Orthomolecular Interventions

Vitamin B3 (niacin)

Vitamin B3 is also known as niacin – which is the generic term for nicotinic acid, niacinamide, and other related niacin-derived molecules.

However, the term niacin is commonly used to refer to the nicotinic acid form of vitamin B3.

The two main forms of vitamin B3 known medically, are nicotinic acid and nicotinamide.

Vitamin B3 and sleep

  • Vitamin B3 has roles in several pathways involved with sleep regulation (Szentirmai & Kapás, 2019).

Vitamin B3 and tryptophan

  • The sleep-promoting hormone melatonin, is made by a series of enzyme reactions from the dietary amino acid tryptophan. Tryptophan is first converted to 5-HTP, then serotonin, followed by melatonin.
  • With low levels of the vitamin B3 metabolite nicotinamide adenine dinucleotide (NAD), tryptophan is diverted to NAD production, thereby reducing the amount of tryptophan available for melatonin production.
  • A study of 509 Dutch university students showed decreasing amounts of insomnia with increasing amounts of dietary niacin and tryptophan (Verster et al., 2015).

Vitamin B3 and circadian rhythm

  • Niacinamide supplementation inhibits an enzyme (tryptophan pyrrolase) which breaks down tryptophan in the liver, which increases tryptophan available for melatonin production (Gaby, 2011).

Vitamin B3 and sleep pressure

  • Prostaglandins are hormone-like molecules made by the body from lipids.
  • Prostaglandin D2 (PGD2) is a powerful substance for sleep promotion 35. (Szentirmai & Kapás, 2019)
  • Niacin has been shown to stimulate PGD2 synthesis (Morrow et al., 1989).

Vitamin B3 after sleep loss

  • Vitamin B3 promotes the activation of immune cells known as macrophages. Activated macrophages support sleep maintenance after sleep loss and in cold environments t39. (Szentirmai & Kapás, 2019).

Causes of vitamin B3 deficiencies (Niacin, 2014):

  • inadequate oral intake
  • poor bioavailability from grain sources
  • issues with absorption of tryptophan
  • some metabolic disorders, and the long-term chemotherapy treatments

Top food sources of vitamin B3 based on serving size:

  • chicken
  • tuna
  • turkey
  • salmon
  • beef

Comprehensive food list:
Table 2. Some Food Sources of Niacin (Niacin, 2014)

Referenced Dietary Intakes

Tolerable Upper Intake Level (UL) for Niacin and niacinamide (mg/day)
Children (9-13 years): 20
Adolescents (14-18 years): 30
Adults (19 years and older): 35

The Food and Nutrition Board set the tolerable upper intake level (UL) for niacin (nicotinic acid and nicotinamide) at 35 mg/day in adults to avoid the adverse effect of flushing. (Niacin, 2014)

Supplementing vitamin B3 in insomnia

  • A small study showed 3 grams a day of niacin increased rapid eye movement (REM) sleep in women with and without insomnia. The women with insomnia experienced increased the amount of time asleep while in bed (sleep efficiency) after 2–3 weeks (Robinson et al., 1977).
  • Niacinamide activates benzodiazepine receptors which promotes healthy sleep (Head & Kelly, 2009).
  • Supplementing tryptophan and niacinamide together (500 –1000 mg of each) before bed, may be more effective at addressing insomnia than taking either of these nutrients alone (Gaby, 2011).

1. Vitamin B3 (niacin) Supplementation

  • Amounts of niacin/nicotinic acid used in practice and research range from 100–3000 mg/day in divided doses (Niacin, 2014).


  • People who may be more susceptible to the effects of excess niacin intake include those with: abnormal liver function or liver disease, diabetes, active peptic ulcer disease, gout, cardiac arrhythmias, inflammatory bowel disease, migraine headaches, or alcoholism (Niacin, 2014).
  • Extended-release niacin has been associated with increased risk of serious adverse events (Anderson et al. 2014).

2. Vitamin B3 (nicotinamide) Supplementation

  • Amounts of nicotinamide used in practice and research range from 300–3000 mg/day in divided doses (Niacin, 2014).
  • Dr. Abram Hoffer recommended 1500–6000 mg of niacinamide for all patients with psychiatric syndromes (Hoffer, 1995).
  • Most people need a minimum of  2000–4500 mg/day of niacinamide, and relief of symptoms can be seen within one month (Prousky, 2015).


  • Niacinamide supplementation doses of 1500-6000 mg have been used for extended amounts of time in children and adolescents without side effects or complications (Hoffer, 1971: Hoffer 1999).
  • Niacinamide does not generally cause flushing. The most common side effect of niacinamide supplementation is sedation (Werbach, 1997, p133-60).
  • At very high doses (≥10 g/day), nausea, vomiting, and signs of liver toxicity (elevated liver enzymes, jaundice) have been observed (Niacin, 2014).

Vitamin D

Vitamin D and sleep

The actions of vitamin D in the body are facilitated by vitamin D receptors. Vitamin D receptors are present in parts of the brain that have important roles in sleep regulation including (Abboud, 2022; Gao et al., 2018):

  • hypothalamus
  • prefrontal cortex
  • midbrain central gray
  • substantia nigra
  • raphe nuclei

Vitamin D receptors are also know to be located in areas of the brain known as pacemaker cells. These cells play an important role in the timing of sleep (Sharifan et al., 2020).

Vitamin D in regards to sleep:

  • has been shown in experimental studies to participate in the regulation of clock genes – genes that control physiological and behavioural rhythms  (Larsen et al., 2021)
  • is involved in the transmission of light signals that help regulate circadian rhythms (Lucock et al., 2015)
  • is vital for the production of melatonin (Romano et al., n.d.) by regulating tryptophan hydroxylase – the enzyme that converts tryptophan to 5-HTP. 5-HTP is converted to serotonin, then melatonin.
  • has roles in decreasing inflammatory molecules that inhibit sleep – including TNF-α, cytokines and prostaglandins (Abboud, 2022).

Vitamin D and sleep disruptors

  • Chronic pain is a known cause of sleep deprivation.
  • Vitamin D has been shown to decrease levels of inflammatory molecules associated with chronic pain and sleep apnea (Gao et al., 2018).
  • Deficiency of vitamin D is known to increase myopathic (muscle) pain which in turn, affects sleep quality Lee, Greenfield, & Campbell, 2009). (Sharifan et al., 2020).
  • Restless leg syndrome can negatively affect sleep. Vitamin D has roles in regulating two key factors involved in restless leg syndrom – dopamine and iron (Prono et al., 2022).

