingly anabolic sleep, bro!"

The reasons ZMA (unfortunately) hasn't disappeared, yet, is still in the TOP10 of an unfortunately high number of supplement retailers' sales-lists, though, is not only bropaganda. It's bropaganda that appears plausible, because both, B-vitamins and magnesium, play an important role in the physiology of human sleep.

Learn more about the effects of GABA & co at the SuppVersity

GABA Diabesity Treatment

Phenibut Addic- tive or Harmless?

All About GABA at SHR

Melatonin = Easy Fat Loss?

Letrozole? Use Melatonin Instead

Bone & Tooth? Melatonin Helps

It is thus only logical that they made it on a list scientists from Portugal and Spain compiled and published in "Arch Med Deporte" in form of a review. A review which does, unlike a dozen of articles on fitness websites, mislead its readers to believe that supplements were the basis or at least necessary for optimal sleep in athletes.

Figure 1: Rules of optimal sleep hygiene for athletes - Sleep hygiene measures that may contribute to improving the quantity and quality of sleep in athletes (from Ordóñez 2017).

You wouldn't have believed such bogus, anyway, would you? I mean, we all know that the basis of optimal sleep ain't different for athletes vs. couch potatoes, it's always sleep hygiene. The rules of sleep hygiene, on the other hand, may well differ. Periodization and a sensible control of one's training volume and intensity, for example, are nothing you'd find on the average couch potato's list because he's already training way too little to get optimal sleep.

Why do we care about sleep as athletes (and wanna-be athletes)? (1) Performance - not sleeping enough has direct negative effects on your cardio-respiratory capacity and possible negative effect on maximum and sub-maximum strength levels; (2) recovery - a lack of sleep will impair your recovery and predispose you to overtraining, with all its nasty symptoms, such as depression, confusion, anger, fatigue and reduced vigour, as well as increased levels of catabolic hormones, such as cortisol, in rest and reduction of anabolic hormones, like GH, IGF-1 and testosterone; (3) injury risk - you'll be more likely to get injured, because of sign. reductions in cognitive performance and proprioceptive and neuromuscular alterations (+ the aforementioned recovery deficits); (4) infections - a lack of sleep will impair your immune competence which, in turn, will make you more susceptible to infections; (5) muscle loss and fat gain - the former are direct effects of the previously mentioned changes in the hormonal balance [see (2)].

For you, who is obviously not a sedentary couch potato, my first advice to "fix your sleep" is thus: make sure you're not following the invalid "more helps more" approach and have been overtraining for weeks (that's in contrast to overreaching | learn more). When you've your sleep hygiene ducks in a row, go ahead and read the following paragraphs about supplements:

• 

  Figure 1: Changes in sleep in response to TRYP (Silber 2010).

  the serotonin precursor tryptophan - while it is unquestionably essential for optimal sleep, the amount of the serotonin precursor tryptophan in our diet is usually more than high enough to fulfill our dietary requirements;
  
  still, if your intake is low and/or your requirements are increased (e.g. low niacin intake and/or requirements of the tryptophan based-vitamin) or you've been stupid enough to block the entry of tryptophan into the brain by guzzling BCAAs all day (learn more), taking at least 1g (best consumed on empty) before going to bed may help you fall asleep and improve subjective sleep quality
• vitamins from the B-complex - yes, here it is B-vitamin, but the infamous B6 (pyridoxin) from ZMA, is required only in very low doses and together with folate as a co-factor in serotonin synthesis; in fact, taking too much (which is what you will find in most ZMA products) can ruin your sleep by giving you the weirdest kind of dreams;

  

  Figure 1: Possible mechanisms of the influence of dietary components on the synthesis of serotonin and melatonin (from Peuhkuri 2012). One thing you should remember, though: Most of us get all the necessary nutrients from our diet, accordingly you must not expect exorbitant benefits from taking supplements.

