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​​What are circadian rhythms?

Circadian rhythms are physical, mental, and behavioral changes that follow a 24-hour cycle. These natural processes respond primarily to light and dark and affect most living things, including animals, plants, and microbes. Chronobiology is the study of circadian rhythms. One example of a light-related circadian rhythm is sleeping at night and being awake during the day. The Average Teen Circadian Cycle image shows the circadian rhythm cycle of a typical teen.

What are biological clocks?

Circadian rhythm cycle of a typical teenager. Credit: NIGMS.
Circadian rhythm cycle of a typical teenager. Credit: NIGMS.

Biological clocks are organisms’ natural timing devices, regulating the cycle of circadian rhythms. They’re composed of specific molecules (proteins) that interact with cells throughout the body. Nearly every tissue and organ contains biological clocks. Researchers have identified similar genes in people, fruit flies, mice, plants, fungi, and several other organisms that make the clocks’ molecular components.

What is the master clock?

A master clock in the brain coordinates all the biological clocks in a living thing, keeping the clocks in sync. In vertebrate animals, including humans, the master clock is a group of about 20,000 nerve cells (neurons) that form a structure called the suprachiasmatic nucleus, or SCN. The SCN is in a part of the brain called the hypothalamus and receives direct input from the eyes.

 

 

Does the body make and keep its own circadian rhythms?

Yes, natural factors in your body produce circadian rhythms. For humans, some of the most important genes in this process are the Period and Cryptochrome genes. These genes code for proteins that build up in the cell’s nucleus at night and lessen during the day. Studies in fruit flies suggest that these proteins help activate feelings of wakefulness, alertness, and sleepiness. However, signals from the environment also affect circadian rhythms. For instance, exposure to light at a different time of day can reset when the body turns on Period and Cryptochrome genes.

How do circadian rhythms affect health?

Circadian rhythms can influence important functions in our bodies, such as:

  • Hormone release
  • Eating habits and digestion
  • Body temperature

However, most people notice the effect of circadian rhythms on their sleep patterns. The SCN controls the production of melatonin, a hormone that makes you sleepy. It receives information about incoming light from the optic nerves, which relay information from the eyes to the brain. When there is less light—for example, at night—the SCN tells the brain to make more melatonin so you get drowsy.

Nobel Prize

In 2017, researchers Jeffrey C. Hall, Michael Rosbash, and Michael W. Young won the prestigious Nobel Prize for their circadian rhythms research. By studying fruit flies, which have a very similar genetic makeup to humans, they isolated a gene that helps control the body’s clock. The scientists showed that the gene produces a protein that builds up in cells overnight, then breaks down during the day. This process can affect when you sleep, how sharply your brain functions, and more. All three researchers were funded by NIGMS when these major discoveries were made.

Circadian rhythm neurons in the fruit fly brain. Credit: Matthieu Cavey and Justin Blau, New York University
Circadian rhythm neurons in the fruit fly brain. Credit: Matthieu Cavey and Justin Blau, New York University

 

Melatonin is a hormone that makes you sleepy. Credit: iStock
Melatonin is a hormone that makes you sleepy. Credit: iStock

 

What factors can change circadian rhythms?

Changes in our body and environmental factors can cause our circadian rhythms and the natural light-dark cycle to be out of sync. For example:

  • Mutations or changes in certain genes can affect our biological clocks.
  • Jet lag or shift work causes changes in the light-dark cycle.
  • Light from electronic devices at night can confuse our biological clocks.

These changes can cause sleep disorders, and may lead to other chronic health conditions, such as obesity, diabetes, depression, bipolar disorder, and seasonal affective disorder.

How are circadian rhythms related to jet lag?

When you pass through different time zones, your biological clock will be different from the local time. For example, if you fly east from California to New York, you “lose” 3 hours. When you wake up at 7:00 a.m. on the East Coast, your biological clock is still running on West Coast time, so you feel the way you might at 4:00 a.m. Your biological clock will reset, but it will do so at a different rate. It often takes a few days for your biological clock to align with a new time zone. Adjusting after “gaining” time may be slightly easier than after “losing” time because the brain adjusts differently in the two situations.

How do researchers study circadian rhythms?

Scientists learn about circadian rhythms by studying humans and by using organisms with similar biological clock genes, such as fruit flies and mice. Researchers doing these experiments control the subject’s environment by altering light and dark periods. Then they look for changes in gene activity or other molecular signals. Scientists also study organisms with irregular circadian rhythms to identify which genetic components of biological clocks may be broken.

Understanding what makes biological clocks tick may lead to treatments for jet lag, sleep disorders, obesity, mental health disorders, and other health problems. It can also improve ways for people to adjust to nighttime shift work. Learning more about the genes responsible for circadian rhythms will also help us understand more about the human body.

Traveling across time zones disrupts your circadian rhythms. Credit: iStock
Traveling across time zones disrupts your circadian rhythms. Credit: iStock

source

Circadian Rhythm

Stephanie Booth source

Although you won’t hear it tick, your body has its own clock. The physical and mental changes it causes are called circadian rhythms. Most living things have them, including animals, plants, and even some germs.Circadian rhythms affect your sleep patterns as well as other ways your body works, like your hormones, body temperature, and eating habits. When they get out of sync, they might also cause problems with your health. They’ve been linked to different disorders including diabetes, obesity, and depression.To get good, healthy sleep, it helps to know what keeps your body’s clock on track and what might throw its rhythm off.

How Circadian Rhythms Work

About 20,000 nerve cells make up your “master clock,” a part of your brain called the suprachiasmatic nucleus. This structure, which sits inside an area called the hypothalamus, controls your circadian rhythms. While largely guided by your genes and other natural factors inside your body, things in the outside world can also alter them.

