Why Do We Sleep?
It’s surprisingly difficult to pin down the biological purpose of sleep. We know that sleep is conserved across nearly all animals (even nematodes have periods of quiescence). But sleep is also risky because you can’t fight off a predator while unconscious. Given that sleep is evolutionarily expensive, it must be doing something really important.
Many researchers agree that sleep does “something really important”, they’re just not sure what that mystery function is yet. Dr. Dement, who co-discovered REM sleep famously quipped:
As far as I know, the only reason we need to sleep that is really really solid is because we get sleepy.
Despite centuries of research, sleep remains mysterious. One of the most promising explanations comes from Dr. Nedergaard.
Sleep as Housekeeping For The Brain
I once had the pleasure of meeting Dr. Maiken Nedergaard at a sleep conference in Texas. She had just published an elegant paper in Science (Sleep Drives Metabolite Clearance from the Adult Brain) which showed that sleep cleans the brain. What does that mean?
Her group at the University of Rochester used real-time assessments of tetramethylammonium diffusion and two-photon imaging to visualize what’s happening in the brain of live mice during sleep.
Nedergaard and colleagues reported that sleep is associated with a 60% increase in the interstitial space. This expansion of interstitial space increases the convective exchange of cerebrospinal fluid with interstitial fluid, enhancing the clearance of neurotoxins like beta-amyloid during sleep . Beta-amyloid is that pesky protein that forms plaques in the brains of patients with Alzheimer’s disease.
On a more practical note, in this post, I’ll share with you what I’ve learned about sleep enhancement and an integrative medicine approach to insomnia.
Sleep is Underrated
Sleep is highly underrated. Millennials seem interested in cutting corners and figuring out ways to do more with less sleep. One of my goals has always been the opposite: to enhance sleep quality, sleep longer, and find ways to make sleep more restorative and refreshing.
Sleep affects every bodily system. Sleep loss has many effects you might not expect. For example, sleep loss increases appetite  and skews your preferences toward sugary foods.
No “Magic Bullets” For Insomnia
There’s no doubt that prescription drugs can be lifesaving.
But for some, the adverse effects of prescription drugs outweigh the benefits. The popular z-drug Ambien (zolpidem) is associated with a number of serious cognitive side effects like amnesia and an increased risk of later developing dementia .
Simply put, prescription drugs are no “magic bullets” for insomnia. Antihistamines like Benadryl are anticholinergic and impair memory . Benzodiazepines and z-drugs make it easier to fall asleep, but the sleep they provide is shallow and non-restorative . Melatonin mimetics like rozerem have tolerable side effects it’s unclear whether they’re more effective than melatonin itself. Patient reports about the efficacy of suvorexant (Belsomra) – a new orexin antagonist – have been disappointing.
Natural sleep aids are probably less effective than prescription drugs but carry fewer (and less serious) side effects. If you suffer from insomnia, it may make sense to experiment with supplements to enhance sleep quality as the first line of defense.
Types of Insomnia
Sleep problems come in two flavors:
- Difficulty initiating sleep
- Difficulty maintaining sleep
Researchers quantify “difficulty initiating sleep” by measuring sleep latency. If you turned the lights off and lay down right now, your sleep latency would be the amount of time it takes you to fall asleep. Shorter sleep latencies indicate increased sleep pressure, which reflects the homeostatic drive to sleep.
Here are some other terms that will crop up in the following discussion:
- Sleep consolidation – more consolidated sleep is better. If you’re waking up every 5 minutes due to sleep apnea then your sleep is fragmented (not consolidated).
- Sleep efficiency – more efficient sleep is better. Sleep efficiency is the amount of time you spend asleep divided by the amount of time you spend in bed. If you fall asleep the moment your head hits the pillow and leave your bed on waking then your sleep is 100% efficient.
Magnesium is an essential dietary mineral. In fact, magnesium is essential to the basic biochemistry of all living organisms. Over 300 enzymes require magnesium ions to catalyze reactions. ATP – the cellular energy currency of all life – is naturally found as a chelate with the magnesium ion.
