INL Article - The Brain and Sleep Disorders

Unlocking the Brain to Treat Sleep Disorders

Often famed for its high paced life and heavy work hours, Hong Kong could be the city that doesn’t sleep. A University of Hong Kong study addressed the prevalence of poor sleep in adults in the city. It showed a weighted prevalence of insomnia at about 40%, equivalent to 2.2 million affected people, and this was in 2010. (1)

Fast forward to 2020, a year like other for patients and practitioners alike and another study from HKU confirms that a high proportion of people in Hong Kong felt that their sleep had worsened since the COVID-19 outbreak. (2) This further compounds an existing problem already created by the anti-government protests of 2019 with up to 57% of Hong Kongers having insufficient or ‘very insufficient’ sleep. (3)

So now more than ever it with sleep disturbances now confirmed to be a leading risk factor for obesity, diabetes, impaired glucose tolerance, cardiovascular disease, hypertension, depression and alcohol use. (4)

Reconnecting with the poorly understood science of sleep

Sleep states are characterized by clearly defined stages of rapid and non-rapid eye movement (REM and NREM), and these follow a rhythm throughout the night. The dreamless NREM sleep or deep-sleep steps should occur at intervals through the night amounting to more than an hour of deep sleep in total. Deep sleep promotes the refreshed feeling upon waking and is associated with the brain’s glymphatic oriented system, most famously known for eliciting the neuroprotective aspects of sleep. (5)

Noradrenaline, acetylcholine, histamine, dopamine and serotonin and other neurochemicals promote wakefulness. In contrast, GABA and adenosine are responsible for the promotion of sleep. GABA-a receptors are essential therapeutic targets for the treatment of sleep disorders such as insomnia due to their ability to inhibit neurotransmission and participate in tonic inhibition. (6)

It’s this inhibitory process that gave birth to the majority of sleep medications such as Zopiclone and the benzodiazepines making the GABA and its receptor the primary target for sleep restoration within the central nervous system.

All these generations of drugs decrease waking, increase slow-wave sleep and enhance the intermediate stage of sleep at the expense of the last stage of sleep which is considered why some people can feel somewhat unrefreshed on waking. Many of these medications are also either toxic or addictive, so their prescriptions are restricted to temporary use only.

Even though GABA is correctly the therapeutic target as far as neurotransmission goes, a long-running controversy regarding serotonin’s role was only settled halfway through last year. This controversy is due to the prevailing theory that it played a role in wakefulness only.

A group of researchers settled this controversy via a study that focused on the raphe nuclei in the brain, the region that has the most considerable number of serotonergic neurons. After conducting different experiments either via removing or stimulating the raphe, the researcher hypothesized that the firing of the raphe and the consequential release of serotonin is a way for the brain to build up sleep pressure, an essential part of the sleep process. (7)

We can now understand better that the singular neurotransmitter targets may not help our patients enough, especially when they receive no benefit from their initial prescriptions.

Finding the ideal sleep aid for an individual with neurotransmitter disturbances is not easy. Still, there is a selection of herbal and natural interventions that can offer a minimally toxic option for better sleep over more extended periods as compared to pharmaceuticals.

Kava is an underused herb for insomnia with anxiety

Piper methysticum or Kava Kava has long been an integral part of the Pacific Island culture. Kava was also an essential part of the traditional medicine system in the Pacific Islands with the traditional beverage regarded as a sedative and relaxing to both the mind and the body.

The resin of the herb is the phytotherapeutic focus of Kava that contains the active kava lactones. Major kava lactones are kavain, dihydrokavain, methysticin, dihydromethysticin, yangonin and desmethoxyyangonin. Extracts used in natural medicine always come standardized for kava lactone content.

Kava’s anxiolytic effects have been well-known for decades within research journals. An action the Cochrane review of 2003 confirmed stating that compared with placebo, kava extract was an effective symptomatic treatment for anxiety. (8) This trajectory was halted after an incorrect conclusion on Kava’s effect on the liver and Kava was removed from the market. This ban was overturned after a reevaluation of the benefit/risk ratio was conducted both the German and Australian regulatory bodies. (9)

Kavain, one of the vital kava lactones, has been the focus now for a lot of Kava’s activity. It is particularly crucial in its role for sleep management due to its interaction with the GABA-a receptors. (10) Studies confirmed this in 2016 after much speculation as to how Kava was achieving its lauded anti-anxiety action.