  often forgotten, but at least as important, especially for athletes, whose requirements may be significantly increased, is vitamin B3 aka niacin, the endogenous production of which will otherwise be favored by your body over the synthesis of serotonin from tryptophan (Peuhkuri 2012); some evidence also exists for B12, which is necessary for the proper synthesis of melatonin, and should thus have possible positive effect on the quantity of sleep, especially in vegetarian athletes, who often don't get enough B12 from their meatless and thus in many cases cobalamine-deficient diet
• overrated, but important magnesium - while there's little doubt that magnesium is important for the 5-Hydroxytryptamine enzyacetyltransferase to convert 5-HT into N-Acetyl-5-Hydroxytryptamine and which is then transformed into N-Acetyl-5-methoxy tryptamine aka Melatonin, there's little evidence that taking extra Mg has beneficial effects on sleep; in fact, scientists have yet to establish, if low magnesium is the cause of just a corollary factor of sleep problems (Nielsen 2010 | this could still mean that Mg supplementation will solve the underlying problems that keep you awake, though) and beneficial effects of supplementation have only been established in elderly subjects (Abbasi 2012), where it has been found to reverse the age-related neuroendocrine and sleep EEG changes (Held 2002)

No such conclusive evidence exists for zinc, the third ingredient in the supplement everybody will name when you ask for "sleep supplements for athletes". While an older rodent study suggests that a full-blown zinc deficiency goes hand in hand with reduced melatonin levels (Abbasi 2012), there's no evidence that zinc deficiency is (a) causally involved, (b) a major problem in the average athlete and (c) no human data to support improved sleep with zinc. Similarly promising, but not fully convincing evidence exists for

• GABA and phenibut, which I've discussed in detail (see "GABA - An Effective Sleep Aid W/ GH Boosting Effects that Works Within 30 Minutes - Only 100 mg Pre-Bed Will Suffice" | read it, and "Phenibut, Addictive Sleep Aid With Unhealthy Hangover? Dosages, Effects, Side Effects and Safety Concerns" | read it), ...
• plain dietary calcium and potassium, which are, much like magnesium, essential for protein encoding that facilitates sleep and regeneration, ...
• dietary (or supplemental) L-ornithine, the anti-stress effects of which I've likewise addressed in previous articles ( "L-Ornithine an Anti-Stress Agent: Lower Cortisol, Higher DHEA, Better Sleep W/ Only 400mg of Ornithine Pre-Bed" | read more) and 
• reduced intakes of palmitic acid (aka hexadecanoic acid), which have been found to be significantly associated with difficulties falling asleep (Grandner 2014).

All these dietary links that have been outlined quite nicely by Zeng et al. a 2014 paper about their potential use in functional foods (see Figure 3):

Figure 3: Possible mechanisms of functional components in foods promote sleep (from Zeng 2014).

Certainly effective in some, but highly debated among both scientists and practitioners, is the last supplement on the list: melatonin. Useful dosages for athletes appear to range from 3-12 mg with higher doses not necessarily working better, but increasing the risk of side effects ranging from headaches over nausea and drowsiness during the day or nightmares, all of which could potentially negatively affect your performance. I would thus not necessarily call melatonin a "must have" supplement for athletes - well,... unless you're traveling over several time zones regularly. In that case, you can use it to combat jet lag and reprogram your internal clock; or, as a Cochrane Review says you could use its "remarkabl[e effectivity] in preventing or reducing jet lag [... whenever you cross] five or more time zones, particularly in an easterly direction, and especially if [you have experienced jet lag on previous journeys" (Herxheimer 2002).

Always remember: You want to control cortisol, not eradicate it if you want to melt away your belly fat, beat your personal bests and feel just great! Learn how to control cortisol.

So, what's the verdict then? I still maintain that overtraining is the #1 reason why athletes and gymrats will have trouble sleeping. It will still make sense to keep an eye on your B-vitamin, magnesium and tryptophan intake as a complement to practicing appropriate sleep hygiene (see Figure 1).

If nothing helps, a visit to the doctor who can exclude underlying physical problems like hyperthyroidism, adrenal problems, sleep apnea and a whole host of other health problems that may affect your sleep ... I can guarantee, though, in 99% of the cases not being able to fall asleep, cannot sleep through or cannot sleep at all a lack of sleep hygiene (unable to fall asleep) and/or overtraining (waking up at  1-3AM) are to blame | Comment!