Vitamin D deficiency and sleep

A study of vitamin D and sleep in over 9000 people, showed vitamin D deficiency increased risk of (Abboud, 2022; Gao et al., 2018):

  • sleep disorders
  • sleeping difficulty
  • poor sleep quality
  • waking up during the night
  • short sleep duration

25(OH)D, a marker of vitamin D status, has been shown to be lower in people with sleep disorders (McCarty et al., 2012).

Risk of poor sleep was found to be significantly increased with a blood 25(OH)D level below 20 ng/mL (49.92 nmol/l) (Abboud, 2022).

An inverse correlation exists between serum 25(OH)D and sleep disorders – as 25(OH)D levels decrease, risk of sleep disorders increases (Gao et al., 2018).

Babies with low vitamin D levels at birth have been shown to have increased risk of persistent short sleep between 2 and 6 years of age (Yong et al., 2019).

Causes of vitamin D deficiency include:

  • limited sun exposure
  • strict vegan diet (most sources of vitamin D are animal-based)
  • darker skin (the pigment melanin reduces the vitamin D production by the skin)
  • digestive tract and kidney issues
  • obesity (vitamin D is sequestered by fat cells)

Measuring vitamin D

The best indicator of vitamin D status is serum 25(OH)D, also known as 25-hydroxyvitamin D. 25(OH)D reflects the amount of vitamin D in the body that is produced by the skin and obtained from food and supplements.

Vitamin D levels and health status
Institute of Medicine, Food and Nutrition Board. (2010)

Serum (ng/ml)  and Health status
<20  deficient
20–39  generally considered adequate
40–50  adequate
>50–60   proposed optimum health level
>200  potentially toxic

Top sources of vitamin D based on serving size (Office of Dietary Supplements – Vitamin D, 2020)

  • cod liver oil
  • trout
  • pink salmon
  • sardines
  • fortified cereal, milk, and orange juice
  • fortified almond, soy, and oat milks
  • egg yolk

Comprehensive food list

Table 3: Vitamin D Content of Selected Foods

Referenced Dietary Intakes

RDAs for vitamin D (IU/day)
Adolescents (14-18 years): 600 (M) 600 (F)
Adults (19-50 years): 600 (M) 600 (F)
Adults (51 years and older): 800 (M) 800 (F)

Tolerable Upper Intake: 4000 IU/day
(Office of dietary supplements, 2020)

Vitamin D supplementation

  • Amounts of vitamin D used in practice and research range from 400-14 000 IU/day. (Vitamin D, 2014)

Supplementing vitamin D in insomnia

  • In a study by Bahrami et al. (2021), supplementation of 50,000 IU of vitamin D once a week for 9 weeks was shown to reduce severity of insomnia and daytime sleepiness in adolescent girls.
  • An intervention study examining 28 U.S. veterans with low vitamin D status and chronic pain, using vitamin D supplementation of 1,200 IU a day, or 50,000 IU once a week for 3 months, resulted in improved sleep latency, duration, and decreased pain scores (Huang et al., 2013).
  • A randomized control trial of 20–50 year-olds, showed that supplementation of 50,000 IU of vitamin D every 2 weeks for 8 weeks improved sleep quality, duration, and decreased sleep latency (Majid et al., 2018).

SAFETY, SIDE EFFECTS (Vitamin D, 2014)

  • “Research suggests that vitamin D toxicity is very unlikely in healthy people at intake levels lower than 10,000 IU/day”.
  • Vitamin D can increase risk of hypercalcemia with calcium-related medical conditions – including primary hyperparathyroidism, sarcoidosis, tuberculosis, and lymphoma.

Some drugs that affect vitamin D absorption or metabolism include (Vitamin D, 2014):

  • cholestyramine
  • colestipol
  • orlistat
  • mineral oil
  • phenytoin
  • fosphenytoin
  • phenobarbital
  • carbamazepine
  • rifampin
  • cimetidine
  • ketoconazole
  • glucocorticoids
  • HIV treatment drugs


Magnesium and sleep

Magnesium has been shown to regulate sleep by (Abbasi et al., 2012):

  • increasing melatonin levels
  • decreasing cortisol levels
  • blocking NMDA receptors (N‑methyl‑D‑aspartic acid)
  • activating GABA receptors

Insomnia is one of the symptoms of magnesium deficiency (Freyre & Flichman, 1970)

Causes of magnesium deficiency include:

  • loss of soil magnesium due to farming practices
  • following the standard American diet pattern, as it is high in processed and nutrient-deficient foods
  • decreased magnesium levels in foods, especially cereal grains (Guo, Nazim, Liang, & Yang, 2016)
  • low dietary protein (needed for magnesium absorption)
  • gastrointestinal disorders (e.g. Crohn’s disease, malabsorption syndromes, and prolonged diarrhea)
  • stress, which causes magnesium to be lost through urine (Deans, 2011)
  • chronically elevated cortisol, which depletes magnesium (Cuciureanu, & Vink, 2011).
  • high doses of supplemental zinc (competes for absorption)
  • alcoholism
  • certain diuretic medications

Elderly adults tend to have lower dietary intake, absorption, and increased loss of magnesium

Top food sources of magnesium by serving size

  • Brazil nuts
  • oat bran
  • brown rice (whole grain)
  • mackerel

Comprehensive list

Table 2. Some Food Sources of Magnesium
(Magnesium, 2014)

Referenced Dietary Intakes

RDAs for magnesium (mg/day)
Adolescents (14-18 years): 410 (M) 360 (F)
Adults (19-30 years): 400 (M) 310 (F)
Adults (31 years and older): 420 (M) 320 (F)

Supplementing magnesium

  • Amounts of magnesium used in practice and research range from 100–750 mg a day in divided doses (elemental magnesium dose).
  • Correction of magnesium deficiency with magnesium supplementation has resulted in significant improvement in psychiatric symptoms (Kanofsky & Sandyk, 1991).

