Definition and Pathophysiology:

Insomnia is a common sleep disorder affecting around 30% of the population and its prevalence is continuously increasing. The quality and quantity of patient’s sleep deeply influences their cardiovascular health, mental well-being, cognitive abilities, memory consolidation, immune function, reproductive health, and hormonal regulation. Likewise, sleep disorders like insomnia, sleep apnoea, and circadian rhythm disorders, as well as disrupted sleep due to lifestyle choices, or medical issues, can lead to significant health problems and worsen existing medical and psychiatric conditions.[1]

Sleep physiology: Sleep is a complex interplay of neural networks and circadian rhythms. Normally, sleep commences and is sustained as arousal systems are suppressed by the accumulation of adenosine during daily wakefulness. Eventually, adenosine activates inhibitory neurons in the brain’s ventrolateral pre-optic area, acting as a sleep switch.[2]

Circadian clocks, particularly the suprachiasmatic nuclei (SCN) in the brain (hypothalamus), follow a 24-hour cycle, influenced by environmental and social cues.[3] Light, especially natural sunlight, is the most potent sleep/wake cue by influencing diurnal rhythms of melatonin and cortisol. Morning light suppresses melatonin and raises cortisol, promoting wakefulness, while reduced evening light increases melatonin, preparing the body for sleep. [4,5] Temperature changes, mealtimes and social interactions also influence our internal clocks.

Sleep architecture: Sleep architecture refers to the rhythmic, cyclic process that alternates between three stages of non-rapid eye movement (NREM) sleep and a fourth stage of rapid eye movement (REM) sleep. This intricate pattern is essential for achieving the full restorative benefits of sleep. When sleep architecture is disrupted, individuals miss these crucial restorative effects, impacting overall health and well-being.[6]

Whilst treatment strategies aim to restore sleep physiology and architecture, long-term sleep improvement involves proper sleep hygiene and behavioural modification.[1]

 

Patient Signs and Symptoms

Insomnia is classified by sleep/wake disturbance, with 3 primary presentations: [7]
• Challenges falling asleep (onset insomnia): inability to fall asleep beyond 20-30 minutes.
• Inability to maintain sleep (middle sleep): frequent waking during the night after sleep onset beyond 20-30 minutes, and difficulty returning to sleep after mid-night wakening.
• Early morning wakefulness (late insomnia): waking at least 30 minutes before the desired time and before sleep reaches 6.5 hours (often with an inability to resume sleep at all)

Characteristic daytime symptoms of insomnia include:
• Fatigue
• Reduced attention
• Impaired cognitive functioning
• Irritability
• Anxiety and low mood.

Risk Factors:

• Circadian disruption: Zeitgebers, or “time-givers,” are external cues that regulate daily circadian rhythms, in particular, light exposure, but also meal and exercise timing light, temperature, and social interactions. Disruptions caused by shift work, travel across time zones, or irregular schedules can lead to circadian misalignment and insomnia. Conversely, chronic insomnia can disrupt these cues, creating a cycle of sleep difficulties. Sleep hygiene involves managing environmental zeitgebers to restore sleep physiology and architecture for health and well-being. [1,9]
• Chronic or severe stress: Early life stress, major life events, and/or genetic factors can increase vulnerability to insomnia. With heightened sensitivity leading to hyperarousal, restful sleep is difficult. Consequently, insufficient sleep exacerbates stress, creating a vicious cycle. Chronic insomnia further disrupts brain circuits and increases the risk of mental health issues. [10]
• Pain: Patients suffering chronic pain conditions such as rheumatoid arthritis, chronic back pain, fibromyalgia, and cancer experience higher prevalence of insomnia compared to the general population.[11]
• Genetic predisposition: So far, this emerging field of science has identified genetic variants which influence clock systems and signalling pathways, as well as the nature, amount, duration, type, intensity, quality, and quantity of sleep.[12]

Red Flags:

• If you think the patient has a sleep disorder such as sleep apnoea or is not responding to behavioural and treatment interventions or is highly distressed refer to a general practitioner or sleep specialist.[13] The Australasian Sleep Association Sleep Services Directory Health professionals information may assist with referrals.
• Psychiatric disorders: Sleep disruptions are a defining feature of several psychiatric disorders, including anxiety, depression, bipolar and post-traumatic stress disorder, with evidence suggesting bi-directional causality.[13] If in doubt, refer to patients General Practitioner or Psychologist. If the patient is deemed at risk of self-harm or harm to others, seek immediate guidance from a CATT or ring triple zero (000) in an emergency.

