Insomnia and Sleep Disruption Naturopathic Protocol

Insomnia and Sleep Disruption Naturopathic Protocol

This Insomnia and Sleep Disruption Naturopathic Protocol is provided as information for patients of HealthMasters Naturopath Kevin Tresize ND as part of a treatment plan to assist patients with understanding of their treatment plan. It is important to note that this is a summary only and is intended to assist discussion between practitioner and patient as part of consultations and should not be substituted for medical advise, diagnosis or treatment. This Insomnia and Sleep Disruption Naturopathic Protocol may be changed to suit the individual requirements of the patient and should not be substituted for medical advice, diagnosis or treatment.

HealthMasters Naturopath Kevin Tresize ND

Pathophysiology: Insomnia and Sleep Disruption

• Insomnia describes disturbances in sleep initiation or maintenance, resulting in restless and nonrestorative sleep that occurs despite adequate circumstances and opportunity for sleep.[1]
• Sleep is regulated by the body’s circadian rhythm, with the natural light and dark cycles maintaining regulatory control of sleep-wake cycles. This is governed by the suprachiasmatic nucleus (SCN), located in the hypothalamus, which is commonly referred to as the ‘master clock’.
• The SCN receives communication from melanopsin (a photo pigment of the eye) containing intrinsically photosensitive retinal ganglion cells (ipRGCs) that respond to the daily light/dark cycles (Figure 1).[2] In response to these cycles, the SCN drives rhythmic expression of melatonin, a hormone produced by the pineal gland involved in sleep onset (which is suppressed in response to light), and cortisol secretion (which is released in response to light).[3]

• In context of normal circadian rhythms, sleep architecture consists of an 80 to 120 minute sleep cycle that repeat three to five times per night,[6] delivering seven to eight hours sleep per night in healthy adults.
• This involves several progressive stages, beginning with rapid-eye movement (REM) then and non-rapid eye movement (NREM) sleep, [7],[8],[9] marked by four stages:

• The pathophysiology of insomnia is generally characterised by SWS deficiency, in addition excessive hyperarousal of the central nervous system (CNS) throughout the night, affecting both REM and NREM sleep.[11]
• Sleep disruption is also associated with cognitive-emotional or behavioural arousal that correlates with increased hypothalamic-pituitary-adrenal (HPA) axis activation and autonomic nervous system function, resulting in increased stimulatory events (i.e. anxiety and palpitations) and  raised cortisol that hinders normal sleep architecture.[12]
• Persistent HPA axis activation leads to a pattern of autonomic and neuroendocrine changes that disrupt gamma-aminobutyric acid (GABA)/glutamate neurotransmitter balance, which also influence sleep-wake cycles.[13]

• Decreased GABA signalling often underlies sleep and anxiety disorders,[16] which perpetuates HPA axis activation, resulting in structural and functional brain changes, including amygdala enlargement and in hippocampal and prefrontal cortex shrinkage, exacerbating insomnia and sleep disorders.
• Clinical presentations of insomnia may include transient and persistent insomnia associated with several variables outlined below.
• Transient insomnia is caused by stressful changes in life circumstances:

• Persistent insomnia is caused by:

 

Figure 1: Light communicates to the SCN, which then regulates rhythmic expression of the hormone melatonin, involved in sleep.[17]

Consultation Overview: Insomnia and Sleep Disruption

Identify Risk Factors

In Clinic Investigations - Refer to Key Drivers and the Clinical Investigation and Pathology sections below for further guidelines:

• Assess patient’s presenting sleep disorder, past and current interventions, sleep cycle patterns, sleep quality, sleep hygiene practices, and potential comorbidities using the Metagenics Sleep Assessment Questionnaire to determine sleep-wake issues and modifiable risk factors.
• Instruct patient to record the duration and features of the bedtime routine, including timing of sleep initiation, wake frequency and total hours slept to monitor sleep changes, noting any sleep variables using the Metagenics Patient Sleep Tracker.
• If mood issues are suspected, have patient complete the Depression Anxiety Stress Scales (DASS) and the Mood and Stress Questionnaire (MSQ).
• Investigate comorbid restless legs and pain conditions, in addition to anxiety, depression or other psychiatric disorders. If patient has been considered a suicide risk, seek immediate guidance from a Crisis Assessment and Treatment Team (CATT) or call triple zero (000) in an emergency.
• Evaluate thyroid function to determine if hyperthyroidism is a contributing factor to sleep symptoms, or if chronic sleep deprivation is impacting thyroid hormone levels. Have patient complete the Basal Body Temperature Tracker to determine changes in metabolic function associated with thyroid dysfunction.

Pathology Investigations - Refer to Key Drivers and the Clinical Investigation and Pathology sections below for guidelines:

• Consider the cortisol awakening response (CAR) test or adrenocortex stress profile to examine HPA axis function.
• If patient presents with symptoms of restless legs, evaluate for nutritional deficiencies (iron, folic acid, magnesium and vitamin D), hypothyroidism (thyroid studies) and hypoglycaemia (fasting and/or random blood glucose) if indicated.
• If patient presents with restless legs and significant gastrointestinal symptoms, consider screening for small bacterial intestinal overgrowth (SIBO) with hydrogen/methane breath test.
• If presenting with chronic pain, refer patient for pathology testing including erythrocyte sedimentation rate (ESR) and high sensitivity C-reactive protein (hs-CRP).
• Where indicated, screen for thyroid function markers: thyroid stimulating hormone (TSH) thyroxine (T4) and triiodothyronine (T3), thyroid peroxidase antibodies (TPOAb), TSH receptor antibodies and thyroglobulin antibodies to rule out thyroid dysfunction as a driver of sleep disruption.

Identify Signs of Insomnia and Sleep Disruption

Insomnia may be acute and self-limited, chronic but intermittent, or chronic and frequent. Clinical features of insomnia include:

• Difficulty initiating sleep, inability to maintain sleep, frequent night-time waking, difficulty falling back to sleep, and/or early morning awakening.
• Significant distress or impairment in daytime functioning such as fatigue or low energy, sleepiness, cognitive impairments, mood disturbances, and/or behavioural problems.
• Difficulty occurs despite adequate opportunity for sleep.