Supplementing magnesium in insomnia

  • A study by Hornyak et al., (1998), showed oral supplementation of 300 mg of magnesium in the evening for 4 to 6 weeks improved sleep in people who had insomnia with restless leg syndrome or periodic limb movements.
  • In a randomized control trial, daily supplementation of 500 mg of magnesium for 8 weeks by 46 elderly patients showed significantly (Abbasi et al., 2012):
    • increased sleep time, sleep efficiency, and melatonin levels
    • decreased cortisol levels and delay in sleep onset


  • Side effects of magnesium supplementation are rare, but can include a laxative effect, dizziness or faintness, sluggishness, cognitive impairment, and depression.
  • An effective strategy for dosing magnesium is to gradually increase the amount to bowel tolerance, then reduce slightly.
  • Magnesium is best taken in divided doses throughout the day. Caution is required for high doses of magnesium with existing kidney disease.

Essential fatty acids

Fatty acids and sleep

  • Fatty acids influence neuronal membrane structure and the activity of complex lipids, prostaglandins, neurotransmitters, amino acids, interleukins – molecules involved in sleep initiation and maintenance (Yehuda et al., 1998).
  • Fatty acids can be broken down by the liver into ketone bodies which in turn, promote production of brain-derived neurotrophic factor (BDNF) . BDNF has roles in regulating the sleep-wake cycle (Muheim et al., 2022).
  • Fatty acid metabolites including prostaglandin D2 and anandamide have roles in sleep/wake cycle regulation (Murphy et al., 2022).

Long-chain polyunsaturated fatty acids (LC-PUFAs):

  • have roles in promoting sleep quality, healthy manifestation of sleep architecture, and cardiovascular function during sleep (Christian et al., 2016)
  • promote sleep efficiency and REM sleep (Papandreou, 2013)
  • promote healthy sleep in infants with sufficient maternal intake during pregnancy (Dai & Liu, 2021)
  • Omega 3 fatty acids have been shown to (Papandreou, 2013):
    • promote sleep efficiency
    • slow wave and REM sleep
    • increase serotonin production, which supports melatonin production

Omega 3 fatty acids have anti-inflammatory actions and, as a result, can lower risk of sleep disorders (Luo et al., 2021)

The omega 3 fatty acid –DHA is known to:

  • increase levels of serotonin in the hippocampus, which is important for melatonin production, sleep initiation and maintenance (Luo et al., 2021)
  • improve sleep quality and increase sleep duration (Christian et al., 2016)
  • decrease risk of severe sleep apnea in obese adults with sleep apnea  (Murphy et al., 2022)
  • support maturation of infant sleep patterns (Patan et al., 2021)

The omega 3 fatty acid – EPA, may protect from too little and too much sleep (Patan et al., 2021).


  • EPA and DHA are both involved in serotonin regulation and the serotonergic system in the brain – which has vital roles in sleep initiation and maintenance (Murphy et al., 2022).

Omega 6 fatty acids and sleep

  • The omega 6 fatty acid arachidonic acid (AA) is a precursor in the production of prostaglandin D2 – a strong promoter of sleep (Murphy et al., 2022).
  • Increased consumption of omega 6 fatty acids has been shown to elevate risk of sleep disorders in the elderly (Luo et al., 2021).
  • Too little or too much omega 6 fatty acid consumption has been shown to increase risk sleep problems (Luo et al., 2021).

Omega 6 to 3 ratio and sleep

  • The ratio of omega 6 to omega 3 fatty acids in the body affects sleep. The higher the ratio, the greater the risk of sleep issues (Luo et al., 2021).
  • An increased ratio of omega 6 to omega 3 fatty acids has been observed to increase risk of sleep issues in people under 60 years old (Luo et al., 2021).
  • A low DHA:AA ratio promotes inflammation, which in turn degrades sleep quality. Poor sleep is known to increase inflammation (Christian et al., 2016).
  • A low DHA:AA ratio has been shown to increase sleep issues in children (Patan et al., 2021).
  • Omega 6 and omega 3 fatty acids have opposing effects in regards to sleep. Both fatty acids are needed for production of the sleep-regulating molecules PGD2 and IL-1 (Yehuda et al., 1998).

Reasons for EFA deficiencies:

  • inadequate dietary intake
  • poor absorption
  • deficiencies of nutrients required for EFA metabolism
  • issues with metabolism that cause decreased incorporation of, or increased removal of, fatty acids from cell membranes

Top EPA and DHA (omega 3) food sources by serving size

  • herring, pacific
  • salmon, chinook
  • sardines, pacific
  • salmon, atlantic
  • oysters, pacific

Comprehensive food list:
Table 4. Food Sources of EPA (20:5n-3) and DHA (22:6n-3) (Office of Dietary Supplements, n.d.)

Commonly suggested amounts for dietary fatty acid consumption:

  • cold water fish – 2 to 3 times a week, or
  • flaxseed oil – 2 to 6 tbsp daily, or
  • ground flax seed –  2 tbsp daily

Flaxseed oil may have negative effects in about 3% people, including: hypomania, mania, behaviour changes. (Prousky, 2015).

Referenced Dietary Intakes

Adequate Intakes for Alpha linolenic acid (Omega 3) (g/day) (Institute of Medicine, 2002)
Adolescents (14–18 years): 1.6 (M) 1.1 (F)
Adults (≥ 19 years): 1.6 (M) 1.1 (F)

Recommendations for long-chain omega-3 fatty acids eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) (mg/day) (European Food Safety Authority, 2009)
Adults: 250 (M+F).

Supplementing omega 3 fatty acids

  • Amounts of omega 3 fatty acids used in practice and research range from 1–4 g a day of combined EPA and DHA, in divided doses.
  • Fish oils, which are sources of EPA and DHA, are considered preferable for addressing schizophrenia, have been shown to have a wide range of neurobehavioural effects (Logan, 2003).

Supplementing fatty acids in insomnia

  • Omega 3 FA consumption through diet and supplementation has been shown in observational studies of children and adults to increase (Dai & Liu, 2021):
    • sleep onset
    • sleep duration
    • sleep quality
  • Forty-three children, in a study by Christian et al., (2016), had fewer waking episodes and longer total sleep duration after 16 weeks of DHA supplementation versus controls.
  • Some studies have shown that omega 3 FA supplementation may be more effective in children with severe, rather than moderate sleep problems (Dai & Liu, 2021).
  • In a study of omega 3 FAs supplemented adjunctively with standard sleep medication, in 50 people with major depressive disorders, showed improved sleep, and decreased symptoms of depression and anxiety (Jahangard et al., 2018).
  • A study by (Patan et al., 2021) which supplemented 900 mg DHA and 270 mg EPA a day for 26 weeks in people with low consumption of oily fish, resulted in significant improvements in sleep efficiency and sleep latency.