Screening and investigations:

In Clinic Investigations

• The Metagenics Sleep Assessment Questionnaire helps determine sleep-wake issues and modifiable risk factors by assessing sleep cycle patterns, past and current interventions, sleep quality, sleep hygiene practices and potential comorbidities.
• The Metagenics Patient Sleep Tracker is used to record the bedtime routine including timing of sleep initiation, wake frequency and total hours slept whilst noting any sleep variables.
• Dass21 questionnaire is an evidence-based questionnaire designed to measure the three related negative emotional states of depression, anxiety and tension/stress.
• Mood and Stress Questionnaire | Metagenics Institute ANZ is an easy to use, digital tool to assess and identify core patient symptoms and relevant therapeutic strategies.

Pathology/Screening Investigations

If presenting with:
• Chronic stress, consider assessing HPA axis function with the cortisol awakening response (CAR) test or Adrenocortex stress profile.
• Restless legs, examine nutritional deficiencies (iron, folic acid, magnesium and vitamin D), hypothyroidism (thyroid studies) and hypoglycaemia (fasting and/or random blood glucose) if indicated.
• Restless legs and significant gastrointestinal symptoms, consider screening for small bacterial intestinal overgrowth (SIBO) with hydrogen/methane breath test.
• Chronic pain and inflammation, refer for pathology testing including erythrocyte sedimentation rate (ESR) and high sensitivity C-reactive protein (hs-CRP).
• Night sweats, anxiety, palpitations and/or unintentional weight loss, consider screening for hyperthyroidism as a driver of sleep disruption.
• Night sweats with daytime hot flushes, consider screening for menopause.

Treatment Recommendations

Core Recommendations

Magnesium with Lutein and Zeaxanthin for Sleep Pattern Support
Dosage: Add 1 scoop (5.7 g) in 200 mL of water once daily in the evening.

Meta Mag® magnesium bisglycinate with ornithine, withania (SensorilTM ashwagandha), lutein and zeaxanthin is blended to redress disrupted sleep architecture to promote sleep efficiency, whilst enhancing melatonin and reducing cortisol to improve stress resilience and sleep quality and quantity. (Figure 1).

Mechanism of Action/Clinical Research:

Magnesium: Decreases serum cortisol, increases melatonin. [14,15]

• 500 mg/day for 8 weeks improved sleep time, efficiency, and onset latency (p<0.03).[15]

Ornithine: Regulates cortisol and DHEAS, reduces stress markers.[16]
• 400 mg/day for 8 weeks improved sleep quality and cortisol/DHEAS ratio in a double-blind trial.[16]

Withania somnifera: Moderates cortisol, counteracts stress-induced HPA overactivity.
• 250-600 mg/day for 8 weeks improved stress scores, reduced morning cortisol, and enhanced sleep quality (p<0.05).[17]

Lutein and Zeaxanthin: Enhances macular pigment optical density (MPOD) to enhance visual performance and blue light filtration, supports melatonin production. [18,19]


Figure 1: Magnesium with Lutein and Zeaxanthin for Sleep Pattern Support restores circadian rhythm and improves sleep quality.

California Poppy and Passionflower for Sleep
Dosage: Take 2 tablets once daily with your evening meal.

Anxiolytic and sedative herbs are blended to enhance GABA synthesis and neurotransmission and inhibit glutaminergic excitation to soothe the nervous system for sleep.

Mechanism of Action/Clinical Research:
Zizyphus enhances GABA synthesis while also sensitising GABA receptors thereby enhancing GABA neurotransmission to promote sleep maintenance.[20]

Passionflower: Modulates GABA system, increases receptor sensitivity to enhance inhibitory effects.[21]
• 1,020 mg/day for 12 weeks improved sleep quality and maintenance in 154 participants.[22]

Lavender Oil: Blocks NMDA receptors to restrict glutamate excitation.[23]
• 80 mg/day for 12 weeks improved anxiety and sleep quality in 170 patients.[23]

California Poppy: Stimulates GABAα receptor binding to provide sedative effects.[24]

OR

Gamma-Aminobutyric Acid (GABA)
Dosage: Take 250 mg – 500 mg before bed.

