Orthomolecular Interventions

Vitamin A

Vitamin A and hypothyroidism 

Lack of vitamin A is linked to (Sworczak & Wiśniewski, 2011):

  • decreased uptake of iodine by the thyroid
  • restricted hormone production and release
  • enlargement of the thyroid gland 
  • higher levels of TSH secretion
  • vitamin A deficiency can lead to reduced binding and uptake of T3 by tissues, as well as decreased hepatic conversion of T4 to T3 (The Relationship between Thyroid Disorders and Vitamin A.: A Narrative Minireview – PMC, n.d.
  • In animals, vitamin A deficiency leads to an enlarged thyroid, reduces the thyroid’s iodine uptake, hampers the production of thyroglobulin and the joining of iodotyrosine residues to create thyroid hormone, and lowers the levels of T3 and T4 within the thyroid. (Zimmermann et al., 2004)
  • TSH hyperstimulation, indicated by higher levels of TSH, thyroglobulin, and thyroid volume, has been shown to decrease with vitamin A treatment. (Zimmermann et al., 2004)
  • There is a significant relationship between the size of a goiter and the severity of vitamin A deficiency. Treatment with just vitamin A resulted in lower TSH levels and smaller goiter size, while the levels of thyroid hormones in the blood remained unchanged. (Sworczak & Wiśniewski, 2011)
  • Multiple studies have shown that a lack of vitamin A raises the risk of developing goiter. Among adults in Senegal and children in Ethiopia, there was a significant negative relationship between worsening goiter severity and levels of serum retinol. (Zimmermann et al., 2004)
  • Vitamin A supplementation helps the body use iodine more effectively. (Zimmermann et al., 2004)
  • Evidence strongly supports the combined fortification and supplementation of iodine and vitamin A in areas where both deficiencies exist. (Zimmermann et al., 2004)

Vitamin A deficiency is common 

  • 75% of adults in the US do not achieve the 3,000 IU/day recommendation for vitamin A intake (Gröber & Holick, 2022).
  • 34% of adults in the US consume less than the EAR (Estimated Average Requirement) for vitamin A (Sestili & Fimognari, 2020).
  • Hospitalized patients have been shown to have significantly lower levels of vitamin A when compared to convalescent persons (Tepasse et al., 2021).
  • Vitamin A deficiency is one of the top micronutrient deficiencies, especially in countries with low protein and meat consumption (Iddir et al., 2020).

Dietary beta carotene needs to be converted to vitamin A (retinol)

  • Conversion has been shown to be impaired in 24–57% of people with associated genetic variations (Sestili & Fimognari, 2020).
  • Decreased conversion of beta carotene to retinol may have clinical consequences, especially for vegans (Sestili & Fimognari, 2020).
  • Vitamin A levels decrease during various infections due to decreased absorption and urinary losses ((Sestili & Fimognari, 2020; Iddir et al., 2020).

Signs of vitamin A deficiency (Office of Dietary Supplements – Vitamin A and Carotenoids, n.d.)

  • dry eyes
  • night blindness

Vitamin A food sources and supplementation

Top sources of preformed vitamin A based on serving size (Vitamin A, 2014)

  • beef liver
  • cod liver oil
  • eggs
  • butter
  • whole milk

Top sources of provitamin A carotenoids based on serving size (Vitamin A, 2014)

  • sweet potato
  • pumpkin
  • carrot
  • cantaloupe
  • mango
  • spinach

Comprehensive food list: Table 3. Some Food Sources of Vitamin A

Referenced Dietary Intakes

RDAs for Vitamin A as preformed vitamin A (mcg/day) (measured as Retinol Activity Equivalents (RAE))
Adolescents (14-18 years): 900 (M) 700 (F)
Adults (19 years and older): 900 (M) 700 (F)

Vitamin A supplementation

Amounts of vitamin A used in practice and research range from 50–7,500 mcg RAE a day in divided doses (Office of Dietary Supplements – Vitamin A and Carotenoids, n.d.).


  • Vitamin A toxicity is rare.
  • Symptoms of long-term high-dose preformed vitamin A intake may include (Vitamin A, 2014):
    • nausea, headache, fatigue, loss of appetite, dizziness, dry skin, desquamation, and cerebral edema
  • Symptoms of lower-dose long-term supplementation of preformed vitamin A intake may include (Vitamin A, 2014):
    • dry itchy skin, anorexia, weight loss, headache, anemia, and bone and joint pain.
  • “Vitamin A, especially when in balance with vitamin D, has low toxicity except at high dosages. For adults, toxicity is typically seen after 100,000 IU/d for 6 months” (Sestili & Fimognari, 2020).