Key Drivers: Insomnia and Sleep Disruption

• Circadian rhythm disruption: Studies suggest that aberrant light exposure at night (use of interactive devices such as tablets, laptops, smart phones etc.) disturbs circadian rhythm, negatively affecting sleep quality. These devices emit blue light, which interferes with the natural rise of melatonin in the evening, while also stimulating brain activity.[19] Circadian rhythm disruptions can lead to impaired neurogenesis and loss of dendritic length in the hippocampus and prefrontal cortex.[20] Volume loss in these areas of the brain are associated with insomnia and mood disorders, including anxiety and depression.[21]
• Chronic or severe stress: Persistent or severe stressed-induced activation influences the structure and function of amygdala neurons, creating maladaptive neuroplasticity and structural changes.[22] When the brain is exposed to excessive stress, elevated glucocorticoids (i.e. corticotropin-releasing hormone [CRH], adrenocorticotrophic hormone [ACTH] and cortisol) rapidly induce the release of glutamate in the hippocampus; the region of the brain responsible for emotion, memory and the autonomic nervous system. Whilst glutamate excitation is necessary for strengthening dendritic branching in neuroplasticity, excessive glutamatergic neurotransmission can lead to neuronal dendritic retraction causing overall underfunctioning and shrinkage of the hippocampus.[23] These alterations are strongly associated with mood disorders, such as anxiety and panic disorder.[24] Structural and functional changes also alter the balance between inhibitory GABA and excitatory glutamate, necessary for sleep maintenance.
• Pain: Chronic pain (present for more than three months) can trigger poor sleep quality and reduce the benefits of the restorative sleep process by increasing sympathetic nervous system activity.[25] Poor sleep quality increases sensitivity to pain, consequently leading to reduced pain tolerance.[26] Imbalanced GABA/glutamate concentrations may also negatively impact pain perception. Specifically, glutamate, acting via the N-methyl-d-aspartate (NMDA) receptor complex, plays a key role in central sensitisation.[27] In response to sustained pain, increased amounts of glutamate are released in the spinal cord, overcoming the inhibitory action of magnesium ions, resulting in activation of the NMDA receptor. This initiates a cascade of intracellular signaling events that lead to prolonged modifications of somatosensory processing, with amplification of pain responses and continued neuronal firing.[28]
• Genetic predisposition: Insomnia may be genetically influenced, with evidence demonstrating that circadian rhythm disorders and narcolepsy are associated with specific genes.[29]

Treatment Priorities: Insomnia and Sleep Disruption

• Attenuate triggers that exacerbate insomnia including poor sleep hygiene habits, overstimulating evening activities and dietary stimulants including caffeine and alcohol determined by the Metagenics Sleep Assessment Questionnaire.
• Provide herbal and nutritional support to enhance NREM sleep quality, increase macular pigment optic density (MPOD) and mitigate night cortisol levels to counter sleep disruption caused by hyperarousal.
• Promote healthy sleep architecture by addressing disrupted sleep cycles and mitigating sleep-limiting effects of stress and blue light exposure.
• Enhance GABAergic activity to reduce glutamate excitation in the brain and encourage optimal sleep-wake cycles.
• Regulate HPA axis activity, reducing excessive production of glucocorticoids and subsequent stimulation of glutamate release via NMDA receptor signalling.
• Enhance neuroplasticity by increasing production of brain derived neurotrophic factor (BDNF), to encourage neurogenesis, neurite growth, maturation and survival, and regulation of synaptic function to promote healthy mood regulation.
• Provide the patient with education and resources to promote sleep hygiene. If indicated, refer patient for additional psychological support such as Cognitive-behavioural therapy for insomnia (CBT-I).
• Monitor patient’s adherence to dietary, lifestyle and supplementary recommendations using Your Guide to Stress Less patient booklet and the Metagenics Patient Sleep Tracker. 

Red Flags: Insomnia and Sleep Disruption

• 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.[30] Structural and functional disturbances in several brain regions including the amygdala, hippocampus and prefrontal cortex lead to aberrant functional activity within these regions, predisposing susceptible individuals to psychiatric illness.[31]  Use the DASS questionnaire and the MSQ and to assess patient’s mental wellbeing and refer to General Practitioner or Psychologist where indicated. If 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.
• Restless legs: A common cause of disturbed sleep; restless legs are a symptom rather than a disease itself, typically cause by underlying drivers including nutrient deficiencies (iron, folic acid, magnesium and vitamin D),[32],[33] hypothyroidism,[34] SIBO,[35]  and hypoglycaemia.[36] If restless legs are associated with insomnia, refer patient for pathology testing including iron studies, folate, magnesium and vitamin D, in addition to thyroid studies and fasting/random blood glucose. If patient also presents with symptoms of gastrointestinal dysfunction, refer patient for hydrogen/methane breath testing to investigate SIBO. 

Treatment Recommendations: Insomnia and Sleep Disruption

Core Treatment

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.

A combination of Meta Mag® magnesium bisglycinate, ornithine, ashwagandha, lutein and zeaxanthin to address disrupted sleep cycle patterns, potentiate NREM sleep and SWS, improve sleep quality and enhance melatonin and reduce cortisol that negatively impact sleep (Figure 2).

Mechanism of Action/Clinical Research: 

• Magnesium has been shown to significantly decrease serum cortisol levels within hours of sleep initiation, resulting in increased in SWS (p<0.01).[37]

• Ornithine also improves sleep quality, as well as reducing stress markers through the regulation of cortisol and dehydroepiandrosterone sulfate (DHEAS) production.[40] 

• Withania somnifera has been shown simultaneously improve sleep quality to moderate cortisol levels, which may counteract stress-induced HPA overactivity in insomnia.

• Lutein and zeaxanthin may assist sleep regulation by enhancing ocular MPOD levels, which is involved in filtering blue light. This in turn supports the production and release melatonin.[44],[45] These carotenoids have been shown to reduce the effects of excessive screen time (i.e. six hours of screen time daily for six months), and improve sleep onset and maintenance. [46]

 

Figure 2: 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.

A blend of sedative herbs, including passionflower, zizyphus and Californian poppy to modulate neurotransmitter pathways, including GABA and glutamate, monoamine and catecholamine activity (which support sleep quality), HPA axis function, formation of synaptic pathways, and brain plasticity for improved sleep and stress adaptation.

Mechanism of Action/Clinical Research: 

• Zizyphus activates glutamic acid decarboxylase, which catalyses GABA synthesis while also sensitising GABA receptors by increasing their subunit expression,[48] thereby enhancing GABA neurotransmission to promote sleep maintenance.
• Passionflower has been found to modulate the GABA system, demonstrating an affinity for both GABAα and GABAβ receptors, increasing its inhibitory effects.[49]

• Lavender oil promotes a GABAergic response by blocking calcium ion channel activity within neurons and suppressing glutamate excitation, with inhibitory effects comparable to those seen in pregabalin (a pharmaceutical agent that mimics the effects of GABA).[51]

• California poppy stimulates binding of the GABAαreceptor site, providing sedative effects.[53]

OR 

Gamma-Aminobutyric Acid (GABA)

Dosage: Take 250 mg – 500 mg before bed. 

GABA functions as a primary inhibitory neurotransmitter in the CNS, reducing neuronal hyperexcitation that contributes to pain and insomnia.

Mechanism of Action/Clinical Research: 

• GABA regulates neuronal excitability via GABA receptor subunits, which are classified into three main groups (alpha, beta and gamma).[54]
• An efficient efflux transport system enhances the passage of GABA across the blood brain barrier that also acts as an efflux pump for the excitatory amino acids, glutamate and aspartate, to reduce the brain interstitial fluid concentrations.[55]
• GABA plays a critical role in pain transmission. GABA neurons and receptors, found in supraspinal sites, regulate sensory information processing in the spinal cord, subsequently altering pain perception in response to painful stimuli.[56]

Additional Considerations

If presenting with anxiety

Herbal Support for Hyper HPA and Stress

Dosage: Take 1-2 tablets 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 contribute to insomnia. 