The biggest cue is light. Your body is wired to sleep when it’s dark and stay awake when it’s light outside. Nerves directly link your eyes and your body’s master clock. When daylight fades, your eyes signal your brain to make more melatonin, a hormone that makes you feel sleepy. And when the sun rises again, the signals tell the brain to turn down the melatonin.Circadian rhythms work by helping to make sure that the body’s processes are optimized at various points during a 24-hour period Trusted SourceNational Institute of General Medical Sciences (NIGMS)The NIGMS supports basic research that increases our understanding of biological processes and lays the foundation for advances in disease diagnosis, treatment, and prevention.nigms.nih.gov. The term circadian comes from the Latin phrase “circa diem,” Trusted SourceNational Library of Medicine, Biotech InformationThe National Center for Biotechnology Information advances science and health by providing access to biomedical and genomic information.pubmed.ncbi.nlm.nih.govwhich means “around a day.”Circadian rhythms exist in all types of organisms. For example, they help flowers open and close at the right time and keep nocturnal animals from leaving their shelter Trusted SourceNational Library of Medicine, Biotech InformationThe National Center for Biotechnology Information advances science and health by providing access to biomedical and genomic information.pubmed.ncbi.nlm.nih.govduring the daytime when they would be exposed to more predators.In people, circadian rhythms coordinate mental and physical systems Trusted SourceNational Library of Medicine, Biotech InformationThe National Center for Biotechnology Information advances science and health by providing access to biomedical and genomic information.pubmed.ncbi.nlm.nih.govthroughout the body. The digestive system produces proteins Trusted SourceNational Institute of General Medical Sciences (NIGMS)The NIGMS supports basic research that increases our understanding of biological processes and lays the foundation for advances in disease diagnosis, treatment, and prevention.nigms.nih.govto match the typical timing of meals, and the endocrine system regulates hormones to suit normal energy expenditure.The circadian rhythms throughout the body are connected to a master clock, Trusted SourceNational Institute of General Medical Sciences (NIGMS)The NIGMS supports basic research that increases our understanding of biological processes and lays the foundation for advances in disease diagnosis, treatment, and prevention.nigms.nih.govsometimes referred to as the circadian pacemaker, located in the brain. Specifically, it is found in the suprachiasmatic nucleus (SCN), which is in a part of the brain called the hypothalamus. At different times of the day, clock genes Trusted SourceNational Institute of General Medical Sciences (NIGMS)The NIGMS supports basic research that increases our understanding of biological processes and lays the foundation for advances in disease diagnosis, treatment, and prevention.nigms.nih.govin the SCN send signals to regulate activity throughout the body.The SCN is highly sensitive to light, which serves as a critical external cue that influences the signals sent by the SCN to coordinate internal clocks in the body. For this reason, circadian rhythms are closely connected to day and night. While other cues, like exercise, social activity, and temperature, can affect the master clock, light is the most powerful influence on circadian rhythms.

Is a Circadian Rhythm the Same As a Biological Clock?

Biological clocks help regulate the timing of bodily processes, including circadian rhythms. A circadian rhythm is an effect of a biological clock, but not all biological clocks are circadian. For instance, plants adjust to changing seasons using a biological clock with timing that is distinct from a 24-hour cycle.

How Does Circadian Rhythm Affect Sleep?

When people talk about circadian rhythm, it’s most often in the context of sleep. The sleep-wake cycle is one of the most clear and critical examples of the importance of circadian rhythms.

During the day, light exposure causes the master clock to send signals that generate alertness Trusted SourceDivision of Sleep Medicine at Harvard Medical SchoolA production of WGBH Educational Foundation and the Harvard Medical School Division of Sleep Medicine.healthysleep.med.harvard.eduand help keep us awake and active. As night falls, the master clock initiates the production of melatonin, a hormone that promotes sleep, and then keeps transmitting signals that help us stay asleep through the night.

In this way, our circadian rhythm aligns our sleep and wakefulness with day and night Trusted SourceDivision of Sleep Medicine at Harvard Medical SchoolA production of WGBH Educational Foundation and the Harvard Medical School Division of Sleep Medicine.healthysleep.med.harvard.eduto create a stable cycle of restorative rest that enables increased daytime activity.

Different Patterns for Different People

You’ve likely noticed that you feel more alert during certain parts of the day and have lower energy at others. This pattern has to do with your “chronotype,” or personal circadian rhythm. They vary from person to person, although they tend to run in families.

Most of the time, people fall into one of two groups:

Early birds: If you find it easy to wake up in the morning and feel you have the most energy early in the day, you’re a morning person or a “lark.” Some research suggests that an early bird’s body clock may run slightly faster than 24 hours.

Night owls: If you’re an evening person, some research suggests that your body clock runs slower than 24 hours. You’ll find it hard to wake up in the mornings and feel alert. You’ll have the most energy much later in the day, like 11 p.m.Your chronotype isn’t set in stone, though. Circadian rhythms naturally change as you age. For example, the body clock shifts during adolescence, making teens want to go to bed later and sleep longer than younger kids.Your work or school schedule may mean that you need to switch from a night owl to an early bird. You can try to alter your circadian rhythm yourself, but do it slowly. For example, try waking up 15 minutes earlier each morning over the course of a week.

Circadian Rhythms Out of Sync

Small changes can upset your circadian rhythms. These include:

Extra sleep. Your body clock works best when you stick to a schedule. In an ideal world, you’ll go to sleep and wake up within a half hour of the same time each day, even on weekends.

Travel. When you pass through time zones, you can adjust your watch but not your body clock. It will try to function on the time it is at your home, a problem you may know as jet lag. The more time zones you pass through, the more off you may feel. Your body clock will reset to the new time you’re in, but it can take a few days.

Screen time. Any amount of light signals your brain that it’s time to be up and alert. Even the blue light from your tablet, smartphone, or TV has this effect. To get a good night’s sleep, unplug from all screens 2 to 3 hours before bed. Other artificial light can have the same effect, so turn off hallway lights and face your alarm clock away from you. If you’re bothered by light outside your home, put up blackout curtains or use a sleep mask.

Night shifts. If you work nights, you’ll need to sleep during the day. This can be tough since your body is programmed to be awake when it’s light outside. Over time, you can start to have what’s called shift work disorder. You’ll find it hard to stay awake at night, yet struggle to sleep during the day. Naps during the day or your night shift can help.

Your period. Many women notice that they sleep worse before their period starts. This may be due, at least in part, to a change in circadian rhythms. Some studies show that less sleep during this time can reset your body clock and give some relief. Bright daylight or light therapy may also make a difference.

What Does Circadian Rhythm Affect Besides Sleep?

While the sleep-wake cycle is one of the most prominent circadian rhythms, these 24-hour internal clocks play a vital role in virtually all systems of the body Trusted SourceNational Institute of General Medical Sciences (NIGMS) BlogThe NIGMS supports basic research that increases our understanding of biological processes and lays the foundation for advances in disease diagnosis, treatment, and prevention.biobeat.nigms.nih.gov.

Research continues to uncover details about circadian rhythms, but evidence has connected them Trusted SourceNational Library of Medicine, Biotech InformationThe National Center for Biotechnology Information advances science and health by providing access to biomedical and genomic information.pubmed.ncbi.nlm.nih.govto metabolism and weight through the regulation of blood sugar and cholesterol. Circadian rhythms influence mental health as well, including the risk of psychiatric illnesses like depression and bipolar disorder as well as the potential for neurodegenerative diseases Trusted SourceMedline PlusMedlinePlus is an online health information resource for patients and their families and friends.medlineplus.govlike dementia.

There are indications that circadian rhythms have an important influence on the immune system as well as processes of DNA repair that are involved in preventing cancer Trusted SourceNational Library of Medicine, Biotech InformationThe National Center for Biotechnology Information advances science and health by providing access to biomedical and genomic information.pubmed.ncbi.nlm.nih.gov. Early-stage research indicates that circadian cycles can influence the effectiveness of anti-cancer drugs Trusted SourceNational Cancer Institute (NCI)The NCI is the federal government’s principal agency for cancer research and training.cancer.govand that new medications may be able to harness biological clocks to kill cancer cells.

What Happens When Circadian Rhythm Is Off?

When circadian rhythm is thrown off, it means that the body’s systems don’t function optimally.