Common side effects of high dose EPA and DHA supplementation include heartburn, nausea, gastrointestinal discomfort, diarrhea, headache, and odoriferous sweat.

The European Food Safety Authority considers long-term consumption of EPA and DHA supplements at combined doses of up to about 5 g/day to be safe.

The FDA recommends not exceeding 3 g/day EPA and DHA combined, with up to 2 g/day from dietary supplements (Office of Dietary Supplements, n.d.).


  • Use caution when supplementing omega 3 fatty acids while taking blood-thinning medications, or blood-sugar issues (Essential fatty acids, 2014).


The main action of tryptophan in the context of sleep is as a precursor molecule for serotonin and melatonin production.

Food sources of tryptophan

Common sources of tryptophan (Richard et al. 2009)

  • turkey
  • chicken
  • tuna
  • oats
  • peanuts

Referenced Dietary Intakes

The recommended daily allowance for tryptophan for adults is estimated to be between 250 mg/day and 425 mg/day (Richard et al. 2009).

With intestinal microflora imbalances, tryptophan available for brain serotonin and melatonin production can be reduced by bacterial consumption (O’Mahony et al., 2015).

1. Supplementing tryptophan

  • Tryptophan is best taken on an empty stomach, and with a small amount of a carbohydrate food (Gaby, 2011).
  • Beneficial effects of tryptophan supplementation may take up to two weeks to be seen (Hartmann et al., 1983).
  • Amounts of tryptophan used in practice and research range from 50–2,000 mg day in divided doses (Prousky, 2015).
  • Carbohydrate consumption increases the amount of TRP that crosses the blood-brain-barrier (BBB) (Richard et al., 2009). Therefore tryptophan is best taken away from meals, but with a small amount of carbohydrate to facilitate absorption. 5-HTP transport across the BBB is not affected by dietary protein consumptions and can be taken with meals (Werbach, 1997).
  • “L-Tryptophan has been reported to relieve depression in patients with low tryptophan levels due with Crohn’s disease (when given at a dose of 0.6–1.2 g/day),32 and in hospitalized alcoholics (when given at a dose of 3 g/day)”(Asheychik et al., 1989).
  • A dosage of 6 g/day or less  is recommended when L-tryptophan is used by itself,  and 4 g/day or less is recommended when given in combination with 2 g/day of niacinamide. These should be given in two separate doses per day to minimize fluctuation of tryptophan concentration (Chouinard et al., 1977) (Chouinard et al., n.d.).
  • The dose required can be reduced by administering L-tryptophan and niacinamide on an empty stomach along with carbohydrates. (Gaby, 2011).
  • For tryptophan-deficient individuals, L-tryptophan supplementation can provide a larger range of benefits than supplementation with 5-HTP.

Supplementing tryptophan in insomnia

  • Clinical trials have shown that supplementing with 1–2 grams of tryptophan, 20–30 minutes before bed, improved insomnia symptoms  – especially with people who have delayed sleep onset and people who awaken 3–6 times during the night (Gaby, 2011).
  • Forty patients with chronic insomnia who did not respond to psychotherapy or sedative-hypnotic medications, were given 2 g day of tryptophan in a study by Henahan (1984).
  • After an average of 4 months, 50% of the patients were sleeping normally, while an additional 30% were much improved.
  • At the 6-month follow-up and again after 2 years, 18 of the 20 patients who had improved were still sleeping well, even though they were no longer taking L-tryptophan. No significant side effects were seen.

Adjunctive use of tryptophan in insomnia

The initial treatment phase for depression with selective serotonin reuptake inhibitors (SSRIs) is often accompanied by severe insomnia. In a study by Levitan et al., 2000):

  • 30 medicated patients with major depressive disorder and insomnia were treated for eight weeks with 20 mg of fluoxetine (SSRI) and either 2–4 g per day or placebo
  • after four weeks of treatment, there was a reduction slow-wave sleep in those taking fluoxetine/placebo, but not in those taking tryptophan – revealing a potential protective effect of tryptophan
  • no cases of serotonin syndrome occurred from concurrent use of fluoxetine and tryptophan in the study


  • Side effects of L-tryptophan supplementation can include heartburn, stomach pain, belching and gas, nausea, vomiting, diarrhea, and loss of appetite, headache, lightheadedness, drowsiness, dry mouth, visual blurring, muscle weakness, and sexual problems in some people (L-Tryptophan: Uses, Side Effects, n.d.).
  • High doses of tryptophan can promote bronchial asthma aggravation and nausea.
  • Tryptophan should not be used during pregnancy, with lupus, or with adrenal insufficiency (Prousky, 2015).
  •  Co-administering L-tryptophan and antidepressants that increase serotonergic activity (SSRIs, amitriptyline, monoamine oxidase inhibitors) may increase the efficacy and toxicity of the drugs (Gaby).


  • Supplementing tryptophan or 5-HTP while on SSRI or MAOI medications is not generally recommended as it may promote an excessive buildup of serotonin  (Birdsall, 1998).
  • Do not supplement tryptophan if taking morphine (Prousky, 2015).

2. Supplementing 5-HTP

Referenced Dietary Intakes
RDAs/Upper intakes for 5-HTP
None established.

  • Amounts of 5-HTP used in practice and research range from 100–900 mg a day in divided doses (Prousky, 2015; Rakel, 2012).
  • 5-HTP can be taken with meals, as opposed to tryptophan, which needs to be taken away from meals.


  • Side effects of 5-HTP supplementation are typically minimal and can include heart burn, flatulence, rumbling sensations, feeling of fullness, mild, nausea, vomiting, and hypomania (Werbach 1999: Murray & Pizzorno, 1998, p. 391-93).
  • Other possible side effects include, stomach pain, diarrhea, drowsiness, sexual problems, and muscle problems (5-Htp: Uses, Side Effects, n.d.).
  • High-dose supplementation – from 6-10 grams daily – have been linked to severe stomach problems and muscle spasms (5-HTP: Uses, Side Effects, n.d.).


  • Supplementing tryptophan or 5-HTP while on SSRI or MAOI medications is not generally recommended as it may cause an excessive buildup of serotonin (Birdsall, 1998).
  • Avoid taking tryptophan or 5-HTP (or limit to very low doses) if receiving electroconvulsive therapy (Gaby, 2011).