References:

• Abbasi, Behnood, et al. "The effect of magnesium supplementation on primary insomnia in elderly: a double-blind placebo-controlled clinical trial." Journal of Research in Medical Sciences 17.12 (2012).
• Grandner, Michael A., et al. "Sleep symptoms associated with intake of specific dietary nutrients." Journal of sleep research 23.1 (2014): 22-34.
• Held, Katja, et al. "Oral Mg2+ supplementation reverses age-related neuroendocrine and sleep EEG changes in humans." Pharmacopsychiatry 35.04 (2002): 135-143.
• Herxheimer, Andrew, and Keith J. Petrie. "Melatonin for the prevention and treatment of jet lag." The Cochrane Library (2002).
• Ordóñez, Fernando Mata, et al. "Sleep improvement in athletes: use of nutritional supplements." Nº 135 (Murc Tlf (2017): 93.
• Nielsen, Forrest H., LuAnn K. Johnson, and Huawei Zeng. "Magnesium supplementation improves indicators of low magnesium status and inflammatory stress in adults older than 51 years with poor quality sleep." Magnesium Research 23.4 (2010): 158-168.
• Peuhkuri, Katri, Nora Sihvola, and Riitta Korpela. "Diet promotes sleep duration and quality." Nutrition Research 32.5 (2012): 309-319.
• Silber, B. Y., and J. A. J. Schmitt. "Effects of tryptophan loading on human cognition, mood, and sleep." Neuroscience & Biobehavioral Reviews 34.3 (2010): 387-407.
• Wilborn, Colin D., et al. "Effects of zinc magnesium aspartate (ZMA) supplementation on training adaptations and markers of anabolism and catabolism." Journal of the International Society of Sports Nutrition 1.2 (2004): 12.
• Zeng, Yawen, et al. "Strategies of functional foods promote sleep in human being." Current signal transduction therapy 9.3 (2014): 148-155.

Trying to Lose Fat & Get "Toned" W/Out Training or Diet? Taking 1-3 mg Melatonin Helps Women Lose 7% Body Fat, Gain 3.5% Lean Mass in Recent 12 Months-Long RCT

Since the natural melatonin production decreases as we age, it is (unfortunately) possible that younger women wouldn't see the same benefits as the >56 year-old subjects of the study at hand.

No, I am not recommending laziness here, and I doubt that you will arrive at a cover model physique with nothing but a handful of melatonin pills, but the results of a recent study from the Aarhus University Hospital in Denmark are too intriguing not to devote a whole SuppVersity article to them.

In said study, Anne Kristine Amstrup and colleagues tested whether there's anything to the rumors that have it that "melatonin [has] a positive effect on body weight and energy metabolism" (Amstrup. 2015). As the researchers rightly point out, previous "evidence for this relies mainly on animal models" (ibid). It was thus about time for someone to "determine the effects of melatonin on body composition, lipid and glucose metabolism in humans" (ibid).

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In this case, said human beings were 81 post-menopausal Caucasian women (aged 56-73 years) diagnosed with osteopenia (T-score between -1 and -2.5 in the hip or spine). The Danish scientists randomized the women to receive

• either melatonin, at a dosage of 1 or 3 mg per day, or
• an identically looking placebo nightly (timing matters!)

for a total time-period of 12 months. There were no dietary or exercise interventions, but all study subjects received a daily supplementation of 800mg calcium and 20ug vitamin D3 (which obviously wouldn't affect the results, also because all of the participants had taken Ca + D3 for at least 3 months before the study began). With DXA, ...

"To assess body composition, we used a whole body scan by dual X-ray absorptiometry (DXA, Hologic Inc., Waltham, MA, USA). We performed scans at baseline and after one year of treatment. Assessments included total and subtotal body mass (g), lean mass (g), fat mass (g) and percentages of body fat. We calculated body mass index (BMI) as body weight (kg) divided by height² (in metres)" (Amstrup. 2015).

... and a detailed analysis of the blood of their subjects, the body composition and biochemical analyses were similarly thorough as the randomization protocol which was performed by an external pharmacy (Skanderborg Pharmacy).

Beware! If you take melatonin anytime but 1-2h before bed (fasted), it may backfire! If you don't remember why and how timing matters, I suggest you re-read my 2014 article about how taking melatonin at the wrong time of the day may actually make you fat and insulin resistant.

Each block consisted of eight individuals. In the blocks, the women were randomly allocated to treatment, i.e. four received placebo, while two received 1mg of melatonin and two received 3mg melatonin.

Figure 1: Changes in body composition (left) and adiponectin (right) in response to 1-3mg of melatonin taken at night over a 12-months period without further exercise or diet intervention (Amstrup. 2015).

This is also why I have little doubt that we can rely on the data in Figure 1 which shows an astonishingly pronounced reduction in fat mass and a borderline-significant increase in lean mass in the melatonin groups, when the subjects on the placebo supplements gained total (and %) body fat and lost lean mass in the same 12-months period.