GABA is the main inhibitory neurotransmitter in the CNS, balancing neuronal excitation and inhibition. Insufficient GABA activity, due to stress or neurological conditions, can cause stress, anxiety, depression, sleep issues, and pain. Supplementing with GABA may reduce anxiety, improve sleep, and relieve pain.

Clinical Research:
• For improving sleep, 100-300 mg GABA in the evening has been shown to reduce sleep latency and improve early sleep parameters with prolonged use over 1-4 weeks.[25]

Additional Considerations

If presenting with day-time anxiety
Herbal Support for Hyper HPA and Stress
Dosage: Take 1 tablet three times daily.

Anxiolytic herbs that enhance GABA activity and work against glutamate-mediated excitability in the brain to alleviate anxiety, nervous tension and agitation that may contribute to insomnia.

Mechanism of Action/Clinical Research:

• Zizyphus has been shown to modify the GABAα receptor subunits expressional levels,[26] which opposes glutamate-mediated excitability in the brain, contributing to its anxiolytic effects.[27]

• Passionflower has been found to modulate the GABA system, demonstrating an affinity for both GABAα and GABAβ receptors, increasing its inhibitory effects.[21]

o A clinical trial involving 154 participants with prolonged nervous tension were treated with 1,020 mg/d of passionflower for 12 weeks. Passionflower significantly improved stress-associated symptoms including restlessness, sleep disturbances, exhaustion, anxiety, poor concentration, nausea, tremors, and palpitations. [22]

• Kudzu has demonstrated β-adrenoceptor blocking activity [28,29] similar to pharmacological beta-blockers, which are used to reduce the physical effects of anxiety and stress such as palpitations, high blood pressure, tremor and sweating.

• Magnolia active constituent, honokiol, supplementation has shown enhanced transitioning from wakefulness to non-rapid eye movement (NREM) by be modulating the benzodiazepine site of the GABAα receptor in an animal study, suggesting a benefit in reducing time to sleep onset. [30]


If patient presents with low mood/depression

BCM-95® Turmeric & Saffron for Depression

Dosage: Take 1 capsule twice daily with food.
An anti-inflammatory herbal blend to reduce HPA axis activity, preventing stress-induced elevation of cortisol and glutamate excitotoxicity, while also supporting BDNF production for enhanced neurogenesis in patients who experience low mood and insomnia.

Mechanism of Action/Clinical Research:

• Both saffron and turmeric have been found to inhibit the activation of proinflammatory transcription factors, such as nuclear factor kappa beta (NFκB) and mitogen activated protein kinase (MAPK). They also inhibit inflammatory cytokines including tumour necrosis factor alpha (TNF-α), interleukin-1β (IL-1β) and IL-6, all of which can affect neurotransmitter metabolism. [31,32]
o A randomised, double-blind, placebo-controlled study involving 123 participants that were prescribed 500 mg/d of BCM-95® Turmeric combined with 30 mg/d of saffron, revealed significant reductions in depression and anxiety symptoms after 12 weeks.[33]

• Safranal and crocin, present in saffron, have been shown to reduce HPA axis activity and decrease stress-induced plasma corticosterone levels.[34] Safranal has also been shown to exert anxiolytic and sedative effects via activation of the GABAergic pathway.[35]
• Turmeric activates glutamate decarboxylase (GAD), which converts glutamate to GABA. [36]


For Emotional Support
Ginseng Complex for Emotional Resilience
Dosage: 3 capsules twice daily.

A traditional Chinese herbal blend specifically designed to address disordered neurological and hormonal patterns in patients adversely affected by stress. This blend of herbs is particularly indicated to support emotional resilience in sensitive patients who may be teary, weepy and anxious.