A disturbed sleep-wake circadian rhythm can give rise to serious sleeping problems. Without the proper signaling from the body’s internal clock, a person can struggle to fall asleep, wake up during the night, or be unable to sleep as long as they want into the morning. Their total sleep can be reduced, and a disrupted circadian rhythm can also mean shallower, fragmented, and lower-quality sleep.Eric Suni, Staff Writer source

What Can Disrupt Circadian Rhythm?

Disruptions to circadian rhythm can occur over the short- or long-term. Experts have identified a number of types of circadian rhythm sleep-wake disorders (CRSWD) based on their characteristics and causes.

  • Jet Lag Disorder: This occurs when a person crosses multiple time zones in a short period of time and gets its name from the fact that it is often experienced by people who take intercontinental flights. Until a person’s circadian rhythm can acclimate to the day-night cycle of their new location, they are likely to suffer sleeping problems and fatigue from jet lag.
  • Shift Work Disorder: Work obligations can cause major disruptions in a person’s circadian rhythm. Shift work, which requires having to work through the night and sleep during the day, puts a person’s sleep schedule directly at odds with the local daylight hours.
  • Advanced Sleep Phase Disorder: People with this type of disruption find that they get tired early in the evening and wake up very early in the morning. Even if they want to be up later at night or sleep later in the morning, people with an advanced sleep phase disorder usually cannot do so. This disorder is relatively rare, affecting around 1% of people in middle and older age Trusted SourceNational Library of Medicine, Biotech InformationThe National Center for Biotechnology Information advances science and health by providing access to biomedical and genomic information.pubmed.ncbi.nlm.nih.gov, and occurs more frequently in older adults. In some cases, advanced sleep phase disorder may be related to an inherited genetic cause.
  • Delayed Sleep Phase Disorder: This type of circadian rhythm disruption is associated with “night owls” who stay up late at night and sleep in late in the morning. It is rare among the general population — affecting just 1 or 2 people out of every 1,000 — but impacts up to 16% of teens. The exact cause is unknown but may be related to genetics, underlying physical conditions, and a person’s behavior.
  • Non-24 Hour Sleep Wake Disorder: This condition occurs primarily in people who are blind Trusted SourceNational Organization for Rare Disorders (NORD)NORD is a patient advocacy organization dedicated to individuals with rare diseases and the organizations that serve them.rarediseases.organd are not able to receive light-based cues for their circadian rhythm. Their body still follows a 24-hour cycle, but their sleeping hours constantly shift backward by minutes or hours at a time.
  • Irregular Sleep-Wake Rhythm Disorder: People with this rare disorder have no consistent pattern to their sleep and may have many naps or short sleeping periods throughout a 24-hour day. It is frequently connected to conditions that affect the brain Trusted SourceNational Library of Medicine, Biotech InformationThe National Center for Biotechnology Information advances science and health by providing access to biomedical and genomic information.pubmed.ncbi.nlm.nih.gov, such as dementia or traumatic brain injury, that limit the proper functioning of the master clock in the hypothalamus.

As this list demonstrates, there are diverse causes of circadian rhythm disorders. Some circadian disruptions are related to individual behavior, such as for travel or work, that puts sleep schedules out of whack with normal daylight exposure. Other disorders stem from an underlying issue that causes an inability to receive or process environmental cues that regulate the body’s master clock. In certain situations, genetic causes may be involved, or the cause may remain unknown.

How To Maintain a Healthy Circadian Rhythm

While we don’t have full control over our circadian rhythm, there are healthy sleep tips that can be taken to try to better entrain our 24-hour sleep cycles.

  • Seek out sun: Exposure to natural light, especially early in the day, helps reinforce the strongest circadian cue.
  • Follow a consistent sleep schedule: Varying your bedtime or morning wake-up time can hinder your body’s ability to adjust to a stable circadian rhythm.
  • Get daily exercise: Activity during the day can support your internal clock and help make it easier to fall asleep at night.
  • Avoid caffeine: Stimulants like caffeine can keep you awake and throw off the natural balance between sleep and wakefulness. Everyone is different, but if you’re having trouble sleeping, you should avoid caffeine after noon.
  • Limit light before bed: Artificial light exposure at night can interfere with circadian rhythm. Experts advise dimming the lights and putting down electronic devices in the lead-up to bedtime and keeping electronics out of the bedroom and away from your mattress.
  • Keep naps short and early in the afternoon: Late and long naps can push back your bedtime and throw your sleep schedule off-kilter.

These steps to improve sleep hygiene can be an important part of supporting a healthy circadian rhythm, but other steps may be necessary depending on the situation. If you have persistent or severe sleeping problems, daytime drowsiness, and/or a problematic sleep schedule, it’s important to talk with a doctor who can best diagnose the cause and offer the most appropriate treatment.

Related News

 

Circadian Rhythm: What Is It And How To Reset Your Body Clock?

Humans have clock genes that make the body tick like a well-oiled machine. Learn about your circadian rhythm and how it affects your health and disease risks.

 

A circadian rhythm is a 24-hour biological clock that affects your sleep, digestion, and metabolism. When your circadian rhythm is disrupted, it can even increase your disease risks.

The circadian rhythm is a body clock that organises all the biological processes necessary for life. It is dictated by clock genes that trigger essential metabolic activities, like storing energy, transporting oxygen, getting rid of waste, and releasing hormones and neurotransmitters.

Table of contents

Even though you can’t see or feel this clock, circadian health is essential for your health and wellbeing. In this article, you’ll discover what happens when the cycle rhythm is disrupted, how to reset your body clock, and how to fix your sleep schedule.

What is a circadian rhythm?

 

How does your body know what time it is? (Ted Ed video)

The circadian rhythm is a 24-hour clock that dictates millions of invisible metabolic processes that keep the body alive. It determines digestive rhythms, fat burning and fat storage, sleeping patterns, and much more. This biological rhythm is run by clock genes that signal when each process should take place.

Approximately 20% of genes turn on and off during the 24-hour cycle.

Going to bed late, playing with your phone at midnight, eating late in the evening, and working night shifts are all factors that can shift your circadian cycle. Scientific evidence now indicates that circadian rhythm disruptions are associated with serious, but preventable, chronic diseases like diabetes type II, heart disease, obesity, stroke, and cancers.

How the circadian cycle works

 

A circadian rhythm chart can help you optimise your daily activities

The circadian rhythm is made up of a set of clocks and a central “master clock”, called the suprachiasmatic nucleus (SCN). The SCN is located in the hypothalamus, the part of the brain responsible for regulating stress, reproduction, and growth hormones. It also indirectly impacts sleep hormones.

The body’s clock contains about 20,000 cells, which are located just above the intersection of the optic nerves. The cycle rhythm is set by signals from special melanopsin cells in the retina in response to light exposure. Blue light (from bright daylight, phone screens, and TVs) has the strongest effect on melanopsin receptors, followed by green and red light.

The circadian rhythm reacts to light: it wakes you up, and it puts you to sleep by triggering cascades of chemical events in your brain.