Mechanism of Action/Clinical Research:

• Zizyphus has been shown to modify the GABAα receptor subunits expressional levels,[57] which opposes glutamate-mediated excitability in the brain, contributing to its anxiolytic effects.[58]
• Passionflower has been found to modulate the GABA system, demonstrating an affinity for both GABAα and GABAβ receptors, increasing its inhibitory effects.[59]

• Kudzu has demonstrated β-adrenoceptor blocking activity[61],[62] 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 exhibits muscle relaxing effects via GABAergic mechanisms,[63] as well as neuroprotective properties.[64],[65]

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:

• Adults who get fewer than seven hours sleep, whether for just one night or over several months, have increased mood disturbances compared with people who sleep seven to nine hours per night.[66]
• Both saffron and turmeric have been found to inhibit the activity of proinflammatory transcription factors, such as nuclear factor kappa beta (NFκB) and mitogen activated protein kinase (MAPK).[67],[68] Saffron and turmeric 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.

• Safranal and crocin, present in saffron, have been shown to reduce HPA axis activity and decrease stress-induced plasma corticosterone levels.[70] Safranal has also been shown to exert anxiolytic and sedative effects via activation of the GABAergic pathway.[71]
• Turmeric activates glutamate decarboxylase (GAD), which converts glutamate to GABA.[72] 

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 has been used in Asian medicine for over 500 years.  Korean ginseng has been found to inhibit the activity of enzyme, 11-beta hydroxysteroid dehydrogenase 1, which catalyses the conversion of cortisol to inactive cortisone. It is proposed that inhibition of enzyme activity preserves cortisol levels and abolishes excess glucocorticoid production by the adrenals at times of stress, leading to maintenance of normal adrenal function.[73]
• Zizyphus is widely used in Chinese herbal formulas for the treatment of anxiety, frustration, irritability, and excessive night sweats.[74]  Jujuboside A, an active constituent of zizyphus, may protect neurons by blocking the release of extracellular glutamate in the hippocampus of the brain.[75]

If insomnia is due to pain:

Meta Mag® Magnesium Bisglycinate, Corydalis and California Poppy for Pain

Dosage: Add 1 level scoop (9.8 g) to 200 mL of water twice daily, with food.

Nutrients and herbs that augment glutamate activity involved in nociceptive pathways, to reduce pain signaling that contributes to insomnia.

Mechanism of Action/Clinical Research:

• Alkaloid compounds, dehydrocorybulbine (DHCB) and L-tetrahydropalmatine (1-THP), in corydalis have demonstrated analgesic actions in both inflammatory and neuropathic pain, without inducing tolerance with repeated use.[76] DHCB has been found to be a potent antagonist of dopamine receptors, inducing antinociception, with the effect sustained over three hours.[77]
• Magnesium has been found to block glutamate via inhibition of the NMDA receptor and reduce excitatory neurotransmission.[78]

• Precursor nutrient, glutamine, involved in the GABA-glutamate-glutamine cycle, helps maintain normal physiological homeostasis of pain.
• Taurine acts as an inhibitory neurotransmitter and has membrane stabilising effects,[80] protecting against glutamate excitotoxicity, modulating neuronal excitability and assisting with normalisation of pain.
• Vitamin C is involved in of noradrenaline and serotonin production and modulates GABAergic transmission.[81]

Supportive Programs: Insomnia and Sleep Disruption

The Wellness and Healthy Ageing program combines diet, lifestyle and supplemental interventions to support optimal health, wellbeing and quality of life, while also reducing factors that contribute to insomnia. 

Diet and Lifestyle Recommendations

Diet:

• 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.
• Reduce caffeine, alcohol, and/or tobacco late in the day, particularly during the evening.[82]
• Time restricted feeding has shown promising benefits in improving metabolic parameters, including sleep.[83]

Lifestyle:

•  Support circadian rhythm by addressing excessive light exposure and increasing day time light exposure:

Alternatively, blue light filter apps or settings can be installed/activated on devices to minimise blue light exposure.

• Increase daytime exposure to natural light in addition to limited night light exposure.[88]

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.

• Increase daytime activity, but avoid exercise within 3 to 5 hours of bedtime to prevent evening overstimulation.[89]
• Consider white and pink noise as a background sound for the sleep environment.[90]

Sleep Hygiene:

• Support patients to go to bed with a calm mind, try to resolve arguments or set a time earlier in the day to review problems and perhaps write down plans, solutions, or things to do.[91]
• Cognitive-behavioural therapy for insomnia (CBT-I) offers evidence-based techniques that includes behavioural and cognitive strategies to enhance sleep quality outlined in Table 1.[92]

Refer to the Australasian Sleep Association (ASA) service directory for treatment centers (www.sleep.org.au). 

Table 1: Cognitive and behavioural components of CBT-I.[96]

Behavioural strategies

Sleep restriction[97]	Sleep restriction aims to increase sleep efficiency and reduce time spent awake in bed by limiting the amount of time patients allow themselves to spend in bed.[98] This increases the desire to sleep (also known as sleep drive or sleep pressure) and improves sleep efficiency.[99] Patients can achieve this by tracking sleep patterns, recording their bedtime, time spent asleep, time spent in bed, and time they get up on a daily basis to calculate the time spent asleep. This determines the amount of time patients should spend in bed during sleep restriction (e.g. if patients only sleep for a total five hours, they should allow themselves to be in bed for five hours). Patients should not spend less than four hours in bed, not even if they feel like they sleep less. Once patients are sleeping at least 85% of the time they are spending in bed, they should increase the time in bed by 15 minutes, and keep increasing the time in bed with >85% sleep efficiency until sleep patterns stabilise. Sleep efficiency is the amount of time spent asleep divided by the time spent in bed (i.e. 5 hours asleep divided by 8 hours spent in bed equals 62.5% sleep efficiency). Patients should refrain from napping during the day. In patients older than 65 years old, a reasonable sleep efficiency goal is 80% and patients are allowed a single 30-minute nap during the day. Following sleep hygiene guidelines is also key to following sleep restriction strategies.
Stimulus control[100]	Behaviours that require wakefulness in bed (e.g. watching TV, using social media) could result in bedtime being associated with hyperarousal, thereby perpetuating sleep difficulties. Stimulus control helps to re-associate bed with being asleep, thereby reversing arousal. Individuals are instructed to go to bed only when sleepy, and not when alert. This helps re-associate bed with sleepiness. Individuals limit activities in bed to only sleeping and sex, and carry out waking behaviours that may previously be associated with bed (e.g. using a mobile phone) outside of bed. Individuals are instructed to have a ‘time out’ if they are unable to sleep within what feels like 15–30 minutes (without looking at the clock). During the time out, individuals complete a non-stimulating task (i.e. reading, breathing exercises), returning to bed when they feel comfortable. The same rise-time is recommended even if sleep the night before is poor. Both sleep restriction and stimulus control may cause increased daytime sleepiness in the short term. Monitoring and management of daytime sleepiness are important when administering either component.
Relaxation[101]	Relaxation strategies can include progressive muscle relaxation and diaphragmatic breathing with the intent of addressing arousal. The goal is to release tension and arousal.
Sleep hygiene[102]	General behavioural and environmental strategies can help patients improve and maintain good sleep outlined in Table 2 below.
Facilitating circadian rhythm[103]	Patients can be encouraged to adopt a regular sleep and wake schedule across weekdays and weekends to consolidate sleep and strengthen the circadian system. Optimising light exposure (natural or artificial) in the morning while limiting light exposure (e.g. electronic devices) in the evening helps with synchronising the human circadian system, given the known impact on melatonin production.