Vitamin D

Key actions of vitamin D in regards to hypothyroidism:

  • anti-inflammatory
  • anti-autoimmune

Vitamin D and immunity

  • Vitamin D is recognized as a natural modulator of the immune system. When its vitamin D receptors  are activated, vitamin D controls calcium metabolism, cell growth, proliferation, apoptosis, and various immune functions. (Agmon-Levin et al., 2013)
  • Vitamin D has a significant role in modulating Th1, Th2, and Th17 cells, and in regulating the secretion of cytokines such as IFN-γ, IL-4, and IL-17 [44–47]. (Wang et al., 2015)
  • Thyroid autoimmunity, which involves elevated levels of thyroid autoantibodies such as anti-thyroid peroxidase) and anti-thyroglobulin), is linked to vitamin D deficiency (Mirhosseini et al., 2017)

Vitamin D and TSH regulation

  • TSH levels are strongly linked to vitamin D levels. In winter, when vitamin D production is minimal and its levels are at their lowest, thyroid cells respond less to TSH, causing a decrease in thyroid hormones (T4) and an increase in serum TSH levels  (Mirhosseini et al., 2017).

Vitamin D deficiency common

  • In Canada, one out of ten people has a thyroid disorder, with half of these cases remaining undiagnosed. Additionally, one-third of Canadians are deficient in vitamin D (25(OH)D levels below 50 nmol/L), and fewer than 10% have vitamin D levels above 100 nmol/L. (Mirhosseini et al., 2017)

Vitamin D deficiency and hypothyroidism

  • In a study by Mirhosseini et al., 2017 individuals with hypothyroidism were three times more likely, and those with subclinical hypothyroidism nearly twice as likely to have vitamin D deficiency compared to healthy individuals (Mirhosseini et al., 2017)

Vitamin D deficiency and autoimmune

  • A deficiency in vitamin D has been linked to a higher risk of developing hypothyroidism and autoimmune thyroid diseases. (Mirhosseini et al., 2017)
  • Low vitamin D levels have been linked to the presence of antithyroid antibodies and abnormal thyroid function tests (Agmon-Levin et al., 2013)

25(OH)D and hypothyroidism

  • Mansournia and colleagues conducted a study with 41 hypothyroid patients and 45 healthy controls, finding an inverse relationship between 25(OH)D levels and the risk of hypothyroidism (Kmieć & Sworczak, 2015).

25(OH)D and thyroid autoimmunity

  • 25-hydroxyvitamin D (25(OH)D), is the main circulating form of vitamin D in the blood and is considered the best indicator of vitamin D status in the body.

Low I25(OH)D and thyroid autoimmunity

  • It has been shown that as 25(OH)D levels decrease thyroid peroxidase antibody prevalence increases (Kmieć & Sworczak, 2015)(Camurdan et al. 2012). 
  • Low serum 25(OH)D levels increase the likelihood of developing autoimmune thyroid disease . Vitamin D deficiency is commonly seen in thyroid disorders, and low serum 25-hydroxyvitamin D (25(OH)D) levels are linked to the development of both Hashimoto’s thyroiditis and Grave’s disease. (Mirhosseini et al., 2017)
  • A recent meta-analysis of 20 case–control studies revealed that individuals with autoimmune thyroid disease had lower serum 25(OH)D levels compared to healthy controls. (Mirhosseini et al., 2017)

25(OH)D sufficiency and hypothyroidism

  • Enhancing serum 25(OH)D levels also significantly influenced inflammation by reducing hs-CRP levels, which could explain why improving 25(OH)D status benefits thyroid function. (Mirhosseini et al., 2017)
  • Maintaining proper thyroid function necessitates maintaining physiological levels of serum 25(OH)D, typically between 100–130 nmol/L. It is recommended that these levels be sustained over a significant duration, such as 2–3 years, to achieve the goal of preventing or treating chronic diseases. (Mirhosseini et al., 2017)
  • • Keeping serum 25(OH)D levels above 125 nmol/L lowered the risk of elevated TSH and alleviated symptoms associated with low thyroid function, such as brain fog, weight gain, low mood, unrefreshing sleep, and low energy. (Mirhosseini et al., 2017)
  • Of participants in a health and wellness program that provided vitamin D supplementation, who attained serum 25(OH)D levels above 100 nmol/L, only 8.8% remained at risk for autoimmune thyroid disease,  one year later (Mirhosseini et al., 2017).

25(OH)D sufficiency decreases risk of thyroid autoimmunity

  • A study by Mirhosseini et al., 2017, showed that: 
    • 25(OH)D levels greater than or equal to 125 nmol/L – significantly reduced risks for elevated levels of anti-thyroid peroxidase, anti-thyroglobulin antibodies, and inflammation (hs-CRP), as well as a 60% lower chance of low thyroid hormone levels (FT4) and a 14% lower chance of low FT3 levels
    • 25(OH)D levels less than125 nmol/L were associated with 115% higher risk of elevated anti-TG antibodies, 118% higher risk of anti-thyroid peroxidase antibodies, and a 107% higher risk of elevated TSH. 

Causes of vitamin D deficiency

  • 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 https://ods.od.nih.gov/factsheets/VitaminD-HealthProfessional/

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 regard to thyroid health

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


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.


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).


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.).

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