Magnesium deficiency is surprisingly common, even in developed countries. In the US, only about 1/3 of people meet the recommended daily intake of 300-400mg .
Relevance to Sleep
Under physiologic conditions, the magnesium ion blocks the pore of NMDA-type glutamate receptors . By sitting in this pore, magnesium prevents these receptors from transmitting a signal inside the cell. Without magnesium, calcium rushes into nerve cells and depolarizes (or activates) neurons.
In brief, magnesium prevents neurons from being becoming hyperactive. Magnesium thus has a neuroprotective effect , and tends to reduce anxiety , insomnia, while promoting rest. Magnesium may also enhance learning and memory by improving the signal-to-noise ratio in the brain.
Abbasi et al. tested the effect of magnesium supplementation on primary insomnia . The authors reported that dietary magnesium had a statistically significant effect on sleep time (p = 0.002), sleep efficiency (p = 0.03), sleep onset latency (p = 0.02) and serum cortisol (p = 0.008), and melatonin (p = 0.007).
Rondanelli tested the effect of melatonin, magnesium and zinc supplementation on primary insomnia in a double-blind, placebo-controlled clinical trial. The authors found that supplementation improved ease of falling asleep (p < 0.001), sleep quality (p < 0.001), and total sleep time (p < 0.001). One limitation of this study was that since the authors used a combination supplement itâ€™s hard to isolate the effect of magnesium on sleep.
Lavender encompasses a genus of 47 species of flowing plants that belong to the mint family. Lavender oil has anti-inflammatory, antiseptic, and anxiolytic properties. Lavender is also used in salads and dressing and as a condiment.
Toyoshi Umezu et al. evaluated the chemical composition of lavender using GC/MS. The authors reported the following constituents:
- a-pinene (0.22%)
- camphene (0.06%)
- B-myrcene (5.33%)
- p-cymene (0.3%)
- limonene (1.06%)
- cineol (0.51%)
- linalool (26.12%)
- borneol (1.21%)
- terpinene-4-ol (4.64%)
- linalyl acetate (26.32%)
- geranyl acetate (2.14%)
- caryophyllene (7.55%)
Linalool is the major pharmacologically active agent involved in the anti-anxiety effects of lavender oil.
Relevance To Sleep
There’s a lot of overlap between anxiety and insomnia. Anxiety keeps you up at night, and insomnia itself paves the way for anxiety. Both anxiety and insomnia involve states of hyperarousal and sympathetic hyperactivity .
The sympathetic nervous system mediates the fight-or-flight response, e.g., the adrenaline jolt you experienced when facing threatening situations. Sometimes the sympathetic nervous system becomes activated at inappropriate times (like when you’re trying to fall asleep). Sympathetic hyperactivity is a common mechanism underlying both anxiety and insomnia.
It’s well known that lavender has anti-anxiety effects. In double-blind, placebo-controlled trials, people feel less anxious after lavender treatment . On this basis, we would expect lavender to also be useful for insomnia.
Guillemain J et al. tested the effects of lavender oil mice. The authors found that lavender increased total time sleep, decreased sleep latency, and interacted with pentobarbital (a barbiturate and CNS depressant). Sedatives tend to have synergistic effects. These results may be promising, but few studies have been conducted on lavender oil as a treatment for insomnia in humans.
Many studies have investigated the effect of Lavender scent  on insomnia. I’m less interested in these studies because the pharmacologically active agent in lavender, linalool, doesn’t have a high enough vapor pressure to be delivered in the air. There’s also the confound that any pleasing odor could promote relaxation and alleviate insomnia.
Nevertheless, lavender oil is one of my favorite supplements because it’s a safe, plant-derived sedative with minimal side effects.
Melatonin is an endogenous neurohormone that regulates sleep/wake cycles. No discussion of sleep aids would be complete without mention of melatonin.
There are a few common misconceptions about melatonin that require clarification:
- People tend to take melatonin right before bed. This will actually cause a phase delay and potentially make it more difficult to fall asleep. Ideally, you’d take melatonin 3 hours before bed.