Mechanism of Action/Clinical Research:
• Korean ginseng, used in Asian medicine for over 500 years, is shown to inhibit enzymatic activity of 11-beta hydroxysteroid dehydrogenase 1, which converts cortisol to inactive cortisone. This inhibition is proposed to preserve cortisol and restrict excessive glucocorticoid production by the adrenals in times of stress, leading to maintenance of normal adrenal function. [37]
• Zizyphus is widely used in Chinese herbal formulas for the treatment of anxiety, frustration, irritability, and excessive night sweats.[38] Jujuboside A, an active constituent of zizyphus, may protect neurons by blocking the release of extracellular glutamate in the hippocampus of the brain. [39]

If with insomnia associated with pain:
Highly Bioavailable PEA and Magnesium for Neuromuscular Support and Pain

Dosage: Add 1 level scoop (5 g) to 200 mL of water twice daily, with food.
A combination of palmitoylethanolamide (PEA) and Meta Mag® Magnesium bisglycinate with anti-inflammatory, glutamate-blocking and endocannabinoid-like actions to reduce pain signalling associated with impaired physical function.
Mechanism of Action/Clinical Research:
• Magnesium has been found to block glutamate via inhibition of the N-methyl-D-aspartate (NMDA) receptor and reduce excitatory neurotransmission associated with pain signalling and sensitisation. [40]
• Through enhancing endogenous cannabinoid system (ECS) activity, PEA reduces pain amplification in inflammatory conditions that is driven by immune cells (i.e. microglial and astrocytes) and helps to downregulate TRPV1 nociceptor sensitivity. [41,42]

Diet and Lifestyle

Sleep hygiene refers to behavioural and lifestyle interventions around sleep time and throughout the day that positively influence sleep quality and duration. Key strategies for sleep hygiene include: [43]

• Sleep Duration: Aim for 7-9 hours of sleep. Less than 7 hours can harm health, while more than 9 hours might be needed for young adults or those with illnesses.
• Consistent Sleep Schedule: Go to bed and wake up at the same time daily, even on weekends. This helps regulate your internal clock and improves sleep quality.
• Exercise: Engage in at least 150 minutes of moderate or 75 minutes of vigorous aerobic activity weekly. Exercise can enhance sleep quality and reduce pre-sleep anxiety.
• Weight Loss: Maintaining a healthy weight can improve sleep, especially for those with sleep-disordered breathing.
• Napping: Limit naps to 20-30 minutes in the early afternoon to avoid disrupting nighttime sleep.
• Light Exposure: Reduce light exposure from screens and ambient sources before bedtime to promote better sleep.
• Caffeine: Limit caffeine intake in the afternoon and evening to prevent sleep disturbances.
• Alcohol: Avoid alcohol before bed as it can interfere with sleep quality.
• Mindfulness: Practice relaxation techniques to improve sleep.
• Sleep Environment: Ensure your bedroom is dark, cool, and quiet. Use comfortable bedding and reserve the bed for sleep only. 

Cognitive behavioural therapy for insomnia (CBTI) is first-line treatment for insomnia.[44] Meta-analysis shows that CBT-I reduces sleep onset latency and nocturnal arousals while improving sleep efficiency with effect sizes comparable in magnitude to hypnotics such as benzodiazepines and non-benzodiazepines.[45] Unlike hypnotic medications, improvements in sleep following CBT‑I are maintained after treatment cessation for up to three years.[46]
In Australia, CBT-I sessions are covered by a mental healthcare plan. Refer to the Australasian Sleep Association (ASA) service directory for treatment centres (www.sleep.org.au).
Key strategies in CBT-I include:[44]

• Sleep Education: Understanding sleep basics and factors affecting sleep.
• Sleep Hygiene: Adopting habits that promote good sleep, such as maintaining a regular sleep schedule and creating a restful environment.
• Stimulus Control: Associating the bed with sleep by avoiding wakeful activities in bed and going to bed only when sleepy.
• Sleep Restriction: Limiting time in bed to match actual sleep time to increase sleep efficiency.
• Cognitive Therapy: Addressing negative thoughts and beliefs about sleep that contribute to insomnia.
• Relaxation Techniques: Practicing methods like deep breathing and progressive muscle relaxation to reduce pre-sleep anxiety. 

CBT-I is typically delivered over several sessions with a trained therapist and has been shown to be highly effective in treating insomnia without the need for medication.

