Vitamin D2 or D3 for depression?

Background

Vitamin D is an essential, fat-soluble vitamin.

First, it is important to know the difference between essential and non-essential vitamins and fat-soluble vs water-soluble vitamins.

An essential vitamin must be obtained from the diet, where a non-essential vitamin can be synthesized in the body. Some sources consider vitamin D a non-essential vitamin because your body can synthesize it when exposed to sunlight, while other sources consider vitamin D an essential vitamin because many still need to obtain vitamin D in the diet. For example, people who live in climates without much sunlight may need to get vitamin D from their diet, additionally, melanin absorbs the ultraviolet radiation that initiates vitamin D synthesis so people with darker skin tones may not produce as much vitamin D from sun exposure.

Vitamin D is fat-soluble, which means that it is dissolvable in fat and stored in the liver and fatty tissues for future use. Water-soluble vitamins are dissolvable in water and are either used immediately or excreted in the urine. If too much of a water-soluble vitamin is taken, then it is excreted and rarely causes problems, but taking too much of a fat-soluble vitamin can lead to dangerous effects. Fat-soluble vitamins are vitamin A, D, E, and K.

There are a few types of vitamin D such as ergocalciferol (vitamin D2) and cholecalciferol (vitamin D3). Both types are metabolized to calcitriol, which is the active form. Foods that contain vitamin D include oily fish, red meat, liver, eggs, and fortified foods. Many people get their vitamin D through supplementation.

How does vitamin D help with depression?

Depression is associated with inflammation in the brain and low vitamin D levels are associated with higher levels of inflammatory markers. Therefore, vitamin D may be beneficial in depression by decreasing neuroinflammation. A study of vitamin D in children with ADHD found that vitamin D3 supplementation increased serum dopamine levels (but not serotonin or BDNF levels) and increasing dopamine levels can be helpful in depression.¹ The exact mechanism of how vitamin D helps with depression is not understood.

Dosing

In the United States, vitamin D dosing is listed in micrograms (mcg), while in other countries, the dosing may be listed in international units (IU). To convert from IU to mcg, divide the IU by 40.

The recommended daily dietary allowance of vitamin D depends on age.

Age 1-70: 600 IU (15 mcg)
Age 71 and older: 800 IU (20 mcg)

The current recommended daily dietary allowance assumes that vitamin D2 and vitamin D3 are equally absorbed. This is not thought to be the case and some evidence suggests that cholecalciferol (vitamin D3) is absorbed three times as readily as ergocalciferol (vitamin D2).

Taking vitamin D with a high-fat meal can increase absorption by 20% because vitamin D is a fat-soluble vitamin.

Effectiveness

Can vitamin D deficiency cause depression?

Low vitamin D levels do seem to be associated with depression. A meta-analysis of 32,424 patients showed that the group with the lowest vitamin D level were more than twice as likely to develop depression as compared to the group with the highest vitamin D level.²

Does vitamin D treat depression?

A meta-analysis of 948 patients showed that vitamin D had a moderate effect size in the treatment of depression. Studied varied in length from 8 weeks to 52 weeks. Three of the trials were of oral vitamin D with doses between 1,500 IU daily and 50,000 IU weekly. One trial included intramuscular vitamin D. Of note all four trials used vitamin D3.³

Another meta-analysis found efficacy in studies that measured vitamin D before and after supplementation to show an increase in serum levels. The study concluded vitamin D supplementation (≥800 I.U. daily) had an effect size that was comparable to that of anti-depressant medication.⁴

Does vitamin D prevent depression?

A trial followed 18,353 adults over the age of 50 for five years. People in the treatment group took vitamin D3 (2000 IU/d) and fish oil and the other group took a placebo. Treatment with vitamin D3 and fish oil did not show a statistically significant difference in the prevention of depression and the authors of the study do not support the use of vitamin D3 in adults to prevent depression.⁵

Safety

Natural medicines database deems vitamin D to be likely safe when used orally or intramuscularly at appropriate doses. Oral long-term doses should not exceed 4000 IU (100 mcg) per day for adults, but much higher doses can be used short-term to treat vitamin D deficiency.

Side effects

Generally, vitamin D is well tolerated. Side effects are rare but possible, especially when too much is taken

Vitamin D intoxication can cause

Hypertension
Dry mouth
Decreased libido
Osteoporosis
Eye problems like calcific conjunctivitis and photophobia
Psychosis
Hypercalcemia

Drug interactions

Many potential interactions exist. Some interactions are as follows:

Atorvastatin: Vitamin D may reduce the absorption of atorvastatin
CYP3A4 substrates: Vitamin D may induce CYP3A4 enzymes
Digoxin: Vitamin D in high doses may increase the risk of arrhythmias
Calcium: vitamin D increased the absorption of calcium
Carbamazepine, corticosteroids, phenobarbital, phenytoin and more drugs: may reduce blood levels of vitamin D

References:

Seyedi M, Gholami F, Samadi M, Djalali M, Effatpanah M, Yekaninejad MS, Hashemi R, Abdolahi M, Chamari M, Honarvar NM. The Effect of Vitamin D3 Supplementation on Serum BDNF, Dopamine, and Serotonin in Children with Attention-Deficit/Hyperactivity Disorder. CNS Neurol Disord Drug Targets. 2019;18(6):496-501. doi: 10.2174/1871527318666190703103709. PMID: 31269890.
Anglin RE, Samaan Z, Walter SD, McDonald SD. Vitamin D deficiency and depression in adults: systematic review and meta-analysis. Br J Psychiatry. 2013 Feb;202:100-7. doi: 10.1192/bjp.bp.111.106666. PMID: 23377209.
Vellekkatt F, Menon V. Efficacy of vitamin D supplementation in major depression: A meta-analysis of randomized controlled trials. J Postgrad Med. 2019;65(2):74-80. doi:10.4103/jpgm.JPGM_571_17.
Spedding S. Vitamin D and depression: a systematic review and meta-analysis comparing studies with and without biological flaws. Nutrients. 2014;6(4):1501-1518. Published 2014 Apr 11. doi:10.3390/nu6041501.
Okereke OI, Reynolds CF, Mischoulon D, et al. Effect of Long-term Vitamin D₃ Supplementation vs Placebo on Risk of Depression or Clinically Relevant Depressive Symptoms and on Change in Mood Scores: A Randomized Clinical Trial. JAMA. 2020;324(5):471–480. doi:10.1001/jama.2020.10224.