Cognitive strategies

Psychoeducation[104]

It is important to educate the patient about the purpose of sleep to address misconceptions about sleep. Some CBT-I programs encourage clinicians to use the Spielman model referring to the ‘Theory and Assessment of Insomnia’ model to educate patients. The Spielman model of chronic insomnia is made up of three components: Predisposing factors, precipitating factors, and perpetuating factors.[105] According to this model, predisposing factors may cause the occasional night of poor sleep, but in general, the person sleeps well until a precipitating event (e.g. death of a loved one) occurs, which triggers acute insomnia. If bad sleep habits develop, or other perpetuating factors set in, the insomnia becomes chronic and will persist even with removal of the precipitating factor.[106]

Cognitive therapy[107]

Cognitive therapy teaches patients to be aware, identify, evaluate and respond constructively to their unhelpful thoughts and beliefs about sleep. The cognitive therapy approach works by identifying distorted thinking, and then to test or alter distortions using cognitive restructuring techniques. Techniques such as examining the evidence for and against a thought, or decentering and taking the perspective of a compassionate other are helpful approaches.

• To manage stress-induced insomnia, physical symptoms of stress can be reduced through relaxation exercise, including activities that involve progressive muscle relaxation and breathing control (yoga, Pilates, meditation).[108]

Applications such as Headspace provide access to guided meditations, including specific sessions that concentrate on anxiety, stress, sleep and focus.

 

Promotes sleep	Prevents sleep
Go to bed and get up at same time Have an early, light dinner Comfortable mattress and bedding Read a book in bed Relaxation exercises (i.e. visualisations, sound therapy) Low light or blocking blue light at night Time spent in nature, particularly in the afternoon	Going to bed when not tired Coffee and chocolate after dinner Stress and anxiety Poor quality bedding Hot bedroom with no ventilation Using interactive devices at night Bright light/blue light at night Indoors all day, no exercise

Clinical Investigation and Pathology: Insomnia and Sleep Disruption

Clinical Screening	Rationale
Mood and Stress Questionnaire (MSQ)	A questionnaire designed to help Practitioners establish levels of stress, anxiety and mood concerns, prioritised in relation to each other. Appropriate treatment strategies based on common response patterns under stress and neurotransmitter patterns.
Metagenics Sleep Assessment Questionnaire (SAQ)	A questionnaire designed to help Practitioners screen patients for sleep disorders, past and current interventions, sleep cycle patterns, sleep quality, sleep hygiene practices and potential comorbidities that may negatively impact their health.
Metagenics Patient Sleep Tracker.	A symptom tracker to allow patients to track their response to treatment and provide Practitioners insight into patient sleep routines and habits.
Depression Anxiety Stress Scales (DASS)	A self-report questionnaire designed to measure the three related negative emotional states of depression, anxiety and tension/stress.
Basal Body Temperature Tracker	Using a digital thermometer, take temperature under the tongue on waking (before getting out of bed), preferably at the same time each day. Record temperature on Basal Body Temperature Tracker for at least four consecutive mornings, with an average taken of the readings. Normal reading: 36.5-37.0ºC

 

Pathology Testing	Ideal Reference Range	Rationale
Cortisol Awakening Response (CAR) Profile	Cortisol waking: 8.0 to 18.0 nmol/L Cortisol waking +30 min: 8.0 to 18.0 nmol/L Cortisol waking +60 min: 8.0 to 18.0 nmol/L Cortisol profile, Total CAR: 23.0 to 42.0 nmol/L	A non-invasive saliva test that serves as a reliable marker of the stress response. The CAR test measures the predictable rise and fall in cortisol within the first hour of awakening and can be used to evaluate the overall function of the HPA axis.
Adrenocortex Stress Profile	Cortisol morning: 6.0 to 42.0 nmol/L Cortisol noon: 2.0 to 11.0 nmol/L Cortisol afternoon: 2.0 to 11.0 nmol/L Cortisol evening: 1.0 to 5.0 nmol/L DHEA profile morning: 2.5 to 25.0 nmol/L DHEA/cortisol AM: 0.20 to 0.60 ratio	Salivary cortisol and dehydroepiandrosterone (DHEA) testing is a non-invasive saliva test that evaluates bioactive levels of the body’s important stress hormones. This test examines four saliva samples over a 12-hour period for levels of cortisol and DHEA at 8 am, 12 pm, 4 pm, and 8 pm.
Iron studies	Serum iron: 14 to 30 µmol/L Total Iron Binding Capacity: 45 to 80 µmol/L % Transferrin Saturation: Female: 20 to 55% Male: 20 to 60% Ferritin: 20 to 250 µg/L	To assess iron deficiency anaemia as a cause of restless legs.
Folate	Red cell: 360 to 1,400 nmol/L Serum: 7 to 45 nmol/L	Assessment of folate deficiency as a cause of restless legs.
Magnesium	<1 week of age: 0.60 to 1.00 mmol/L 1 week to <18 years: 0.65 to 1.10 mmol/L >18 years: 0.70 to 1.10 mmol/L	Assessment of hypomagnesaemia as a cause of restless legs.
Vitamin D	Ideal: 100-150 nmol/L Normal: 40-100 nmol/L Deficient: 0-40 nmol/L	Assessment of vitamin D deficiency as a cause of restless legs.
Serum TSH	0.4 to 4.0 mlU/L Ideal range: 0.4 to 2.0 mlU/L Ideal range for preconception/pregnancy: Preconception: <2.5 mlU/L First trimester: 0.1 to 2.5 mlU/L Second trimester: 0.2 to 3.0 mlU/L Third trimester: 0.3 to 3.0 mlU/L	Assessment of thyroid dysfunction/hypothyroidism, which may also contribute to restless legs. TSH is the first line test for assessment of thyroid function.
Serum fT4	10 to 25 pmo/L	Assessment of thyroid dysfunction/hypothyroidism, which may also contribute to restless legs. Considered to provide a reliable indication of true thyroid function.
Serum fT3	4 to 8 pmol/L	Assessment of thyroid dysfunction/hypothyroidism, which may also contribute to restless legs. Performed as part of a comprehensive evaluation of thyroid function.
Thyroid peroxidase antibodies (TPO-Ab)	Ideal range: <50 IU/mL Increased risk of thyroid dysfunction: 50 to 100 IU/mL	Elevations correlate with changes in the thyroid gland, which may reflect inflammation and tissue destruction.
Thyroglobulin antibodies (TgAb)	Reference range: <4 IU/mL Ideal range: <1IU/mL	Often raised in autoimmune thyroid conditions.
TSH receptor antibodies	Ideal range:<55 IU/L [109]	Used for evaluation of suspected Graves’ disease.[110]
Glucose (fasting)	3.5 to 6.0 mmol/L	Assessment of hypoglycaemia as a cause of restless legs.
Glucose (random)	3.5 to 9.0 mmol/L	Assessment of hypoglycaemia as a cause of restless legs.
Erythrocyte Sedimentation Rate (ESR)	Female: 17 to 50 years: 3 to 12 mm/hr <50 years: 5 to 20 mm/hr Male: 17 to 50 years: 1 to 10 mm/hr >50 years: 2 to 15 mm/hr	ESR is a non-specific indicator of inflammation that may be elevated in pain syndromes.
High Sensitivity C-reactive Protein (Hs-CRP)	Normal value <10 mg/L However, ideal is <1 mg/L	Assessment of acute phase reaction in inflammatory disorders, which may be elevated in pain syndromes.
Hydrogen/Methane Breath Testing	Refer to individual laboratories for reference ranges	SIBO can be diagnosed with a hydrogen/methane breath test, which is indicated by a significant rise in breath hydrogen or methane levels above baseline during the test.