GABA (gamma-aminobutyric acid)

GABA (Gamma-Aminobutyric Acid) is:

  • a non-protein amino acid that acts as a neurotransmitter
  • the main inhibitory neurotransmitter in the brain (Yamatsu et al., 2016)
  • increases parasympathetic nerve activity, promoting relaxation and decrease in core body temperature (Yamatsu et al., 2015)

GABA-producing neurons regulate: brain circuits to influence stress responses as well as REM and non-REM sleep (Hepsomali et al., 2020).

GABA and sleep

GABA promotes sleep by inhibiting neurotransmitter activity related to wakefulness and by suppressing of arousal systems (Morgan et al., 2012).

GABA and insomnia

  • Low levels of GABA or GABA functioning, are known to be associated with insomnia and other sleep problems (Gottesmann, 2002). (Hepsomali et al., 2020).
  • GABA levels have been shown to be decreased by 30% in people with insomnia (Morgan et al., 2012).

There are no food sources of GABA.

Referenced Dietary Intakes

RDAs/Upper intakes GABA
Not established.

Supplementing GABA

  • Amounts of GABA used in practice and research range from 25–3000 mg/day in divided doses.
  • It has been proposed that GABA taken orally does not cross the blood-brain barrier in amounts sufficient for an effect. However, many people do see results from oral supplementation.
  • GABA is best taken away from meals.
  • 125 mg of GABA taken sublingually has been shown to promote mental and physical relaxation.
  • One or two 250–500 mg doses of GABA can be taken at bedtime or during times of stress.
  • Supplementing 2 to 3 g/day of GABA has been shown to help with sleep, promote relaxation, and control symptoms of anxiety (Braverman, 2010).

Supplementing GABA in insomnia

  • GABA supplementation has been shown to (Yamatsu et al., 2015):
  • improve sleep
  • decrease night-time urination frequency
  • improve sleep in elderly people

In a randomized, single-blind, placebo-controlled crossover study by Yamatsu et al. (2016), patients were given an oral dose of 100 mg of GABA. After one week patients experienced:

  • decreased delay in sleep onset
  • increased non-REM sleep


Commonly reported side effects include (Gamma Aminobutyric Acid, n.d.):

  • upset stomach
  • headache
  • sleepiness
  • muscle weakness


  • Supplementing GABA while taking blood pressure medications may cause blood pressure to drop too low.
  • Consult medical advice before supplementing GABA with antidepressant medications (3 Amazing Benefits of GABA, n.d.).


  • Melatonin is a hormone that is produced by the brain in response to darkness.
  • It helps regulate and strengthen various circadian rhythms in the body (Atul Khullar, 2012).
  • Creation of melatonin in the body involves the process of converting the amino acid tryptophan into serotonin. Serotonin is then converted into melatonin by the pineal gland.
  • Normally, melatonin production in the body starts around 2 hours before sleep onset, and peaks about 5 hours later (Bartlett et al., 2013).
  • Melatonin from food and supplementation bind the same receptors and has the same actions as melatonin made by the body (Xie et al., 2017).

Melatonin and sleep

Roles of melatonin that are related to sleep include (Xie et al., 2017):

  • circadian rhythm regulation
  • sleep regulation, including sleep onset and duration
  • antioxidant protection
  • inhibiting inflammatory cytokine expression
  • increasing levels of BDNF

Melatonin has been shown to improve sleep latency and sleep efficiency in shift workers who had difficulty falling asleep (Sadeghniiat-Haghighi et al., 2016).

Causes of melatonin deficiency

  • light exposure at night
  • elevated cortisol (stress)
  • low amounts of dietary tryptophan
  • nutrient deficiencies that result in decreased conversion of tryptophan to serotonin, or serotonin to melatonin
  • age, as melatonin levels decrease with age (Xie et al., 2017)

Supplementing melatonin

“Melatonin supplementation has been shown to be a safe and effective method to improve sleep onset latency, duration, and quality in children, adolescents, older adults and postmenopausal women”
(Xie et al., 2017).

Melatonin supplementation has been shown to be effective treatment for:

  • age-related insomnia and delayed sleep phase syndrome (Garfinkel et al., 1999; Haimov et al., 1995; Kayumov et al., 2001)
  • pediatric sleep disorders and for patients with major depressive disorders or chronic schizophrenia (Dolberg et al., 1998; Shamir et al., 2000)
  • sleep onset latency, increasing total sleep time, and overall sleep quality (Ferracioli-Oda et al., 2013)

Effects of melatonin supplementation do not appear to diminish with ongoing use (Ferracioli-Oda et al., 2013).

In study of melatonin supplementation in children with chronic sleep initiation and sleep maintenance problems (Ivanenko et al., 2003):

  • twenty-nine children (91%) showed improvement or complete resolution of their sleep problems.
  • the average time to sleep onset decreased from 90 minutes to 25 minutes
  • the average number of nocturnal awakenings per week decreased from 18.7 to 1.2 (93.5% reduction
  • The average effective daily dose was:
  • 1.4 mg for children aged 2–6 years
  • 2.0 mg for those aged 7–11 years
  • 2.8 mg for children aged 12–18 years

A study of melatonin-deficient elderly insomniacs (Haimov et al., 1995) found:

  • fast-release melatonin to be effective for sleep initiation
  • sustained-release melatonin to be effective for sleep maintenance
  • sleep quality deteriorated after cessation of treatment

In a study of melatonin used adjunctively with medication (Garfinkel et al., 1999);

  • Thirty-four patients (average age, 68 years) who were receiving benzodiazepine medication for insomnia, were given either 2 mg of controlled-release melatonin or placebo, 2 hours before bedtime, for 6 weeks (Garfinkel et al., 1999).
  • They were encouraged to reduce their benzodiazepine dosage by 50% during week 2, 75% during weeks 3 and 4, and to discontinue the drug completely during weeks 5 and 6.
  • By the end of the first 6 weeks, significantly more patients had discontinued benzodiazepines in the melatonin group than in the placebo group.
  • Sleep quality was also significantly better in the melatonin group than in the placebo group.

Melatonin supplementation:

  • is well-tolerated (Xie et al., 2017)
  • has no short or long-term adverse effects (Xie et al., 2017)
  • does not promote tolerance with ongoing use (Ferracioli-Oda et al., 2013)
  • is not associated with habituation (Ferracioli-Oda et al., 2013)

In a dose-escalation study to assess melatonin safety and efficacy, healthy volunteers were given melatonin doses of 20, 30, 50, or 100 mg. The doses were well tolerated, and no safety concerns were seen (Galley et al., 2014).