Body clock genes have been discovered in nearly every organ of the human body. These genes turn on and off at predictable times, switching on and shutting down the production of proteins that perform essential functions within the body’s cells.

Science-bites--NEW-orange

Sleep washes Alzheimer’s particles from the brain

 

Interestingly, studies show that blind mice and blind people still have active melanopsin receptors that regulate their biological clock. This helps to explain why patients suffering from blindness can “sense” light, even if they can’t see it.

☝Find out more about your genes☝ Take the Atlas DNA Test to explore how your genetic make-up affects your health and wellbeing.

Do you need a body clock reset?

 

Sleeping at irregular times, using devices, eating late at night, and other pernicious habits displace the cycle rhythm. When a person’s biological cycle isn’t on schedule, it causes a wide range of minor health issues that can affect everyday life.

Low energy, mood swings, food cravings, weak immunity, and having trouble losing weight are common side effects of circadian disruption according to Professor Satchidananda Panda, author of the Circadian Code.

Area Common problems
Sleep Difficulty falling or staying asleep, sleeping too much
Weight Weight gain, inability to lose weight
Vitality Low energy, reliance on caffeinated products
Diet Late-night food cravings, stomach cramps & indigestion
Mood Depression, emotional outbursts & irrational anger
Immunity Weak immune system, frequent illness & infections

Circadian rhythm and digestion

 

The digestive system secretes the most gastric juices, enzymes, and hormones in the first half of the day. This activity reduces as the afternoon progresses into evening. These molecules are all essential for healthy digestion, which is why eating late at night can cause indigestion.

Circadian rhythm and sleep

 

Your circadian rhythm is run by clock genes by Moritz Kindler for Unsplash.
Your circadian rhythm is run by clock genes

At night, the circadian rhythm is focused on putting the body to sleep, removing waste products, and repairing tissues from the wear-and-tear of daytime activities. In fact, sleep is the only time for the brain to remove the waste products of chemical reactions.

When you mess with your sleep schedule, or deprive yourself of sleep, you impair the brain’s ability to operate at maximum efficiency.

Circadian rhythm and disease

 

Living out of sync with the body’s circadian rhythm over the short and long term is associated with serious, chronic, and preventable diseases that affect the body’s metabolism, according to a 2016 systematic review on the “Interaction between circadian rhythms and stress”.

In one referenced study, the human participants with impaired circadian rhythm function had “higher blood glucose and insulin levels as well as elevated blood pressure, which are markers for metabolic and cardiovascular disease.”

The study’s summary of its effects on night shift workers demonstrated that such professionals have “a higher incidence of obesity, diabetes type II and related metabolic disturbances along with hypertension (high blood pressure), coronary heart disease, and ischemic stroke”.

How to fix your sleep schedule

 

Light and darkness are the main determinants in circadian rhythm. When daylight or screen light is detected by your eyes, it sends signals to the suprachiasmatic nucleus, which regulates all the clock genes in your body.

To reset your body clock, you need to put yourself on a schedule that respects your body’s metabolic rhythm. While this may be impossible for night shift workers, it is an achievable goal for people with day jobs.

  • Go to bed and get up at the same time every day.
  • Turn off TV screens, phones, and tablets 1-2 hours before bed.
  • Eat your biggest meal early in the day when digestive juices are highest.
  • Stay away from caffeinated beverages in the afternoon and evening.
  • Cut down on alcohol at night because it affects sleep quality.
  • Stop eating at least 3 hours before bed to avoid indigestion.
  • Get blackout curtains and dim light bulbs for your bedroom.
Sources:

What Happens When Circadian Rhythm Is Off? Learn More

Do You Wake Up Every Night At The Same Time? Learn More

How to Reset Your Sleep Cycle When You Live With Insomnia Learn More

What You Eat Affects How You Sleep? Learn More

GABA / L-theanine mixture Improves REM Sleep, Antidepressant, and Mood-stabilizing Study Says Learn More

 

]]> GABA and L-theanine mixture Improves REM Sleep, Antidepressant, and Mood-stabilizing Study Says https://goodshepherdmedia.net/gaba-and-l-theanine-mixture-improves-rem-sleep-antidepressant-and-mood-stabilizing-study-says/ Sat, 08 Jan 2022 08:32:10 +0000 https://goodshepherdmedia.net/?p=4625 GABA and L-theanine mixture Improves
REM Sleep, Antidepressant, and Mood-stabilizing Study Says

Abstract

Context: γ-Aminobutyric acid (GABA) is the main inhibitory neurotransmitter and it is well established that activation of GABAA receptors favours sleep. l-Theanine, a naturally occurring amino acid first discovered in green tea, is a well-known anti-anxiety supplement with proven relaxation benefits.

Objective: This study investigated the potential synergistic sleep enhancement effect of GABA/l-theanine mixture.

Materials and methods: Pentobarbital-induced sleep test was applied to find proper concentration for sleep-promoting effect in ICR mice. Electroencephalogram (EEG) analysis was performed to investigate total sleeping time and sleep quality in normal SD rats and caffeine-induced awareness model. Real-time polymerase chain reaction (RT-PCR) was applied to investigate whether the sleep-promoting mechanism of GABA/l-theanine mixture involved transcriptional processes.

Results: GABA/l-theanine mixture (100/20 mg/kg) showed a decrease in sleep latency (20.7 and 14.9%) and an increase in sleep duration (87.3 and 26.8%) compared to GABA or theanine alone. GABA/l-theanine mixture led to a significant increase in rapid eye movement (REM) (99.6%) and non-REM (NREM) (20.6%) compared to controls. The use of GABA/l-theanine mixture rather than GABA or l-theanine alone restored to normal levels sleep time and quality in the arousal animal model. The administration of GABA/l-theanine led to increased expression of GABA and the glutamate GluN1 receptor subunit.

Conclusions: GABA/l-theanine mixture has a positive synergistic effect on sleep quality and duration as compared to the GABA or l-theanine alone. The increase in GABA receptor and GluN1 expression is attributed to the potential neuromodulatory properties of GABA/l-theanine combination, which seems to affect sleep behaviour.

Keywords: γ-Aminobutyric acid, insomnia, pentobarbital-induced sleep test, electroencephalography

Introduction

Sleep loss and other related disturbances pose an important health problem, as they can lead to significant functional impairments. Sleep disturbances can affect daily life considerably and reduce the quality of life. The importance of a good night’s sleep is well-established, nevertheless many people suffering from sleep disorders prefer not to use hypnotic drugs, despite providing effective symptomatic relief.

Hypnotic drugs, such as benzodiazepine analogues, zolpidem and doxepin, can cause unexpected side effects and can lead to drug resistance and dependence (Longo and Johnson ; Victorri-Vigneau et al. ; Lichstein et al. ). These types of sleeping drugs are not suitable for the treatment of temporary anxiety or sleep disturbances due to the observed drug resistance and dependence that has been associated with their long-term use (Oh et al. ). However, herbal remedies have been reported as effective and with a relatively low side effect risk for the treatment of insomnia (Wheatley ). Therefore, it is necessary to develop new bioactive substances derived from natural sources that present with similar efficacy but fewer side effects than hypnotic drugs, for the successful treatment of sleep-related disturbances.