Pharmaceutical Treatments: Insomnia and Sleep Disruption

Contact Metagenics Clinical Support to ensure product recommendations are suitable for use in conjunction with pharmaceutical medications.

• Benzodiazepine receptor agonists: Inhibit neuronal activity via acting on the GABAergic pathway and are beneficial for short-term management of sleep-onset insomnia and maintenance insomnia.[111]
• Benzodiazepine sedative-hypnotics: Reduce neuronal excitability via acting on the GABAergic pathway, while also providing muscle relaxing and anxiolytic effects.[112]
• Tricyclic antidepressants (TCAs): TCA agents inhibit re-uptake of the amines noradrenaline (norepinephrine) and serotonin at synaptic clefts. The therapeutic effect is noticeable within one to two weeks, however adverse effects can be troublesome during this period (sedation, anticholinergic effects, postural hypotension, lowering of the seizure threshold and cardiotoxicity).[113]
• Melatonin: Melatonin (synthetic derivative) has been shown to shorten sleep-onset latency in those who experience insomnia caused by circadian rhythm disruptions.[114]

Additional Resources: Insomnia and Sleep Disruption

• Depression Anxiety Stress Scales (DASS) - A self-report questionnaire designed to measure the three related negative emotional states of depression, anxiety and tension/stress.
• Australasian Sleep Association- ASA is the peak scientific body in Australia and New Zealand representing clinicians, scientists and researchers working in sleep health and sleep medicine. It promotes and provides education and training to members and the broader health community. ASA also fosters scientific research and establishes best-practice clinical guidelines.
• The Beyond Blue organisation can provide information and additional support to patients affected by anxiety, depression, substance abuse and additional mental health conditions.

Footnotes:

[*] Blue light has the shortest wavelengths detectable by the human eye. Sunlight and incandescent light contain a broad range of wavelengths. However, the light from electronic devices and light-emitting diodes (LEDs) have a much narrower range of wavelengths, thereby are a concentrated source of blue light.

References: Insomnia and Sleep Disruption

[1] Ferri FF. Ferri’s clinical advisor 2020. Philadelphia (USA): Elsevier/Churchill Livingstone; 2020. p. 796-98.

[2] Mazzoccoli G, De Cosmo S, Mazza T. The biological clock: a pivotal hub in non-alcoholic fatty liver disease pathogenesis. Front Physiol. 2018 Mar 15;9:193. doi:10.3389/fphys.2018.00193.

[3] Braun R, Kath WL, Iwanaszko M, Kula-Eversole E, Abbott SM, Reid KJ, et al. Universal method for robust detection of circadian state from gene expression. Proc Natl Acad Sci U S A. 2018 Sep;201800314. doi:10.1073/pnas.1800314115.

[4] Culver MF, Bowman J, Juturu V. Lutein and zeaxanthin isomers effect on sleep quality: a randomized placebo-controlled trail. Biomedical Journal of Scientific & Technical Research. 2018; 9(2): 1-7. doi: 10.26717/BJSTR.2018.09.001775.

[5] Stringham JM, Stringham NT, O’Brien KJ. Macular carotenoid supplementation improves visual performance, sleep quality, and adverse physical symptoms in those with high screen time exposure. Foods. 2017; 6(47). doi: 10.3390/foods6070047.

[6] Medic G, Wille M, Hemels ME. Short- and long-term health consequences of sleep disruption. Nat Sci Sleep. 2017;9:151-161. doi: 10.2147/NSS.S134864.

[7] Roth T. Slow wave sleep: does it matter? J Clin Sleep Med. 2009;5(2 Suppl):S4-S5. PMID: 19998868.

[8] Carskadon MA, Dement WC. Monitoring and staging human sleep. In: Kryger MH, Roth T, Dement WC, editor. Principles and practice of sleep medicine. 5th ed. St. Louis: Elsevier Saunders; 2011. p. 16-26.

[9] Porkka 2013: Porkka-Heiskanen T, Zitting KM, Wigren HK. Sleep, its regulation and possible mechanisms of sleep disturbances. Acta Physiol (Oxf). 2013;208(4):311-328. doi: 10.1111/apha.12134.

[10] Carskadon MA, Dement WC. Monitoring and staging human sleep. In: Kryger MH, Roth T, Dement WC, editor. Principles and practice of sleep medicine. 5th ed. St. Louis: Elsevier Saunders; 2011. p. 16-26.

[11] Merica H, Blois R, Gaillard JM. Spectral characteristics of sleep EEG in chronic insomnia. Eur J Neurosci. 1998 May;10(5):1826-34. doi: 10.1046/j.1460-9568.1998.00189.x.

[12] Riemann D, Nissen C, Palagini L, Otte A, Perlis ML, Spiegelhalder K. The neurobiology, investigation, and treatment of chronic insomnia. Lancet Neurol. 2015 May;14(5):547-58. doi: 10.1016/S1474-4422(15)00021-6.

[13] Wisden W, Yu X, Franks NP. GABA receptors and the pharmacology of sleep. Handb Exp Pharmacol. 2019;253:279-304. doi:10.1007/164_2017_56.

[14] Meyerhoff DJ, Mon A, Metzler T, Neylan TC. Cortical gamma-amino butyric acid and glutamate in posttraumatic stress disorder and their relationships to self-reported sleep quality. Sleep. 2014 May 1;37(5):893-900. doi:10.5665/sleep.3654.

[15] Jones BE. Principal cell types of sleep-wake regulatory circuits. Curr Opin Neurobiol. 2017 Jun;44:101-109. doi: 10.1016/j.conb.2017.03.018.

[16] Martin EI, Ressler KJ, Binder E, Nemeroff CB. The neurobiology of anxiety disorders: brain imaging, genetics, and psychoneuroendocrinology. Psychiatr Clin North Am. 2009 Sep;32(3):549-75.

[17] Koch BC, Nagtegaal JE, Kerkhof GA, ter Wee PM. Circadian sleep-wake rhythm disturbances in end-stage renal disease. Nat Rev Nephrol. 2009 Jul;5(7):407-16. doi: 10.1038/nrneph.2009.88.

[18] Spiegel K, Leproult R, Van Cauter E. Impact of sleep debt on metabolic and endocrine function. Lancet. 1999 Oct 23;354(9188):1435-9. doi: 10.1016/S0140-6736(99)01376-8.

[19] Chang AM, Aeschbach D, Duffy JF, Czeisler CA. Evening use of light-emitting eReaders negatively affects sleep, circadian timing, and next-morning alertness. Proc Natl Acad Sci U S A. 2015 Jan 27;112(4):1232-7.

[20] Bedrosian TA, Nelson RJ. Timing of light exposure affects mood and brain circuits. Transl Psychiatry. 2017 Jan 31;7(1):e1017. doi:10.1038/tp.2016.262 

[21] Bedrosian TA, Nelson RJ. Timing of light exposure affects mood and brain circuits. Transl Psychiatry. 2017 Jan 31;7(1):e1017. doi: 10.1038/tp.2016.262.