3 Amazing Benefits of GABA. (n.d.). Psychology Today. Retrieved October 29, 2020, from 

Abbasi, B., Kimiagar, M., Sadeghniiat, K., Shirazi, M. M., Hedayati, M., & Rashidkhani, B. (2012). The effect of magnesium supplementation on primary insomnia in elderly: A double-blind placebo-controlled clinical trial. Journal of Research in Medical Sciences : The Official Journal of Isfahan University of Medical Sciences, 17(12), 1161–1169. 

Anderson, T. J., Boden, W. E., Desvigne-Nickens, P., Fleg, J. L., Kashyap, M. L., McBride, R., & Probstfield, J. L. (2014). Safety Profile of Extended-Release Niacin in the AIM-HIGH Trial. New England Journal of Medicine, 371(3), 288–290. . 

Asheychik, R., Jackson, T., Baker, H., Ferraro, R., Ashton, T., & Kilgore, J. (1989). The efficacy of L-tryptophan in the reduction of sleep disturbance and depressive state in alcoholic patients. Journal of Studies on Alcohol, 50(6), 525–532. 

Atul Khullar, M. D. (2012). The Role of Melatonin in the Circadian Rhythm Sleep-Wake Cycle. 29. 

Bahrami, A., Rezaeitalab, F., Farahmand, S. K., Mazloum Khorasani, Z., Arabi, S. M., Bahrami-Taghanaki, H., Ferns, G. A., & Ghayour-Mobarhan, M. (2021). High-dose Vitamin D Supplementation and Improvement in Cognitive Abilities, Insomnia, and Daytime Sleepiness in Adolescent Girls. Basic and Clinical Neuroscience, 12(3), 339–348. 

Bartlett, D. J., Biggs, S. N., & Armstrong, S. M. (2013). Circadian rhythm disorders among adolescents: Assessment and treatment options. The Medical Journal of Australia, 199(8), S16-20. 

Birdsall, T. C. (1998). 5-Hydroxytryptophan: A clinically-effective serotonin precursor. Alternative Medicine Review: A Journal of Clinical Therapeutic, 3(4), 271–280. 

Braverman, E. R. (2012). The Healing Nutrients Within: Facts, Findings, and New Research on Amino Acids (3rd ed. Edition). Basic Health Publications, Inc. 

Chouinard, G., Young, S. N., Annable, L., & Sourkes, T. L. (1977). Tryptophan-nicotinamide combination in depression. Lancet (London, England), 1(8005), 249. 

Chouinard, G., Young, S. N., Annable, L., & Sourkes, T. L. (n.d.). Tryptophan-nicotinamide, imipramine and their combination in depression. Acta Psychiatrica Scandinavica, 59(4), 395–414. Retrieved August 26, 2021, from – 

Christian, L. M., Blair, L. M., Porter, K., Lower, M., Cole, R. M., & Belury, M. A. (2016). Polyunsaturated Fatty Acid (PUFA) Status in Pregnant Women: Associations with Sleep Quality, Inflammation, and Length of Gestation. PLoS One, 11(2), e0148752.  

Cuciureanu, M. D., & Vink, R. (2011). Magnesium and stress. In R. Vink & M. Nechifor (Eds.), Magnesium in the Central Nervous System. University of Adelaide Press. 

Dai, Y., & Liu, J. (2021). Omega-3 long-chain polyunsaturated fatty acid and sleep: A systematic review and meta-analysis of randomized controlled trials and longitudinal studies. Nutrition Reviews, 79(8), 847–868. 

Deans, E. (2011, June 12). Magnesium and the Brain: The Original Chill Pill. Psychology Today. 

Dolberg, O. T., Hirschmann, S., & Grunhaus, L. (1998). Melatonin for the treatment of sleep disturbances in major depressive disorder. The American Journal of Psychiatry, 155(8), 1119–1121. 

Essential Fatty Acids. (2014, April 28). Linus Pauling Institute. 

European Food Safety Authority. Labelling reference intake values for n-3 and n-6 polyunsaturated fatty acids. (2009, July 10). 

Ferracioli-Oda, E., Qawasmi, A., & Bloch, M. H. (2013). Meta-analysis: Melatonin for the treatment of primary sleep disorders. PloS One, 8(5), e63773. 

Freyre, A. V., & Flichman, J. C. (1970). Spasmophilia caused by magnesium deficit. Psychosomatics, 11(5), 500–501. 

Gaby, A. R. (2011). Nutritional Medicine (VitalBook file). 

Galley, H. F., Lowes, D. A., Allen, L., Cameron, G., Aucott, L. S., & Webster, N. R. (2014). Melatonin as a potential therapy for sepsis: A phase I dose escalation study and an ex vivo whole blood model under conditions of sepsis. Journal of Pineal Research, 56(4), 427–438. 

Gamma Aminobutyric Acid: Uses and Side Effects of GABA Supplement. (n.d.). Retrieved October 29, 2020, from 

Gao, Q., Kou, T., Zhuang, B., Ren, Y., Dong, X., & Wang, Q. (2018). The Association between Vitamin D Deficiency and Sleep Disorders: A Systematic Review and Meta-Analysis. Nutrients, 10(10), Article 10. 

Garfinkel, D., Zisapel, N., Wainstein, J., & Laudon, M. (1999). Facilitation of benzodiazepine discontinuation by melatonin: A new clinical approach. Archives of Internal Medicine, 159(20), 2456–2460. 

Gottesmann, C. (2002). GABA mechanisms and sleep. Neuroscience, 111(2), 231–239. 

Guo, W., Hussain, N., Liang, Z., & Yang, D. (2016). Magnesium deficiency in plants: An urgent realistic problem. 4, 83–91. 

Haimov, I., Lavie, P., Laudon, M., Herer, P., Vigder, C., & Zisapel, N. (1995). Melatonin replacement therapy of elderly insomniacs. Sleep, 18(7), 598–603. 

Hartmann, E., Lindsley, J. G., & Spinweber, C. (1983). Chronic insomnia: Effects of tryptophan, flurazepam, secobarbital, and placebo. Psychopharmacology, 80(2), 138–142. 