Additional dietary considerations:

• Opt for a nutrient-rich, wholefood diet, inclusive of high intake of fruits and vegetables, lean protein, quality essential fatty acids, and wholegrains (limiting starchy grains and vegetables), with low intake of sugar/refined foods.
• Time restricted feeding is shown to improve metabolic parameters, as well as sleep. Research shows that caloric intake over 15 hours a day can cause circadian disruption. Alternatively, circadian rhythms may be realigned by eating within a 6-to-11-hour daily window, ideally after sunrise and before sunset. [47]
• Reduce liquids in the last 4 hours before bedtime to prevent night-time urination.

Additional lifestyle recommendations:

Minimise artificial evening light exposure and increasing daytime light exposure:
o Avoid screens for at least 1 hour before bed (television, laptops, computers, tablets, smart phones).
o Use eye masks and/or black out curtains while sleeping.
o Glasses that block blue light may prevent the effects of blue light on melatonin production and are indicated for patients who use interactive devices in the evening.[48]
 Alternatively, blue light filter apps or settings can be installed/activated on devices to minimise blue light exposure.
o Increase daytime exposure to natural light in addition to limited night light exposure.
 Spend at least 30 minutes outside with sunlight on the skin (while being SunSmart) in the morning, i.e. sunrise, between 11.00 am and 1.00 pm and twilight.
o Increase daytime activity but avoid exercise within 3 to 5 hours of bedtime to prevent evening overstimulation.
• Consider white and pink noise as a background sound for the sleep environment.[49] White noise creates a constant ambient sound that helps to mask other noises, such as traffic. Pink noise is similar but slightly louder and more powerful at the lower frequencies (i.e. white noise with a stronger bass tone).
• Listening to binaural beats may also enhance sleep.[50]
o Using headphones to listen to multiple sound frequencies at the same time (i.e. left ear receives a 300 hertz (hz) tone and right ear receives a 280 hz tone) allows the brain to process and absorb a low-frequency 10 hz soundwave.
o This is turn may slow brain wave activity, reducing arousal and thereby supporting sleep cycles.
• Consumer wrist-worn wearables help patients prioritise and track their sleep, but their accuracy remains limited. A systematic literature review indicates that the devices with higher relative agreement and sensitivities to multistate sleep (i.e. Fitbit Charge 4, Garmin Vivosmart 4, and WHOOP) seem appropriate for deriving suitable estimates of sleep parameters.[51]

Pharmaceutical Treatments:

In Australia, medications approved for the treatment of insomnia include benzodiazepines, benzodiazepine receptor agonists (referred to as ‘Z-drugs’) and dual orexin receptor antagonists. Other medications include sedative antidepressants, melatonin, antihistamines and calcium channel alpha-2 ligands.[45]

• Benzodiazepines are the most used and widely prescribed sleep medication, and they include temazepam, nitrazepam, oxazepam and flunitrazepam. Whilst they are effective in reducing sleep onset latency, they have also been found to cause daytime drowsiness and memory impairment. Discontinuation of benzodiazepines is best achieved slowly, by 25% over a 10-week period was superior when supported with CBT-I, compared to medication tampering alone.
• Benzodiazepine sedative-hypnotics: Non-benzodiazepines preferentially bind to GABAα receptor subtypes and have a short half-life (between approximately two and six hours). Common examples include zolpidem and zopiclone. Non-benzodiazepines reduce sleep onset latency and waking after sleep onset while increasing total sleep time. Discontinuation guidelines are the same as above.
• Dual orexin receptor antagonists, also referred to orexin receptor antagonists, are a new class of medication for the treatment of insomnia. Daytime sleepiness is the most common side effect.
• Sedating antidepressants, whilst not approved for the first-line treatment of insomnia, may be useful for insomnia with comorbid depression. Antidepressants that may be useful include amitriptyline, doxepin, nortriptyline, mirtazapine and agomelatine.
• Melatonin: Melatonin (synthetic derivative) has been shown to shorten sleep-onset latency in those who experience insomnia caused by circadian rhythm disruptions.

Contact Metagenics Clinical Support to check recommendations suitable for use with pharmaceutical medications.

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