γ-Glutamylethylamine, also known as l-theanine, and γ-aminobutyric acid (GABA) are known agents for improving sleep disturbances (Khan et al. ). GABA is a non-proteinogenic amino acid and is the main inhibitory neurotransmitter in the mammalian brain. Hence GABAA receptors are a primary target in the search for natural anxiolytic compounds or sedatives (Khom et al. ; Trauner et al. ). There is an increasing interest in investigating the effect of GABA-mediated inhibitory neurotransmission, in respect to its potential benefit on counteracting sleep disruption caused by various conditions, such as stress, diseases and caffeine intake, etc. (Wong et al. ). Therefore, GABA is widely used in functional food and pharmaceutical industries, and various researches have been investigated for biosynthesis and their efficacy as metabolites of plants and microorganisms produced by the decarboxylation of glutamic acid (Coda et al. ; Dhakal et al. ; Yang et al. ) l-Theanine, an amino acid exclusively found in tea leaves, composes only 1–2% (w/w) of the weight of dried tea leaves (Graham ) and is chemically or biologically synthesized for use as an active ingredient that induces sedation (Juneja et al. ; Yan et al. ). There are several reports indicating that l-theanine exerts neuroprotective effects (Kim et al. ), modulates neurotransmitter activity (Kakuda ) and reduces psychological stress (Kimura et al. ) and sleep disturbances (Jang et al. ). Nathan et al. () also reported that l-theanine intake increases serotonin, dopamine and GABA levels in the brain.

In recent years, there have been numerous ‘relaxation beverages’ available on the market containing relaxation-inducing nutraceuticals, such as valerian, l-theanine, GABA, 5-hydroxytryptophan (5-HTP) and the sleep-aid, melatonin. Therefore, the combination of GABA and l-theanine may synergistically promote symptomatic relief for sleep disorders, despite the scarce experimental data supporting this process. The purpose of this study was to investigate whether the effect of GABA/l-theanine mixture on sleep disturbances is greater than GABA or l-theanine alone and to determine the most effective dosing combination.

Materials and methods

Materials

GABA (90.8%) and l-theanine (99.3%) was supplied by Neo Cremar Co. Ltd (Seoul, Korea) and BTC Co. Ltd (Ansan, Korea), respectively. Caffeine was purchased from Sigma-Aldrich (St. Louis, MO) and pentobarbital sodium was purchased from Hypharm. Co. Ltd. (Gyeonggi-do, Korea). All other reagents were purchased at the highest commercial grade available.

Animals

Male ICR mice (4 weeks old, 18–20 g) and Sprague-Dawley (SD) rats (8 weeks old, 160–180 g) were purchased from Orient Bio (Orient Bio Inc., Seongnam, Korea). All animals were caged at 22 ± 2 °C and 55 ± 5% humidity with a 12 h light/dark cycle. Normal pellet diet and water were freely provided. Rodents were acclimatized for at least one week before starting pentobarbital-induced sleep testing and electroencephalography (EEG) analysis. The ages of the animals used in this study were to ensure the functional integrity of the brain and central nervous system, which usually does not occur in older animals, which normally have degraded morphological and functional characteristics (Verdú et al. ). In this study, all animal experimental protocols were approved by the Korean University Animal Care Committee (KUIACUC-2017-49, Seoul, Korea).

Pentobarbital-induced sleep test

Pentobarbital-induced sleep was performed according to previously established methods with slight modifications (Yang et al. ). Sodium pentobarbital (42 mg/kg) was administered intraperitoneally in each mouse 40 min after oral administration of GABA, l-theanine or both (GABA/l-theanine). The time elapsed from compound administration to the loss of righting reflex (sleep latency) and the time from the loss of righting reflex to its return (sleep duration) were measured in seconds. Mice that did not sleep 15 min after the injection were excluded from the experiment.

Electrophysiological analysis

Male SD rats were anesthetized with 2% isoflurane (Troikaa Pharmaceutical Ltd., Gujarat, India), using a gas anesthesia mask in a stereotaxic instrument frame (Stoelting Inc., Wood Dale, IL). For the EEG recording, EEG screw electrodes were implanted into the cortex, striatum and hippocampus, as previously described (Hong et al. ). All rats received antibiotics and were kept individually in cages under a temperature-controlled facility with water and food. The rats were randomly divided into control and treatment groups at 7 days after recovery. Experiments were conducted from 10 am to 5 pm for 9 days. GABA, l-theanine or GABA/l-theanine mixture was orally administered 1 h before EEG signal analysis. EEG signals were amplified, filtered (0.5–30 Hz), recorded and stored using Iox2 (version. 2.8.0.13, emka Technologies, Paris, France). EEG spectra were analyzed in 1 Hz frequency bins and standard frequency bands (β: 13–30 Hz; α: 8–13 Hz; θ: 4–8 Hz; δ: 0.5–4 Hz). After the EEG recording, fast Fourier transform (FFT) was performed every 2 sec. Based on the FFT average data obtained at 10-sec intervals in the range of 0–30 Hz, the ecgAUTO3 program (version. 3.3.0.20, emka Technologies) was used to calculate the awake and sleep time. Caffeine (10 mg/kg) was used to induce the arousal condition before the experiments.

Quantification of receptor mRNA levels

Total RNA was extracted from mouse brains using TRIzol® (Invitrogen, CA), while genomic DNA was removed using Direct-zolTM RNA Miniprep (ZYMO Research, CA) according to the manufacturer’s protocol. Quality-controlled RNA (1 μg) was reverse transcribed using SuperScript® III Reverse Transcriptase (Invitrogen) with oligo d(T) as the primer. The generated cDNA was subjected to quantitative real-time PCR (qRT-PCR) using a Power Taqman PCR Master Mix kit (Applied Biosystems, Foster City, CA). For qRT-PCR, cycling conditions were 50 °C for 2 min, 95 °C for 10 min, followed by 40 cycles at 95 °C for 15 s and 60 °C for 1 min. Quantitative analysis was conducted using StepOne plus Software version 2.0 (Applied Biosystems, Inc., Foster City, CA). The endogenous housekeeping gene, GAPDH (NM_008084.2), was used for result normalization. Information for the target genes used for qRT-PCR is as follows: GABAA receptor (NM_008076.3), GABAB receptor 1 (NM_01 9439.3), GABAB receptor 2 (NM_001081141.1), GluA1 (NM_00111 3325.2), GluN1 (NM_001177656.2) and GluN2A (NM_008170.2).

Statistical analysis

Testing results were evaluated for statistical differences using SPSS version 12.0 (SPSS, Chicago, IL) by one-way analysis of variance (ANOVA) followed by both Tukey’s multiple comparisons and Bonferroni post hoc test. Different letters indicate significant differences (p < 0.05) among groups by Tukey’s multiple comparison tests. All data are expressed as the means ± standard error (SE) comparisons between groups, n = 8.