Head, K., & Kelly, G. (2009). Nutrients and Botanicals for Treatment of Stress: Adrenal Fatigue, Neurotransmitter Imbalance, Anxiety, and Restless Sleep. 14(2). 

Henahan, J. (1984). Chronic insomnia yields to serotonin precursor. Medical Tribune, August 15(2). 

Hepsomali, P., Groeger, J. A., Nishihira, J., & Scholey, A. (2020). Effects of Oral Gamma-Aminobutyric Acid (GABA) Administration on Stress and Sleep in Humans: A Systematic Review. Frontiers in Neuroscience, 14. 

Hoffer, A. (1971). Vitamin B3 dependent child. Schizophrenia 3:107-13. 

Hoffer, A.(1995). Vitamin B-3: Niacin and its amide. Townsend Letter for Doctors &Patients 147:30-39. 

Hoffer. A. (1999). Dr. Hoffer’s ABC of Natural Nutrition for Children. CCNM Press. 

Hornyak, M., Voderholzer, U., Hohagen, F., Berger, M., & Riemann, D. (1998). Magnesium therapy for periodic leg movements-related insomnia and restless legs syndrome: An open pilot study. Sleep, 21(5), 501–505. 

Huang, W., Shah, S., Long, Q., Crankshaw, A. K., & Tangpricha, V. (2013). Improvement of Pain, Sleep, and Quality of Life in Chronic Pain Patients With Vitamin D Supplementation. The Clinical Journal of Pain, 29(4), 341. 

Institute of Medicine, Food and Nutrition Board. (2010). Dietary reference intakes for calcium and vitamin D. Washington, DC: National Academy Press. 

Institute of Medicine. (2002). Dietary Reference Intakes for Energy, Carbohydrate, Fiber, Fat, Fatty Acids, Cholesterol, Protein, and Amino Acids. 

Ivanenko, A., Crabtree, V. M., Tauman, R., & Gozal, D. (2003). Melatonin in children and adolescents with insomnia: A retrospective study. Clinical Pediatrics, 42(1), 51–58. 

Jahangard, L., Sadeghi, A., Ahmadpanah, M., Holsboer-Trachsler, E., Sadeghi Bahmani, D., Haghighi, M., & Brand, S. (2018). Influence of adjuvant omega-3-polyunsaturated fatty acids on depression, sleep, and emotion regulation among outpatients with major depressive disorders—Results from a double-blind, randomized and placebo-controlled clinical trial. Journal of Psychiatric Research, 107(Complete), 48–56.  

Kanofsky, J. D., & Sandyk, R. (1991). Magnesium deficiency in chronic schizophrenia. The International Journal of Neuroscience, 61(1–2), 87–90.  

Kayumov, L., Brown, G., Jindal, R., Buttoo, K., & Shapiro, C. M. (2001). A randomized, double-blind, placebo-controlled crossover study of the effect of exogenous melatonin on delayed sleep phase syndrome. Psychosomatic Medicine, 63(1), 40–48. 

Larsen, A. U., Hopstock, L. A., Jorde, R., & Grimnes, G. (2021). No improvement of sleep from vitamin D supplementation: Insights from a randomized controlled trial. Sleep Medicine: X, 3, 100040. 

Lee, P., Greenfield, J. R., & Campbell, L. V. (2009). Vitamin D insufficiency—A novel mechanism of statin-induced myalgia? Clinical Endocrinology, 71(1), 154–155. 

Levitan, R. D., Shen, J. H., Jindal, R., Driver, H. S., Kennedy, S. H., & Shapiro, C. M. (2000). Preliminary randomized double-blind placebo-controlled trial of tryptophan combined with fluoxetine to treat major depressive disorder: Antidepressant and hypnotic effects. Journal of Psychiatry & Neuroscience: JPN, 25(4), 337–346. 

Logan, A. C. (2003). Neurobehavioral aspects of omega-3 fatty acids: Possible mechanisms and therapeutic value in major depression. Alternative Medicine Review: A Journal of Clinical Therapeutic, 8(4), 410–425. 

L-Tryptophan: Uses, Side Effects, Interactions, Dosage, and Warning. (n.d.). Retrieved October 29, 2020, from 

Lucock, M., Jones, P., Martin, C., Beckett, E., Yates, Z., Furst, J., & Veysey, M. (2015). Vitamin D: Beyond Metabolism. Journal of Evidence-Based Complementary & Alternative Medicine, 20(4), 310–322. 

Luo, J., Ge, H., Sun, J., Hao, K., Yao, W., & Zhang, D. (2021). Associations of Dietary ω-3, ω-6 Fatty Acids Consumption with Sleep Disorders and Sleep Duration among Adults. Nutrients, 13(5), 1475. 

Magnesium. (2014, April 23). Linus Pauling Institute.  

Majid, M. S., Ahmad, H. S., Bizhan, H., Hosein, H. Z. M., & Mohammad, A. (2018). The effect of vitamin D supplement on the score and quality of sleep in 20-50 year-old people with sleep disorders compared with control group. Nutritional Neuroscience, 21(7), 511–519. 

McCarty, D. E., Reddy, A., Keigley, Q., Kim, P. Y., & Marino, A. A. (2012). Vitamin D, Race, and Excessive Daytime Sleepiness. Journal of Clinical Sleep Medicine : JCSM : Official Publication of the American Academy of Sleep Medicine, 8(6), 693–697. 

Morgan, P. T., Pace-Schott, E. F., Mason, G. F., Forselius, E., Fasula, M., Valentine, G. W., & Sanacora, G. (2012). Cortical GABA Levels in Primary Insomnia. Sleep, 35(6), 807–814. 

Morrow, J. D., Parsons, W. G., & Roberts, L. J. (1989). Release of markedly increased quantities of prostaglandin D2 in vivo in humans following the administration of nicotinic acid. Prostaglandins, 38(2), 263–274. 

Muheim, C. M., Singletary, K. G., & Frank, M. G. (2022). A chemical-genetic investigation of BDNF-NtrkB signaling in mammalian sleep. Sleep, 45(2), zsab237. 

