5-HTP supplements are claimed to provide more raw material to the body's natural serotonin production process. There is a reasonable indication that 5-HTP may not be effective for those who haven't already responded well to an SSRI because of their similar function: SSRIs allow the brain to use its serotonin more effectively, while 5-HTP induces production of more serotonin.

S-adenosyl methionine (SAM-e) is a derivative of the amino acid methionine that is found throughout the human body, where it acts as a methyl donor and participates in other biochemical reactions. It is available as a prescription antidepressant in Europe and an over-the-counter dietary supplement in the United States. Clinical trials have shown SAM-e to be as effective as standard antidepressant medication, with fewer side effects; however, some studies have reported an increased incidence of mania resulting from SAM-e use compared to other antidepressants. Its mode of action is unknown.

Omega-3 fatty acids (found naturally in oily fish, flax seeds, hemp seeds, walnuts, and canola oil) have also been found to be effective when used as a dietary supplement (although only fish-based omega-3 fatty acids have shown antidepressant efficacy.