Melatonin As Potent as Letrozole in Inhibiting Aromatization | more

You are an athlete who does not care about losing weight? Data from a Spanish study leaves no doubt that you can still benefit from taking melatonin. In their soon-to-be-published study, researchers from the Universidad de Granada a high dose of melatonin restored the normal circadian rhythm of melatonin production, reduced the nocturnal activity and the activity and position during lunch/nap time - "[t]ogether, these data reflect the beneficial effect of melatonin to modulate the circadian components of the sleep-wake cycle, improving sleep efficiency," the authors say (Leonardo-Mendonça. 2015).

The one thing I would still like to repeat is what I already mentioned in the caption of the thumbnail to this article: Since the natural melatonin production decreases as we age and menopaus (Okatani. 2000), it is (unfortunately) possible that younger women wouldn't see the same benefits as the >56 year-old subjects of the study at hand.

Figure 2: Rodent studies also show that melatonin supplementation prolongs the lifespan of the average mouse (Pierpaoli. 1994) and rat (see data in graph) significantly (Oaknin-Bendahan. 1995).

In a similar vein, it cannot be said with any certainty, whether men will benefit to the same extent as the post-menopausal women in the study at hand. While studies in rodents clearly suggest that melatonin works its weight reducing, life pro-longing (see Figure 2) in both male and female middle-aged rodents (Rasmussen. 1999; Wolden-Hanson. 2000), as well as rats who are fed an obesogenic diet like the standard American diet (Prunet-Marcassus. 2003), men are no little mice... but I guess you know that ;-)

So what? Well, melatonin is a hormone, not one with that builds muscle, but as the study at hand proves one with non-debatable "beneficial effects on body composition in terms of reduced fat mass and borderline significantly increased lean mass in post-menopausal women".  What's particularly interesting is that this effect can be achieved with relatively small doses of melatonin (1 and 3mg/d) and without any of the unwanted effects on blood lipids, glucose metabolism or markers of kidney and liver health you would see with other hormonal substances with proven body-recompositioning effects.

Will Melatonin Reduce Your Testoste- rone Levels? A Review of the Existing Evidence Experimental Human Data Says: Unlike in rodents, the longterm administrationf melatonin to men appears to rather increase vs. decrease their T levels.

In this context it is also worth mentioning that the authors believe that their "findings may be explained by a melatonin-driven increase in osteogenesis resulting in decreased adipogenesis". Bone instead of fat cells? Well, as SuppVersity reader and follower of the SuppVersity Facebook News-Channel you will have read about the cellular underpinnings of this transformation before. Against that background it is not unreasonable of Amstrup et al. to conclude that "[o]n the basis of [their] study, melatonin maybe an interesting therapeutic agent for future treatment strategies against [...] age-related changes in body composition"  (Amstrup. 2105). Whether it is a must have supplement for younger (more athletic) individuals, though, will have to be determined in future human trials, of which I doubt that they will be publicly funded  | Comment on FB!

References:

• Amstrup, et al. "Reduced fat mass and increased lean mass in response to one year of melatonin treatment in postmenopausal women: A randomized placebo controlled trial." Clinical Endocrinology (2015): Accepted article.
• Leonardo-Mendonça RC,  et al. "The benefits of four weeks of melatonin treatment on circadian patterns in resistance-trained athletes." Chronobiol Int. 11 (2015): 1-10. 
• Oaknin-Bendahan, Sol, et al. "Effects of long-term administration of melatonin and a putative antagonist on the ageing rat." Neuroreport 6.5 (1995): 785-788.
• Okatani, Yuji, Nobuyuki Morioka, and Akihiko Wakatsuki. "Changes in nocturnal melatonin secretion in perimenopausal women: correlation with endogenous estrogen concentrations." Journal of pineal research 28.2 (2000): 111-118.
• Prunet-Marcassus, Benedicte, et al. "Melatonin reduces body weight gain in Sprague Dawley rats with diet-induced obesity." Endocrinology 144.12 (2003): 5347-5352.
• Rasmussen, Dennis D., et al. "Daily melatonin administration at middle age suppresses male rate visceral fat, plasma leptin, and plasma insulin to youthful levels." Endocrinology 140.2 (1999): 1009-1012.
• Wolden-Hanson, T., et al. "Daily Melatonin Administration to Middle-Aged Male Rats Suppresses Body Weight, Intraabdominal Adiposity, and Plasma Leptin and Insulin Independent of Food Intake and Total Body Fat 1." Endocrinology 141.2 (2000): 487-497.