[22] Roozendaal B, McEwen BS, Chattarji S. Stress, memory and the amygdala. Nat Rev Neurosci. 2009 Jun;10(6):423-33.

[23] Van Dalfsen JH, Markus CR. The influence of sleep on human hypothalamic-pituitary-adrenal (HPA) axis reactivity: a systematic review. Sleep Med Revs. 2018 Oct 18;39:187-94. doi: https://doi.org/10.1016/j.smrv.2017.10.002.

[24] Meyerhoff DJ, Mon A, Metzler T, Neylan TC. Cortical gamma-aminobutyric acid and glutamate in posttraumatic stress disorder and their relationships to self-reported sleep quality. Sleep. 2014 May 1;37(5):893-900. doi:10.5665/sleep.3654. 

[25] Roizenblatt S, Neto NS, Tufik S. Sleep disorders and fibromyalgia. Curr Pain Headache Rep. 2011 Oct;15(5):347-57. doi: 10.1007/s11916-011-0213-3. PMID: 21594765.

[26] Marshansky S, Mayer P, Rizzo D, Baltzan M, Denis R, Lavigne GJ. Sleep, chronic pain, and opioid risk for apnea. Prog Neuropsychopharmacol Biol Psychiatry. 2017 July 15; 87:234-44.

[27] Ralston SH, Penman ID, Strachan M, Hobson R. Davidson’s principles and practice of medicine. 23rd ed. Edinburgh (UK): Elsevier/Churchill Livingstone; 2018. p. 1337-1356.

[28] Ralston SH, Penman ID, Strachan M, Hobson R. Davidson’s principles and practice of medicine. 23rd ed. Edinburgh (UK): Elsevier/Churchill Livingstone; 2018. p. 1337-1356.

[29] Ferri FF. Ferri’s clinical advisor 2020. Philadelphia (USA): Elsevier/Churchill Livingstone; 2020. p. 796-98.

[30] Krystal AD. Psychiatric disorders and sleep. Neurol Clin. 2012 Nov;30(4):1389-413. doi: 10.1016/j.ncl.2012.08.018.

[31] Bagherzadeh-Azbari S, Khazaie H, Zarei M, Spiegelhalder K, Walter M, Leerssen J, et al. Neuroimaging insights into the link between depression and insomnia: a systematic review. J Affect Disord. 2019 Nov 1;258:133-143. doi:10.1016/j.jad.2019.07.089.

[32] Wali S, Shukr A, Boudal A, Alsaiari A, Krayem A. The effect of vitamin D supplements on the severity of restless legs syndrome. Sleep Breath. 2015 May;19(2):579-83.

[33] Trenkwalder C, Hening WA, Montagna P, Oertel WH, Allen RP, Walters AS, et al. Treatment of restless legs syndrome: an evidence-based review and implications for clinical practice. Mov Disord. 2008 Dec 15;23(16):2267-302.

[34] Rodríguez Martín C, Miranda Riaño S, Celorrio San Miguel M, Prieto de Paula JM. Restless legs syndrome and hypothyroidism. Rev Clin Esp. 2015 May;215(4):247-9.

[35] Weinstock LB, Fern SE, Duntley SP. Restless legs syndrome in patients with irritable bowel syndrome: response to small intestinal bacterial overgrowth therapy. Dig Dis Sci. 2008 May;53(5):1252-6.

[36] Kurlan R. Postprandial (reactive) hypoglycemia and restless leg syndrome: related neurologic disorders? Mov Disord. 1998 May;13(3):619-20.

[37] Held K, Antonijevic IA, Künzel H, Uhr M, Wetter TC, Golly IC, et al. Oral Mg(2+) supplementation reverses age-related neuroendocrine and sleep EEG changes in humans. Pharmacopsychiatry. 2002 Jul;35(4):135-43. PMID: 12163983.

[38] Abbasi B, Kimiagar M, Sadeghniiat K, Shirazi MM, Hedayati M, Rashidkhani B. The effect of magnesium supplementation on primary insomnia in elderly: a double-blind placebo-controlled clinical trial. J Res Med Sci. 2012 Dec;17(12):1161-9. PMID: 23853635.

[39] Abbasi B, Kimiagar M, Sadeghniiat K, Shirazi MM, Hedayati M, Rashidkhani B. The effect of magnesium supplementation on primary insomnia in elderly: a double-blind placebo-controlled clinical trial. J Res Med Sci. 2012 Dec;17(12):1161-9. PMID: 23853635.

[40] Miyake M, Kirisako T, Kokubo T, Miura Y, Morishita K, Okamura H. Randomised controlled trial of the effects of L-ornithine on stress markers and sleep quality in healthy workers. Nutr J. 2014;13:53. doi: 10.1186/1475-2891-13-53.

[41] Miyake M, Kirisako T, Kokubo T, Miura Y, Morishita K, Okamura H. Randomised controlled trial of the effects of L-ornithine on stress markers and sleep quality in healthy workers. Nutr J. 2014;13:53. doi: 10.1186/1475-2891-13-53.

[42] Miyake M, Kirisako T, Kokubo T, Miura Y, Morishita K, Okamura H. Randomised controlled trial of the effects of L-ornithine on stress markers and sleep quality in healthy workers. Nutr J. 2014;13:53. doi: 10.1186/1475-2891-13-53.

[43] Salve J, Pate S, Debnath K, Langade D. Adaptogenic and anxiolytic effects of ashwagandha root extract in healthy adults: a double-blind, randomized, placebo-controlled clinical study. Cureus. 2019;11(12):e6466. doi: 10.7759/cureus.6466.

[44] Stringham JM, Stringham NT, O’Brien KJ. Macular carotenoid supplementation improves visual performance, sleep quality, and adverse physical symptoms in those with high screen time exposure. Foods. 2017; 6(47). doi: 10.3390/foods6070047.

[45] Culver MF, Bowman J, Juturu V. Lutein and zeaxanthin isomers effect on sleep quality: a randomized placebo-controlled trail. Biomedical Journal of Scientific & Technical Research. 2018; 9(2): 1-7. doi: 10.26717/BJSTR.2018.09.001775.

[46] Culver MF, Bowman J, Juturu V. Lutein and zeaxanthin isomers effect on sleep quality: a randomized placebo-controlled trail. Biomedical Journal of Scientific & Technical Research. 2018; 9(2): 1-7. doi: 10.26717/BJSTR.2018.09.001775.

[47] Culver MF, Bowman J, Juturu V. Lutein and zeaxanthin isomers effect on sleep quality: a randomized placebo-controlled trail. Biomedical Journal of Scientific & Technical Research. 2018; 9(2): 1-7. doi: 10.26717/BJSTR.2018.09.001775.

[48] Shergis JL, Ni X, Sarris J, Zhang AL, Guo X, Xue CC, et al. Zizyphus spinosa seeds for insomnia: a review of chemistry and psychopharmacology. Phytomedicine. 2017 July 2;34:38-43. doi: http://dx.doi.org/10.1016/j.phymed.2017.07.004. 

[49] Fiebich BL, Weiss G, Hoffmann C. Modulation of the y-aminobutric acid (GABA) system by Passiflora incarnate L. Phytother Res. 2011; 25(6):838-843.