Results

Effects of GABA and l-theanine on sleep latency and duration in the pentobarbital-induced sleep model

Sleep latency and duration time following GABA or l-theanine administration were measured in the pentobarbital-included sleep model to identify the optimal combination ratio for sleep enhancement (Figure 1). Sleep latency showed a tendency to decrease with increasing GABA concentration and sleep duration to increase with increasing GABA concentration (Figure 1(A,B)). Regarding sleep latency, there was a significant difference (p < 0.05) following the administration of 100 mg/kg of GABA (3.1 min), as compared to control (3.7 min), but no significant differences with other GABA concentrations were observed (Figure 1(A)). With regards to sleep duration, there was also a significant difference (p < 0.05) following 100 mg/kg of GABA, as compared to control. No significant differences of sleep duration were observed following the administration of any other GABA concentrations (Figure 1(B)). Pentobarbital-induced sleep testing was carried out to assess the potential sleep enhancement effect of l-theanine (Figure 1(C,D)). Following the administration of 20 or 30 mg/kg of l-theanine, sleep latency significantly decreased (2.8 and 2.7 min, respectively), as compared to controls (3.7 min) (p < 0.05 and p < 0.01, respectively). However, the administration of 40 mg/kg of l-theanine not decreased sleep latency (3.7 min). When compared to controls (39.9 min), total sleep time increased in l-theanine-treated animals at a dose of 20 mg/kg (55.2 min), but not with 30 or 40 mg/kg of l-theanine (Figure 1(D), p < 0.01). In summary, administration of 20 mg/kg of l-theanine in mice, resulted in a decrease in sleep latency (23.3%) and an increase in sleep duration time (38.1%).

 

Effects of GABA or l-theanine on sleep latency (A, C) and sleep duration (B, D) in mice administered with a hypnotic dosage of pentobarbital (42 mg/kg, i.p.). Values are presented as the means ± standard error (SE) for each group, n = 8. Different letters indicate significant differences (p < 0.05) among samples by Tukey’s multiple range test. Symbols indicate significant differences by Bonferroni test, as **p < 0.01, *p < 0.05.

Effects of GABA/l-theanine combination on sleep latency and duration in the pentobarbital-induced sleep model

The induced changes in sleep latency and duration time by different ratio combinations of GABA (80 and 100 mg/kg) and l-theanine (20 and 30 mg/kg) were measured (Figure 2). The sleep latency of animals that were administered with either of the GABA/l-theanine dose combinations (80/30 and 100/20 mg/kg) was slightly lower than the control group (Figure 2(A)) (16.8 and 17.7%, respectively). With respect to sleep duration, sleep time showed a tendency increase in all dose combination groups (Figure 2(B)). In particular, the GABA/l-theanine mixture administered at a dose ratio of 100/20 mg/kg, evoked the highest sleep duration increase (100.6 min) (p < 0.01).

Effects of GABA/l-theanine mixture on sleep latency (A, C) and sleep duration (B, D) in mice administered with a hypnotic dosage of pentobarbital (42 mg/kg, i.p.). Values are presented as the means ± standard error (SE) for each group, n = 8. Different letters indicate significant differences (p < 0.05) among samples by Tukey’s multiple range test. Symbols indicate significant differences by Bonferroni test, as **p < 0.01, *p < 0.05.

The effects of the best sleep-promoting GABA/l-theanine dose combination (100/20 mg/kg) were compared to the changes in sleep latency and duration induced by the single administration of GABA or l-theanine (Figure 2(C,D)). The combined use of GABA/l-theanine (100/20 mg/kg) showed a decrease in sleep latency (20.7% and 14.9%, respectively) and an increase in sleep duration (87.3% and 26.8%, respectively) compared to a single administration of GABA (100 mg/kg) or theanine (20 mg/kg). The combined use of GABA/l-theanine showed synergy effects on sleep latency and sleep duration time.

Effects of GABA and l-theanine mixture on sleep architecture

EEG parameters were recorded to more accurately confirm the synergistic effect of GABA/l-theanine mixture observed in the pentobarbital-induced sleep model (Figure 3). The changes in sleep time and architecture were measured after a single administration of GABA 100 mg/kg or l-theanine 20 mg/kg and after GABA/l-theanine mixture (100/20 mg/kg). Figure 3 depicts the longest sleep time recorded following the oral administration of GABA/l-theanine. However, no significant difference in sleep time was detected between GABA/l-theanine mixture and l-theanine alone (Figure 3(A)). The most reduced awake time was detected after oral administration of GABA/l-theanine mixture (1.2 h) and was significantly different from control (2.2 h) (Figure 3(B), p < 0.001). Single GABA administration (100 mg/kg) significantly increased rapid-eye-movement (REM) sleep time, as compared to the control group (71.5%) (p < 0.01), but there was no significant difference in non-REM (NREM) sleep time compared to the control group (Figure 3(C,D)). Single l-theanine administration (20 mg/kg) significantly increased REM time, when compared to controls (88.6%) (p < 0.01), but there was no significant difference in NREM sleep time compared to the control group. NREM (20.7%) and REM (99.6%) were also significantly increased than control levels, after GABA/l-theanine mixture was orally administered (Figure 3(C,D), p < 0.05 and p < 0.001, respectively). The oral administration of GABA/l-theanine mixture improved sleep time and quality, as compared to GABA or l-theanine alone.

Effects of the GABA, l-theanine, and GABA/l-theanine mixture on sleep quantity and quality. Values are presented as the means ± standard error (SE) for each group, n = 8. Different letters indicate significant differences (p < 0.05) among samples by Tukey’s multiple range test. Symbols indicate significant differences at ***p < 0.001, **p < 0.01, *p < 0.05 by Bonferroni test. NS: not significant.

The θ wave was significantly increased after GABA (1.8 h) or l-theanine (2.2 h) single infusion, as well as after GABA/l-theanine combined administration (2.5 h) (Figure 3(E)). The δ wave showed a tendency to decrease when GABA or l-theanine was separately administered and after GABA/l-theanine, but there were no significant differences between groups (Figure 3(F)).

Effects of GABA and l-theanine combination on sleep architecture during three sleep periods

Figure 4 depicts the sleep pattern measured for 9 days divided into 3 periods. Total sleep time increased and awakening time decreased from 1st to 3rd period in all sample groups (Figure 4(A,B)). NREM sleep was significantly increased in the GABA/l-theanine mixture group, as compared to controls during all three periods (Figure 4(C); 1st period: p < 0.05, 2nd period: p < 0.05, 3rd period: p < 0.001). REM sleep was significantly increased at all periods compared to control levels in the GABA or l-theanine alone groups, as well as the GABA/l-theanine mixture group (Figure 4(D)).

Effects of GABA, l–theanine, and GABA/l-theanine mixture on sleep quantity and quality during administration periods. Values are presented as the means ± standard error (SE) for each group, n = 8. Symbols indicate significant differences by Bonferroni test, as ***p < 0.001, **p < 0.01, *p < 0.05.