- The doses in conventional melatonin supplements are far too high. A conventional dose of melatonin from your neighborhood pharmacy will produce melatonin blood levels that are 10x normal. Instead of taking 3mg of melatonin, it’s recommended to take around 0.3 mg (300mcg) to mimic the natural, endogenous levels in your body at night .
Valerian is a perennial flowering plant native to Asia and Europe and naturalized in North America. Valerian has heads of white or pink flowers and can reach a height of 5 feet. It has a distinctive odor that some may find unpleasant.
Valerian has been used medicinally since at least ancient Greece. Its properties were first characterized by Hippocrates, and Galen recommended it to his patients for insomnia in the 2nd century. In World War II, valerian was used in the UK to ameliorate stress associated with air raids.
The chemical composition of valerian is well-documented, but valerian’s weak sedative have not been attributed to any single compound. It’s likely that valerian’s effects result from multiple constituents acting synergistically.
Relevance to Insomnia
The extract of valerian root has been used to treat sleep disorders in Europe for decades and has grown in popularity in the United States. A 2001 study reported that 1.1% of the adult population in the US used valerian in the last week .
The use of valerian for insomnia is controversial in the medical community. On the one hand, meta-analyses like the study by Dr. Stephen Bent suggest that valerian may be an effective alternative to conventional sleep aids with minimal side effects . But on the other hand, Leach’s meta-analysis suggests that valerian is not effective and may even be harmful:
In terms of safety, fewer adverse events were reported among participants treated with chamomile and kava relative to placebo, with a similar number of events reported between wuling and placebo; although, the difference between groups in the frequency of adverse events was not statistically significant. By contrast, a greater number of adverse events per person were reported among subjects treated with valerian compared with placebo.
One explanation for valerian’s sedative effects are that the extract increases synaptic GABA. GABA or gamma-aminobutyric acid is an inhibitory neurotransmitter that suppresses neuronal activity.
This hypothesis comes from Santos MS’ 1994 study  showing that valerian extract induces GABA release from synaptosomes and then blocks GABA’s uptake back into nerve cells. Moreover, valerenic acid, a constituent of valerian extract, inhibits an enzyme that metabolizes GABA. Valerian extract itself contains GABA, though it remains unlikely that GABA crosses the blood brain barrier.
Evidence supporting herbal remedies for insomnia are generally inconclusive but suggestive of benefit. Since valerian, melatonin, lavender and magnesium are generally recognized as safe the downside risk is minimal. I personally use these natural alternatives to manage my own sleep problems because the risk/benefit analysis for prescription somnogens is unfavorable.
Apart from supplements, good nutrition and exercise have a big effect on sleep quality. My sleep regimen also includes:
- Sleeping in cold conditions (cold temperature promotes sleep)
- Practicing good sleep hygiene by going to bed the same time every night
- Avoiding screens an hour before bed
If you have clinical grade insomnia that only responds to prescription drugs, please don’t let this post dissuade you from following the advice of your physician.
References and Further Reading
: Zimmerman JE, Naidoo N, Raizen DM, Pack AI. Conservation of sleep: insights from non-mammalian model systems. Trends Neurosci. 2008;31(7):371-6.
: Xie L, Kang H, Xu Q, et al. Sleep drives metabolite clearance from the adult brain. Science. 2013;342(6156):373-7.
: Chen PL, Lee WJ, Sun WZ, Oyang YJ, Fuh JL. Risk of dementia in patients with insomnia and long-term use of hypnotics: a population-based retrospective cohort study. PLoS ONE. 2012;7(11):e49113.
: Orzechowski RF, Currie DS, Valancius CA. Comparative anticholinergic activities of 10 histamine H1 receptor antagonists in two functional models. Eur J Pharmacol. 2005;506(3):257-64.
: Chen L, Bell JS, Visvanathan R, et al. The association between benzodiazepine use and sleep quality in residential aged care facilities: a cross-sectional study. BMC Geriatr. 2016;16(1):196.