[50] Gibbert J, Kreimendahl F, Lebert J, Rychlik R, Trompetter I. Improvement of stress resistance and quality of life of adults with nervous restlessness after treatment with a passionflower dry extract. Complement Med Res. 2017April 12; 24:83-9. doi:10.1159/000464342.

[51] Kasper S, Anghelescu I, Dienel A. Efficacy or orally administered Silexan in patients with anxiety-related restlessness and disturbed sleep- a randomized, placebo-controlled trial. Eur Neuropsychopharmacol. 2015 July 28;25:1960-67. doi: http://dx.doi.org/10.1016/j.euroneuro.2015.07.024.

[52] Kasper S, Anghelescu I, Dienel A. Efficacy or orally administered Silexan in patients with anxiety-related restlessness and disturbed sleep- a randomized, placebo-controlled trial. Eur Neuropsychopharmacol. 2015 July 28;25:1960-67. doi:http://dx.doi.org/10.1016/j.euroneuro.2015.07.024.

[53] Fedurco M, Gregorova J, Sebrlova K, Kantorova J, Pes O, Baur R, et al. Modulatory effects of Eschscholzia californica alkaloids on recombinant GABAAreceptors. Biochem res Int. 2015 September 15;2015:617-620. doi:http://dx.doi.org/10.1155/2015/617620.

[54] Monograph: Gamma-Aminobutyric Acid (GABA). Altern Med Rev. 2007;12(3):274-279.

[55] Kakee A, Takanaga H, Terasaki T, Naito M, Tsuruo T, Sugiyama Y. Efflux of a suppressive neurotransmitter, GABA, across the blood-brain barrier. J Neurochem. 2001 Oct;79(1):110-8. PMID: 11595763.

[56] Enna SJ, McCarson KE. The role of GABA in the mediation and perception of pain. Adv Pharmacol. 2006;54:1-27. PMID: 17175808.

[57] You ZL, Xia Q, Liang FR, Tang YJ, Xu CL, Huang J, et al. Effects on the expression of GABAA receptor subunits by jujuboside A treatment in rat hippocampal neurons. J Ethnopharmacol. 2010 Mar 24;128(2):419-23. doi:10.1016/j.jep.2010.01.034

[58] Zhang M, Ning G, Shou C, Lu Y, Hong D, Zheng X. Inhibitory effect of jujuboside A on glutamate-mediated excitatory signal pathway in hippocampus. Planta Med. 2003;69(8):692-695. PMID: 14531016.

[59] Fiebich BL, Weiss G, Hoffmann C. Modulation of the y-aminobutric acid (GABA) system by Passiflora incarnate L. Phytotherapy Research. 2011; 25(6):838-843.

[60] Gibbert J, Kreimendahl F, Lebert J, Rychlik R, Trompetter I. Improvement of stress resistance and quality of life of adults with nervous restlessness after treatment with a passionflower dry extract. Complement Med Res. 2017April 12; 24:83-89. doi:10.1159/000464342.

[61] Wang LY, Zhao AP, Chai XS. Effects of puerarin on cat vascular smooth muscle in vitro. Acta Pharmacologica Sinica. 1994;15(2):180-182.

[62] Wong KH, Li GQ, Li KM, Razmovski-Naumovski V, Chan K. Kudzu root: traditional uses and potential medicinal benefits in diabetes and cardiovascular diseases. J Ethnopharmacol. 2011 Apr 12;134(3):584-607. doi: 10.1016/j.jep.2011.02.001.

[63] Ma H, Kim CS, Ma Y, Nam SY, Kim DS, Woo SS, et al. Magnolol enhances pentobarbital-induced sleeping behaviors: possible involvement of GABAergic systems. Phytother Res. 2009 Sep;23(9):1340-4. doi: 10.1002/ptr.2773.

[64] Lee YJ, Lee YM, Lee CK, Jung JK, Han SB, Hong JT. Therapeutic applications of compounds in the Magnolia family. Pharmacol Ther. 2011 May;130(2):157-76. doi:10.1016/j.pharmthera.2011.01.010.

[65] Han H, Jung JK, Han SB, Nam SY, Oh KW, Hong JT. Anxiolytic-like effects of 4-O-methylhonokiol isolated from Magnolia officinalis through enhancement of GABAergic transmission and chloride influx. J Med Food. 2011 Jul-Aug;14(7-8):724-31. doi: 10.1089/jmf.2010.1111.

[66] Adams RJ, Appleton SL, Taylor AW, McEvoy D, Antic N. Sleep health of Australian adults in 2016: results of the 2016 Sleep Health Foundation national survey. Sleep Health. 2017;3(1):35-42. doi: 10.1016/j.sleh.2016.11.005.

[67] Xiong Y, Wang J, Yu H, Zhang X, Miao C. Anti-asthma potential of crocin and its effect on MAPK signaling pathway in a murine model of allergic airway disease. Immunopharmacol Immunotoxicol. 2015 Jun;37(3):236-43.

[68] Dong HJ, Shang CZ, Peng DW, Xu J, Xu PX, Zhan L, et al. Curcumin attenuates ischemia-like injury induced IL-1β elevation in brain microvascular endothelial cells via inhibiting MAPK pathways and nuclear factor-κB activation. Neurol Sci. 2014 Sep;35(9):1387-92.

[69] Lopresti AL, Drummond PD. Efficacy of curcumin, and a saffron/curcumin combination for the treatment of major depression: a randomised, double-blind, placebo-controlled study. J Affect Disord. 2017 Jan 1;207:188-196. doi:10.1016/j.jad.2016.09.047.

[70] Lopresti AL, Drummond PD. Saffron (Crocus sativus) for depression: a systematic review of clinical studies and examination of underlying antidepressant mechanisms of action. Hum Psychopharmacol. 2014 Nov;29(6):517-27.

[71] Hosseinzadeh H, Noraei NB. Anxiolytic and hypnotic effect of Crocus sativus aqueous extract and its constituents, crocin and safranal, in mice. Phytother Res. 2009 Jun;23(6):768-74.

[72] Kurohara S, Asai M, Hayashi M, Yokoigawa K, Ueno H. Microanalysis of GABA: an application for evaluating GABA production in yeast strains and the effect of spice extracts on glutamate decarboxylase. J. Biol. Macromol. 2001;1:45-8.

[73] Liao LY, He YF, Li L, Meng H, Dong YM, Yi F, et al. A preliminary review of studies on adaptogens: comparison of their bioactivity in TCM with that of ginseng-like herbs used worldwide. Chin Med. 2018 Nov 16;13:57. doi: 10.1186/s13020-018-0214-9 

[74] Chen CJ, Li M, Wang XL, Fan-Fu F. Effect of Sour Date (Semen ziziphi spinossae) seed extract on treating insomnia and anxiety. Nuts and Seeds in health and disease prevention. Elsevier. 2011. Chapter 123: 1037-1041.

[75] Sarris J. Herbal medicines in the treatment of psychiatric disorders: a systemic review. Phytotherapy Research. 2007;21(8):703-716.

[76] Ingram SL. Pain: novel analgesics from traditional Chinese medicines. Curr Biol. 2013;24(3):R114-R116.

[77] Zhang Y, Wang C, Wang L, Parks GS, Zhang X, Guo Z, et al. A novel analgesic isolated from a traditional Chinese medicine. Curr Biol. 2014 Jan 20;24(2):117-23.