NREM sleep consists of θ and δ waves, with 4.0–8.0 and 0.5–4.0 Hz bandwidths, respectively. The use of l-theanine alone and GABA/l-theanine mixture increased θ waves over the ones detected in the control group during all periods. Single l-theanine administration led to a significant decrease in δ waves during the 1st period (2.0 h) (p < 0.01), which gradually increased in the 3rd period (3.1 h). When GABA/l-theanine mixture was administered, δ wave oscillations also gradually increased from 1st (2.2 h) to 3rd period (2.7 h) (Figure 4(E,F)). In conclusion, the combined treatment with GABA and l-theanine led to a significant increase in sleep time (22.4%), especially NREM (28.8%), when administered over a long period. In addition, the use of GABA/l-theanine mixture increased θ wave and decreased δ wave oscillations in NREM sleep, when compared to the control group. Nevertheless, δ waves gradually increased with long-term administration. Therefore, the longer the administration of GABA/l-theanine mixture the better the sleep quality and the longer the sleep duration, induced.

EEG acquisition and analysis in a caffeine-induced wakefulness model

EEG was performed to assess the sleep-inducing effects of GABA, l-theanine or the combination of both (GABA/l-theanine mixture) in a caffeine-induced awakening animal model (Figure 5). A significant difference (p < 0.001) in sleeping and awakening times were observed between the arousal group, which was orally administered 10 mg/kg of caffeine and the control group which was orally administered with saline (Figure 5(A,B)). Administration of GABA, l-theanine, or the combination of both, in the caffeine-induced awakening model led to significant differences in sleep and awakening times, when compared to the arousal group (p < 0.001). In the wakefulness model, the use of l-theanine alone or GABA/l-theanine mixture restored NREM sleep time to the control group level (Figure 5(C)). However, the use of GABA/l-theanine mixture in the wakefulness model had a tendency to restore REM sleep time, but there was no significant difference to arousal group. The administration of GABA/l-theanine mixture increased θ wave (1.9 h) and increased δ wave (2.0 h) oscillations in NREM sleep, when compared to the arousal group (1.4 and 2.5 h, respectively) (Figure 5(E,F), p < 0.01). These results suggest that the combined use of GABA and l-theanine rather than GABA or l-theanine alone restores sleep time and quality to normal levels, in the arousal animal model.

Effects of the GABA, l-theanine, and GABA/l-theanine mixture on caffeine-induced wakefulness in rats at a dosage of caffeine (10 mg/kg). Values are presented as the means ± standard error (SE) for each group, n = 8. Different letters indicate significant differences (p < 0.05) among samples by Tukey’s multiple range test. Symbols indicate significant differences by Bonferroni test, as ***p < 0.001, **p < 0.01 compared with arousal group.

Effects of GABA and l-theanine combination on the mRNA levels of neurotransmitter receptors

To investigate whether the sleep-promoting mechanism of GABA/l-theanine mixture mediates neurotransmitter receptor expression changes, the mRNA levels of GABA and glutamate receptors were evaluated (Figure 6). Transcript levels for the GABAA receptor following the combined administration of GABA/l-theanine were 1.53-fold higher than control levels (Figure 6(A), p < 0.01). Moreover, GABA/l-theanine combined infusion led to significant changes in the mRNA levels of GABAB-R2 (21.4%), as compared to controls (Figure 6(C), p < 0.001). However, there was no significant difference in the mRNA levels of GABAB-R1 compared to the control group (Figure 6(B)).

Effects of the GABA/l-theanine mixture on GABA and glutamate receptors mRNA expression in the mouse brain. Values are presented as mean ± standard error of the mean (SEM) for the brain regions of 8 mice and for each group, n = 8. Different letters indicate significant differences (p < 0.05) among samples by Tukey’s multiple range test. Symbols indicate significant differences by Bonferroni test, as ***p < 0.001, **p < 0.01, *p < 0.05. NS: not significant.

GABA/l-theanine mixture significantly increased the mRNA levels of the GluN1 glutamate receptor subunit, as compared to control (13.8%) (Figure 6(E), p < 0.05). However, administration of l-theanine alone also altered the GluR1 glutamate receptor (12.5%) and GluN1 glutamate subunit (7.2%) expressions when compared to controls (Figure 6(D,E), p < 0.05). These results indicate that increased expression of GABA receptors GABAA, GABAB-R1 and GABAB-R2, and the GluN1 glutamate receptor subunit observed with GABA/l-theanine, may possibly lead to improved sleep behaviour and neurological regulation.

Sleep-promoting effects of the GABA/5-HTP mixture in vertebrate models

Abstract

The aim of this study was to investigate the sleep-promoting effect of combined γ-aminobutyric acid (GABA) and 5-hydroxytryptophan (5-HTP) on sleep quality and quantity in vertebrate models. Pentobarbital-induced sleep test and electroencephalogram (EEG) analysis were applied to investigate sleep latency, duration, total sleeping time and sleep quality of two amino acids and GABA/5-HTP mixture. In addition, real-time PCR and HPLC analysis were applied to analyze the signaling pathway. The GABA/5-HTP mixture significantly regulated the sleep latency, duration (p<0.005), and also increased the sleep quality than single administration of the amino acids (p<0.000). Long-term administration increased the transcript levels of GABAA receptor (1.37-fold, p<0.000) and also increased the GABA content compared with the control group 12h after administration (1.43-fold, p<0.000). Our available evidence suggests that the GABA/5-HTP mixture modulates both GABAergic and serotonergic signaling. Moreover, the sleep architecture can be controlled by the regulation of GABAA receptor and GABA content with 5-HTP.

Keywords: 5-Hydroxytryptophan; Electroencephalogram; Pentobarbital; Sleep; Vertebrate; γ-Aminobutyric acid.

The neuropharmacology of L-theanine(N-ethyl-L-glutamine): a possible neuroprotective and cognitive enhancing agent

Abstract

L-theanine (N-ethyl-L-glutamine) or theanine is a major amino acid uniquely found in green tea. L-theanine has been historically reported as a relaxing agent, prompting scientific research on its pharmacology. Animal neurochemistry studies suggest that L-theanine increases brain serotonin, dopamine, GABA levels and has micromolar affinities for AMPA, Kainate and NMDA receptors. In addition has been shown to exert neuroprotective effects in animal models possibly through its antagonistic effects on group 1 metabotrophic glutamate receptors. Behavioural studies in animals suggest improvement in learning and memory. Overall, L-theanine displays a neuropharmacology suggestive of a possible neuroprotective and cognitive enhancing agent and warrants further investigation in animals and humans.

A Novel Theanine Complex, Mg-L-Theanine Improves Sleep Quality via Regulating Brain Electrochemical Activity

Discussion

The pentobarbital-induced sleeping model was used to identify the optimal sleep enhancement dosing ratio for GABA and l-theanine. In this study, the combination of GABA and l-theanine (100/20 mg/kg) not only did it reduce sleep latency but also prolonged sleep duration in pentobarbital-induced sleep model. The key finding of this study is the confirmation of the synergistic action (p < 0.01, compared to control) of GABA and l-theanine on sleep behaviour, which significantly decreased sleep latency and increased sleep duration.