: Rosanoff A, Weaver CM, Rude RK. Suboptimal magnesium status in the United States: are the health consequences underestimated?. Nutr Rev. 2012;70(3):153-64.
: Decollogne S, Tomas A, Lecerf C, Adamowicz E, Seman M. NMDA receptor complex blockade by oral administration of magnesium: comparison with MK-801. Pharmacol Biochem Behav. 1997;58(1):261-8.
: Cho GJ, Hong HR, Hong SC, Oh MJ, Kim HJ. The neuroprotective effect of magnesium sulfate in preterm fetal mice. J Perinat Med. 2015;43(5):537-43.
: Jacka FN, Overland S, Stewart R, Tell GS, Bjelland I, Mykletun A. Association between magnesium intake and depression and anxiety in community-dwelling adults: the Hordaland Health Study. Aust N Z J Psychiatry. 2009;43(1):45-52.
: Slutsky I, Abumaria N, Wu LJ, et al. Enhancement of learning and memory by elevating brain magnesium. Neuron. 2010;65(2):165-77.
: Abbasi B, Kimiagar M, Sadeghniiat K, Shirazi MM, Hedayati M, Rashidkhani B. The effect of magnesium supplementation on primary insomnia in elderly: A double-blind placebo-controlled clinical trial. J Res Med Sci. 2012;17(12):1161-9.
: Rondanelli M, Opizzi A, Monteferrario F, Antoniello N, Manni R, Klersy C. The effect of melatonin, magnesium, and zinc on primary insomnia in long-term care facility residents in Italy: a double-blind, placebo-controlled clinical trial. J Am Geriatr Soc. 2011;59(1):82-90.
: Umezu T, Nagano K, Ito H, Kosakai K, Sakaniwa M, Morita M. Anticonflict effects of lavender oil and identification of its active constituents. Pharmacol Biochem Behav. 2006;85(4):713-21.
: Roth T. Insomnia: definition, prevalence, etiology, and consequences. J Clin Sleep Med. 2007;3(5 Suppl):S7-10.
: Kasper S, Gastpar M, MÃ¼ller WE, et al. Lavender oil preparation Silexan is effective in generalized anxiety disorder–a randomized, double-blind comparison to placebo and paroxetine. Int J Neuropsychopharmacol. 2014;17(6):859-69.
: Delaveau P, Guillemain J, Narcisse G, Rousseau A. Neuro-depressive properties of essential oil of lavender. C R Seances Soc Biol Fil. 1989;183(4):342-8.
: Lee IS, Lee GJ. Effects of lavender aromatherapy on insomnia and depression in women college students. Taehan Kanho Hakhoe Chi. 2006;36(1):136-43.
: Sharkey KM, Eastman CI. Melatonin phase shifts human circadian rhythms in a placebo-controlled simulated night-work study. Am J Physiol Regul Integr Comp Physiol. 2002;282(2):R454-63.
: Reiter RJ, Vaughan MK, Waring PJ. Studies on the minimal dosage of melatonin required to inhibit pineal antigonadotrophic activity in male golden hamsters. Horm Res. 1975;6(4):258-67.
: Barnes PM, Powell-griner E, Mcfann K, Nahin RL. Complementary and alternative medicine use among adults: United States, 2002. Adv Data. 2004;(343):1-19.
: Bent S, Padula A, Moore D, Patterson M, Mehling W. Valerian for sleep: a systematic review and meta-analysis. Am J Med. 2006;119(12):1005-12.
: Leach MJ, Page AT. Herbal medicine for insomnia: A systematic review and meta-analysis. Sleep Med Rev. 2015;24:1-12.
: Santos MS, Ferreira F, Cunha AP, Carvalho AP, Macedo T. An aqueous extract of valerian influences the transport of GABA in synaptosomes. Planta Med. 1994;60(3):278-9.
: Crispim CA, Zalcman I, DÃ¡ttilo M, Padilha HG, Tufik S, Mello MT. [Relation between sleep and obesity: a literature review]. Arq Bras Endocrinol Metabol. 2007;51(7):1041-9.