Murphy, R. A., Tintle, N., Harris, W. S., Darvishian, M., Marklund, M., Virtanen, J. K., Hantunen, S., de Mello, V. D., Tuomilehto, J., Lindström, J., Bolt, M. A., Brouwer, I. A., Wood, A. C., Senn, M., Redline, S., Tsai, M. Y., Gudnason, V., Eiriksdottir, G., Lindberg, E., … Mozaffarian, D. (2022). PUFA ω-3 and ω-6 biomarkers and sleep: A pooled analysis of cohort studies on behalf of the Fatty Acids and Outcomes Research Consortium (FORCE). The American Journal of Clinical Nutrition, 115(3), 864–876. 

Murray, M., & Pizzorno J. (1998). Encyclopedia of Natural Medicine. Revised 2nd ed. Rocklin, CA: Prima Publishing.  

Niacin. (2014, April 22). Linus Pauling Institute.   

O’Mahony, S. M., Clarke, G., Borre, Y. E., Dinan, T. G., & Cryan, J. F. (2015). Serotonin, tryptophan metabolism and the brain-gut-microbiome axis. Behavioural Brain Research, 277, 32–48. 

Office of Dietary Supplements—Omega-3 Fatty Acids. (n.d.). Retrieved October 29, 2020, from – 

Office of Dietary Supplements—Vitamin D. (2020). 

Papandreou, C. (2013). Independent associations between fatty acids and sleep quality among obese patients with obstructive sleep apnoea syndrome. Journal of Sleep Research, 22(5), 569–572. 

Patan, M. J., Kennedy, D. O., Husberg, C., Hustvedt, S. O., Calder, P. C., Middleton, B., Khan, J., Forster, J., & Jackson, P. A. (2021). Differential Effects of DHA- and EPA-Rich Oils on Sleep in Healthy Young Adults: A Randomized Controlled Trial. Nutrients, 13(1), 248. 

Prono, F., Bernardi, K., Ferri, R., & Bruni, O. (2022). The Role of Vitamin D in Sleep Disorders of Children and Adolescents: A Systematic Review. International Journal of Molecular Sciences, 23(3), Article 3. 

Prousky, J. (2015). Anxiety: Orthomolecular diagnosis and treatment (Kindle). CCNM Press. 

Rakel, D., (2012). Integrative Medicine (3rd ed.). Elsiver.  

Richard, D. M., Dawes, M. A., Mathias, C. W., Acheson, A., Hill-Kapturczak, N., & Dougherty, D. M. (2009). L-Tryptophan: Basic Metabolic Functions, Behavioral Research and Therapeutic Indications. International Journal of Tryptophan Research : IJTR, 2, 45–60. 

Robinson, C. R., Pegram, G. V., Hyde, P. R., Beaton, J. M., & Smythies, J. R. (1977). The effects of nicotinamide upon sleep in humans. Biological Psychiatry, 12(1), 139–143.  

Romano, F., Muscogiuri, G., Di Benedetto, E., Zhukouskaya, V. V., Barrea, L., Savastano, S., Colao, A., & Di Somma, C. (2020). Vitamin D and Sleep Regulation: Is there a Role for Vitamin D? Current Pharmaceutical Design, 26(21), 2492–2496. 

Sadeghniiat-Haghighi, K., Bahrami, H., Aminian, O., Meysami, A., & Khajeh-Mehrizi, A. (2016). Melatonin therapy in shift workers with difficulty falling asleep: A randomized, double-blind, placebo-controlled crossover field study. Work (Reading, Mass.), 55(1), 225–230. 

Shamir, E., Laudon, M., Barak, Y., Anis, Y., Rotenberg, V., Elizur, A., & Zisapel, N. (2000). Melatonin improves sleep quality of patients with chronic schizophrenia. The Journal of Clinical Psychiatry, 61(5), 373–377. 

Sharifan, P., Khoshakhlagh, M., Khorasanchi, Z., Darroudi, S., Rezaie, M., Safarian, M., Vatanparast, H., Afshari, A., Ferns, G., Ghazizadeh, H., & Ghayour Mobarhan, M. (2020). Efficacy of low-fat milk and yogurt fortified with encapsulated vitamin D3 on improvement in symptoms of insomnia and quality of life: Evidence from the SUVINA trial. Food Science & Nutrition, 8(8), 4484–4490. 

Szentirmai, É., & Kapás, L. (2019). Nicotinic acid promotes sleep through prostaglandin synthesis in mice. Scientific Reports, 9(1), 17084. 

Verster, J., Fernstrand, A., Bury, D., Roth, T., & Garssen, J. (2015). The association of sleep quality and insomnia with dietary intake of tryptophan and niacin. Sleep Medicine, 16(Supplement 1), S191–S191. 

Vitamin D Supplementation and Sleep: A Systematic Review and Meta-Analysis of Intervention Studies. Nutrients, 14(5), Article 5. 

Vitamin D. (2014, April 22). Linus Pauling Institute. 

Werbach, M. R. (1997). Adverse effects of nutritional supplements. Foundations of Nutritional Medicine. Tarzanna, CA: Third Line Press, Inc,. 

Xie, Z., Chen, F., Li, W. A., Geng, X., Li, C., Meng, X., Feng, Y., Liu, W., & Yu, F. (2017). A review of sleep disorders and melatonin. Neurological Research, 39(6), 559–565. 

Yamatsu, A., Yamashita, Y., Maru, I., Yang, J., Tatsuzaki, J., & Kim, M. (2015). The Improvement of Sleep by Oral Intake of GABA and Apocynum venetum Leaf Extract. Journal of Nutritional Science and Vitaminology, 61(2), 182–187. 

Yamatsu, A., Yamashita, Y., Pandharipande, T., Maru, I., & Kim, M. (2016). Effect of oral γ-aminobutyric acid (GABA) administration on sleep and its absorption in humans. Food Science and Biotechnology, 25(2), 547–551. 

Yehuda, S., Rabinovitz, S., & Mostofsk, D. I. (1998). Essential fatty acids and sleep: Mini-review and hypothesis. Medical Hypotheses, 50(2), 139–145. 

Yong, C. Y., Reynaud, E., Forhan, A., Dargent-Molina, P., Heude, B., Charles, M.-A., Plancoulaine, S., Annesi-Maesano, I., Bernard, J. Y., Botton, J., Charles, M. A., Dargent-Molina, P., de Lauzon-Guillain, B., Ducimetière, P., de Agostini, M., Foliguet, B., Forhan, A., Fritel, X., Germa, A., … Thiebaugeorges, O. (2019). Cord-blood vitamin D level and night sleep duration in preschoolers in the EDEN mother-child birth cohort. Sleep Medicine, 53, 70–74.