[78] Decollogne S, Tomas A, Lecerf C, Adamowicz E, Seman M. NMDA receptor complex blockade by oral administration of magnesium: comparison with MK-801. Pharm Biochem and Behavior. 1997 Sep 1;58(1):261-8.

[79] Abraham GE, Flechas JD. Management of fibromyalgia: rationale for the use of magnesium and malic acid. J Nutr Med. 1992;3:49-59. doi: https://doi.org/10.3109/13590849208997961.

[80] Braun L, Cohen M. Herbs and natural supplements: an evidence-based guide. 3rd ed. Sydney (AU): Elsevier/Churchill Livingstone; 2010. p. 882.

[81] Braun L, Cohen M. Herbs and natural supplements: an evidence-based guide. 3rd ed. Sydney (AU): Elsevier/Churchill Livingstone; 2010. p. 968.

[82] Ferri FF. Ferri’s clinical advisor 2020. Philadelphia (USA): Elsevier/Churchill Livingstone; 2020. p. 796-98.

[83] Gill S, Panda S. A Smartphone app reveals erratic diurnal eating patterns in humans that can be modulated for health benefits. Cell Metab. 2015 Nov 3;22(5):789-98. doi: 10.1016/j.cmet.2015.09.005.

[84] Gill S, Panda S. A Smartphone app reveals erratic diurnal eating patterns in humans that can be modulated for health benefits. Cell Metab. 2015 Nov 3;22(5):789-98. doi: 10.1016/j.cmet.2015.09.005.

[85] Ferri FF. Ferri’s clinical advisor 2020. Philadelphia (USA): Elsevier/Churchill Livingstone; 2020. p. 796-98.

[86] Ferri FF. Ferri’s clinical advisor 2020. Philadelphia (USA): Elsevier/Churchill Livingstone; 2020. p. 796-98.

[87] van der Lely S, Frey S, Garbazza C, Wirz-Justice A, Jenni OG, et al. Blue blocker glasses as a countermeasure for alerting effects of evening light-emitting diode screen exposure in male teenagers. J Adolesc Health. 2015 Jan;56(1):113-9.

[88] Ferri FF. Ferri’s clinical advisor 2020. Philadelphia (USA): Elsevier/Churchill Livingstone; 2020. p. 796-98.

[89] Ferri FF. Ferri’s clinical advisor 2020. Philadelphia (USA): Elsevier/Churchill Livingstone; 2020. p. 796-98.

[90] Ferri FF. Ferri’s clinical advisor 2020. Philadelphia (USA): Elsevier/Churchill Livingstone; 2020. p. 796-98.

[91] Ferri FF. Ferri’s clinical advisor 2020. Philadelphia (USA): Elsevier/Churchill Livingstone; 2020. p. 796-98.

[92] Grima N, Mansfield D. Insomnia Management. Aust J Gen Practice. 2019 Apr:48(4): 198-202

[93]  Trauer JM, Qian MY, Doyle JS, Rajaratnam SM, Cunnington D. Cognitive Behavioral Therapy for Chronic Insomnia: A Systematic Review and Meta-analysis. Ann Intern Med. 2015 Aug 4;163(3):191-204. doi: 10.7326/M14-2841.

[94] Blom K, Jernelöv S, Rück C, Lindefors N, Kaldo V. Three-Year Follow-Up Comparing Cognitive Behavioral Therapy for Depression to Cognitive Behavioral Therapy for Insomnia, for Patients With Both Diagnoses. Sleep. 2017 Aug 1;40(8). doi: 10.1093/sleep/zsx108

[95] Ferri FF. Ferri’s clinical advisor 2020. Philadelphia (USA): Elsevier/Churchill Livingstone; 2020. p. 796-98.

[96] Grima N, Mansfield D. Insomnia Management. Aust J Gen Practice. 2019 Apr:48(4): 198-202

[97] Grima N, Mansfield D. Insomnia Management. Aust J Gen Practice. 2019 Apr:48(4): 198-202

[98] Falloon K, Elley CR, Fernando A 3rd, Lee AC, Arroll B. Simplified sleep restriction for insomnia in general practice: a randomised controlled trial. Br J Gen Pract. 2015 Aug;65(637):e508-15. doi: 10.3399/bjgp15X686137.

[99] Falloon K, Elley CR, Fernando A 3rd, Lee AC, Arroll B. Simplified sleep restriction for insomnia in general practice: a randomised controlled trial. Br J Gen Pract. 2015 Aug;65(637):e508-15. doi: 10.3399/bjgp15X686137.

[100] Grima N, Mansfield D. Insomnia Management. Aust J Gen Practice. 2019 Apr:48(4): 198-202

[101] Grima N, Mansfield D. Insomnia Management. Aust J Gen Practice. 2019 Apr:48(4): 198-202

[102] Grima N, Mansfield D. Insomnia Management. Aust J Gen Practice. 2019 Apr:48(4): 198-202

[103] Grima N, Mansfield D. Insomnia Management. Aust J Gen Practice. 2019 Apr:48(4): 198-202

[104] Grima N, Mansfield D. Insomnia Management. Aust J Gen Practice. 2019 Apr:48(4): 198-202

[105] Spielman AJ, Caruso LS, Glovinsky PB. A behavioral perspective on insomnia treatment. Psychiatr Clin North Am. 1987 Dec;10(4):541-53. PMID: 3332317.

[106] Spielman AJ, Caruso LS, Glovinsky PB. A behavioral perspective on insomnia treatment. Psychiatr Clin North Am. 1987 Dec;10(4):541-53. PMID: 3332317.

[107] Grima N, Mansfield D. Insomnia Management. Aust J Gen Practice. 2019 Apr:48(4): 198-202

[108] Andrews G, Bell C, Boyce P, Gale C, Lampe L, Marwat O, et al. Royal Australian and New Zealand College of psychiatrists clinical practice guidelines for the treatment of panic disorder, social anxiety disorder and generalised anxiety disorder. Aust N Z J Psychiatry. 2018 Nov 30;52(12):1109-72. doi: https://doi.org/10.1177/0004867418799453.

[109] Allelein S, Ehlers M, Goretzki S, Hermsen D, Feldkamp J, Haase M, et al. Clinical evaluation of the first automated assay for the detection of stimulating TSH receptor autoantibodies. Horm Metab Res. 2016 Dec;48(12):795-801. Epub 2016 Dec 6. PMID: 27923250.

[110] Elsevier Clinical Key [Internet]. Melbourne (AUS): Elsevier; 2019. Hyperthyroidism: [Updated December 18 2019; Cited 2020 Feb 18]. Available from https://www.clinicalkey.com.au. subscription required to view.

[111] Ferri FF. Ferri’s clinical advisor 2020. Philadelphia (USA): Elsevier/Churchill Livingstone; 2020. p. 796-98.

[112] Ferri FF. Ferri’s clinical advisor 2020. Philadelphia (USA): Elsevier/Churchill Livingstone; 2020. p. 796-98.

[113] Ralston SH, Penman ID, Strachan MW, Hobson RP. Davidson's principles and practice of medicine. 23rd ed. Edinburgh (UK): Elsevier/Churchill Livingstone; 2018. p. 1179-1207. 

[114] Ferri FF. Ferri’s clinical advisor 2020. Philadelphia (USA): Elsevier/Churchill Livingstone; 2020. p. 796-98.