Further studies have since looked at Kava’s role in the management of sleep with a 4-week double-blind placebo-controlled study involving 61 patients. Using doses of 200mg/day of a 13-20:1 kava extract standardized to 70% kava lactones (140mg/day) the study found that Kava was a compelling choice for sleep disturbances with non-psychotic anxiety disorders. (11)


Honokiol from Magnolia promotes non-rapid eye sleep

Honokiol is a naturally, occurring, pleiotropic lignan extracted from multiple different species of the Magnolia plant. Honokiol is well-known for its anxiolytic (12), (13), analgesic (14) and antidepressant effects in animal studies. (15)

As we have seen with Kava, honokiol, as one of the active constituents in Magnolia has an interaction with the GABA-a receptor. Interestingly, glutamic acid decarboxylase (GAD), an enzyme involved in GABA synthesis is increased in mice treated with honokiol, suggesting that honokiol modulates the synthesis of GABA via more than one pathway. (16)

A more specific study on honokiol and sleep building on this was found to significantly shorten sleep latency whilst concomitantly increasing non-rapid eye movement sleep. (17)

A combination of supplemental GABA and L-theanine may be synergistic for the brain

We have seen the vital role of GABA throughout this article and the herbs can modulate its natural production within the brain, but what about the administration of GABA itself?

Controversy over GABA’s ability to cross the blood-brain barrier has been well-documented. Still, other evidence also points to the fact that oral GABA may have a more potent effect on GABA production in the enteric nervous system. (18)

Supplemental GABA’s role in the brain and how this can then help with sleep management (19) has been studied via the analysis of brain wave patterns. Beta waves are seen during high-stress situations, especially when there is trouble focusing and concentrating. Alpha waves, in contrast, are produced during meditation and anytime the body is relaxed but alert. A small EEG study showed that one hour after oral GABA administration, the GABA increased the alpha waves while beta waves were decreased. (20)

Increases with alpha brain wave have also seen with L-theanine administration. (21) These increases indicate that both GABA and L-theanine may help to induce relaxation and anxiety, thus leading to action in sleep.

A combination of GABA and L-theanine has demonstrated in murine models to decrease in sleep latency and increase in sleep duration compared to GABA or theanine alone. Compared to controls, the GABA and L-theanine combination saw a significant increase in REM sleep of 99.6% and NREM sleep of 20.6%. These results led to conclusions that the combination possesses a positive synergistic effect on sleep quality and duration. (22)

When is there a role for melatonin?

Melatonin naturally increases the response to changes in the light spectrum as the sun goes down, creating a state of quiet wakefulness that help to induce sleep. It has no benefit for sleep-maintenance insomnia (quality of sleep). (23)

For jet lag, a Cochrane metanalysis found that melatonin is effective in preventing or reducing jetlag. Specifically, the period to recover the body clock, especially for adults travelling east over more than five time zones. (24)

Research into blue light emitted from devices such as phones and TVs have already been well-documented as suppressing melatonin. (25) One can take melatonin for temporary relief if working late up or using the internet around bedtime. Melatonin will not reduce anxiety associated with insomnia nor the GABA related disturbances of sleep, a problem induced by late work or internet habits.

Another less-considered problem with melatonin supplements is their quality. A study conducted on 31 different pharmacy and store-bought supplements found that for most, the amount of melatonin in the product did not match the label listing. Worse still, 26% of the supplements studied contained serotonin, a neurotransmitter that can be harmful in even small doses, indicating low standard manufacturing processes and the need for clinical-grade choices. (26)

What’s the message here?

There are many misused herbs and supplements combinations within the natural medicine realm. For example, melatonin doesn’t help sleep quality, only sleep latency.

In the case of Kava, and melatonin, we have seen Cochrane reviews, as well as other double-blind, placebo-controlled studies, validate their use, offering great potential for the rising numbers of people suffering from sleep problems.

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