Amino acid neurotransmitters are important for the function of the central nervous system (CNS). They are fast-acting, inducing responses within milliseconds and play an important role in physiological brain function and neurological diseases (Krystal et al. ). Rapid neurotransmitter regulation and nerve function, facilitation of relaxation without drowsiness, stress relief (including physical stress), and l-theanine-mediated excitement are known strategies used for the improvement of sleep quality and for exhaustion recovery (Rao et al. ).

Sleep deprivation is known to cause serious illnesses such as cardiovascular disease, diabetes, and cancer (Davis and Mirick ; Laposky et al. ; Baron and Reid ). The pentobarbital-induced sleep test and the EEG measurement that have been performed usually in a study of sleep enhancement were used to confirm the synergy effect of GABA/l-theanine mixture in sleep enhancement (Jeon et al. ).

The combination of GABA and l-theanine (80/20 and 100/30 mg/kg) did not show a synergistic effect in sleep latency and sleep duration unlike the GABA/l-theanine mixture (100/20 mg/kg). Lin et al. () reported that the synergistic effects were different depending on the ratio of taurine and caffeine, and it is important to identify specific synergistic ratio in the study of combined sample administration. However, further research is needed to determine that synergistic effects are achieved only at a specific ratio with any pharmacokinetic mechanism.

GABA acts through GABA receptors. There are generally 2 types of GABA receptors: GABAA and GABAB. The most important receptor, with respect to sleep is the GABAA receptor (Gottesmann ). When GABA or another agonist binds to GABAA receptor, it triggers the influx of chloride ions in neuronal cells. This causes a negative membrane potential that inhibits action potential firing. In this way, GABA (and GABA-promoting compounds) reduce activity in brain cells through GABAA receptor activation. It is well-known that the activation of GABAA receptors is beneficial for sleep (Abdou et al. ). The structural similarity of l-theanine to the neurotransmitter glutamic acid has prompted researchers to study its potential competition binding on glutamate receptors in the nervous system (Shinozaki and Ishida ). l-Theanine rapidly induces changes in serotonergic and dopaminergic transmission (Yokogoshi et al. ). These components act as modulating receptors of the neurotransmitter GABA, which is the main inhibitory neurotransmitter in the CNS, and therefore, one of the main molecules responsible for sleeping behaviour (Zanoli and Zavatti ). The decreases in sleep latency, together with a slight improvement in sleep quality, are the possible reasons for the observed increase in sleep efficiency, in our study.

As characterized by EEG recordings, sleep is broadly divided into REM and NREM (Bersagliere et al. ). Combined oral administration of GABA and l-theanine significantly increased the amount of NREM sleep, as compared to controls (Figure 3, p < 0.05), via an increase in theta waves. Moreover, awake time was also significantly decreased following GABA/l-theanine administration, as compared to all other groups (p < 0.001, Figure 3). Brain waves can be classified into four types: α (less than 8–13 Hz), β (more than 13 Hz), θ (less than 4–8 Hz), and δ waves (less than 4 Hz) (Abdou et al. ). Each wave type is associated with a specific mental state. Delta and theta occur in the early stages of deep sleep and sleep, respectively (Ray and Cole ).

We observed a tendency for NREM sleep to increase with increasing dosing periods during the combined oral administration of GABA and l-theanine, probably due to l-theanine (Figure 4). This change in NREM is likely due to changes in delta waves after GABA/l-theanine administration. EEG frequency estimation revealed increased delta and decreased beta activity in the NREM state. Caffeine causes a variety of sleep disturbances, including total sleep time reduction, prolonged sleep onset latency and increased arousal in humans and rats through adenosine receptor blockade (Deckert and Gleiter ).

In Figure 5, caffeine decreased sleep time, especially NREM and increased the awake time in rats. The results indicate that GABA and l-theanine combined intake can reverse caffeine-induced sleep reduction, especially NREM, in rats (Figure 5). Administration of l-theanine has been reported to inhibit caffeine’s convulsive action and to increase GABA brain levels in mice (Kimuraand Murata 1971). l-Theanine is known to decrease norepinephrine levels in the rat brain and suppress caffeine-induced serotonin and 5-hydroxyindoleacetic acid increases in rats (Kimura and Murata ). Furthermore, the neuroprotective effect of theanine has been shown to be mediated via glutamate receptors, as theanine acts as a glutamate receptor antagonist (Kakuda et al. ). The above results suggested that the GABA/l-theanine mixture was significantly superior to GABA or l-theanine alone, for reducing sleep latency, awake time and extending NREM sleep duration. The l-theanine seems to play a major role in the synergistic effect of GABA and l-theanine combination. A trend for prolonged NREM with increasing l-theanine dosing was observed, which was similar to the delta wave increasing trend. In the caffeine-induced arousal model, combined GABA and l-theanine led to a similar synergistic effect on sleep enhancement. The combination of GABA and l-theanine is an attractive NREM sleep-promoting regimen as it increases delta wave oscillations.

As shown in Figure 6, GABAA receptor expression levels were significantly changed in mice with administration GABA/l-theanine mixture compared with the control group (p < 0.01). The GABAA receptor complex is a chloride ionophore, which consists primarily of GABA, barbiturate, benzodiazepine, steroid and picrotoxin binding sites (MacDonald and Olsen ). Parisky et al. () demonstrated that GABAA receptor over expression increases total sleep time, while down-regulation of the receptor decreases sleep duration. The metabotropic GABAB receptor can influence the activation of Ca+2 and K+ ion channels via G-protein coupled second messengers. The affinity of GABA to GABAB receptors is lower than that for GABAA receptors (Chu et al. ). The sedative or sleep-inducing effect of GABA is most likely mediated via GABA receptors. GABA receptor expression in the rat brain was significantly increased following the combined administration of GABA and l-theanine but not after GABA infusion alone. l-Theanine has a similar chemical structure to glutamate and l-theanine has micromolar affinities for kainate, α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA), and N-methyl-D-aspartate (NMDA) glutamate receptors (Kakuda et al. ). l-Theanine can act as a competitive glutamate antagonist. The mRNA level of the NDMA receptor subunit GluN1 was slightly higher following GABA/l-theanine infusion than after l-theanine treatment alone (Figure 6).

In conclusion, our results demonstrate that the combined use of GABA and l-theanine increase sleep activity to more than a single administration of either amino acid or these synergistic sleep-promoting effects are likely mediated via changes in GABA and/or glutamate receptor expression in the brain. In summary, this result suggests that GABA/l-theanine mixture could be used for treatment for insomnia and sleep disorders as a concept of nonpharmacological management of sleep.

Funding Statement

This research was supported by the Ministry of Trade, Industry & Energy (MOTIE), Korea Institute for Advancement of Technology (KIAT) through the Encouragement Program for The Industries of Economic Cooperation Region (R0004012).

Disclosure statement

No potential conflict of interest was reported by the authors.

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cited https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6366437/

https://pubmed.ncbi.nlm.nih.gov/27150227/

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