The Durk Pearson & Sandy Shaw®
Life Extension NewsTM
Volume 11 No. 6 • October 2008

You’d Be Depressed Too If You Were Suspended by Your Tail—
Relief of Depression with SSRIs and 5-HTP

The ability of humans to make serotonin from tryptophan may determine who can benefit from selective serotonin reuptake inhibitors (SSRIs), which are antidepressant drugs, and who cannot. Many depressed people are resistant to drug treatment, including SSRIs such as fluoxetine (generic name for Prozac®). The same is true for mice. C57BL/6 mice, but not NMRI mice, respond to SSRI treatment in the tail-suspension test with decreased immobility (an antidepressant effect). A new study identified the reason why: unlike the C57BL/6 mice, the NMRI mice have a version of the tryptophan hydroxylase 2 (TPH2) gene—tryptophan hydroxylase is the rate-limiting enzyme in the synthesis of serotonin from tryptophan—that results in low levels of brain serotonin.1 “This is analogous to the finding that low TPH2 function is associated with poor responses to SSRIs in depressed patients.”1

The tail-suspension test is used in mice to test antidepressants because the ability of a compound to decrease immobility in this and the forced swimming test are predictors of antidepressant potential in humans.

TPH2 catalyzes the conversion of tryptophan to 5-hydroxytryptophan (5-HTP), the rate-limiting step in the synthesis of serotonin. The researchers1 thus tested the effects of supplementing the NMRI mice with 5-HTP as well as treating them with an SSRI on immobility in the tail-suspension test. They found that serotonin levels were higher in the frontal cortex (but not the hippocampus) after treatment with 12.5 mg/kg of 5-HTP. In tail-suspension tests where the mice received the same dose of 5-HTP as a cotreatment with either of the SSRIs citalopram or paroxetine, the formerly SSRI-unresponsive NMRI mice became significantly less immobile compared to either 5-HTP alone or the SSRI alone. For example, the maximal effect for 5-HTP and paroxetine was found for 5-HTP plus 20 mg/kg paroxetine, which resulted in a 59% decrease in immobility as compared to 5-HTP alone.

Interestingly, the authors cite a paper by other researchers who found, in two other citalopram-insensitive mouse strains, that tryptophan increased citalopram response in the forced swim test. However, in that study, a tryptophan dose of 300 mg/kg was effective, as compared to 12.5 mg/kg of 5-HTP in the new study.1

5-Hydroxytryptophan, a Potent Hydroxyl Radical Scavenger

Also of interest are the findings of another paper,2 in which the researchers compared the hydroxyl radical scavenging ability of 5-hydroxytryptophan to melatonin and vitamin C. “5-HTP showed highest hydroxyl radical scavenging effects with a 50% inhibition concentration (IC50) of 1.8 µM. For vitamin C an IC50 of 12.7 µM was measured, whereas melatonin in pure demineralized water was much less efficient (IC50 = 724 µM).”2

This is interesting because the hydroxyl radical is the most potently damaging radical, able to attack any macromolecule, including lipids, protein, and DNA. Radiation damage is largely caused by the massive creation of hydroxyl radicals. (Another good scavenger for hydroxyl radicals is ethanol, though we do not recommend it for depression.)

We use our 5-hydroxytryptophan-containing formulations (Serene Tranquility™ Night with 5-HTP, which also contains melatonin, and Serene Tranquility Day with 5-HTP), with 75 mg of 5-HTP per serving.


  1. Jacobsen et al. Insensitivity of NMRI mice to selective serotonin reuptake inhibitors in the tail suspension test can be reversed by co-treatment with 5-hydroxytryptophan. Psychopharmacology 199:137-50 (2008).
  2. Keithahn & Lerchi. 5-Hydroxytryptophan is a more potent in vitro hydroxyl radical scavenger than melatonin or vitamin C. J Pineal Res 38:62-6 (2005).

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