5-HTP studies reviewed

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Friday, July 22, 2005 9:14 am Email this article
Below are quotes from a new review paper about 5-Hydroxytryptophan or 5-HTP for short. 5-HTP made from L-tryptophan

“5-HTP is an… amino acid naturally produced by the body from the essential amino acid L-tryptophan.

5-HTP used for 30 years

“5-HTP has been used clinically for over 30 years.

5-HTP used for insomnia, binge eating, headaches and fibromyalgia

“In addition to depression, the therapeutic administration of 5-HTP has been shown to be effective in treating a wide variety of conditions, including

• fibromyaligia [unexplained muscle pain]
• insomnia
• binge eating associated with obesity
• cerebellar ataxia
• chronic headaches.

5-HTP suggested as antidepressant

“Supplementation with 5-HTP is hypothesized to normalize serotonin synthesis, which is putatively related to its antidepressant properties.

Most 5-HTP depression studies done at least 20 years ago

“However, most of the studies involving the use of 5-HTP for depression were conducted 20 or more years ago.

SSRI’s came on the market in 1987; may have reduced interest in 5-HTP

“In December of 1987, the first selective serotonin re-uptake inhibitor (SSRI)–fluoxetine (Prozac)–was approved in the United States. Other SSRIs quickly followed.

“This new class of antidepressants became widely prescribed, as they were found to be both generally effective and safe. It is possible that this series of events led to a loss of interest in 5-HTP.”

Serotonin depletion can induce depression within hours

“In humans, several studies have shown that reducing serotonin synthesis (by depriving the brain of tryptophan) can induce depression within hours.

“Similarly, after oral administration of an amino acid mixture without tryptophan, significant decreases of plasma tryptophan and cerebrospinal fluid levels of 5-HIAA [a metabolite of serotonin] have been reported.

Increasing brain tryptophan increases serotonin release

“It has also been shown that increases in brain tryptophan concentration raise serotonin release.

“Taken together, these data suggest that the concentration of 5-HTP and serotonin depend upon the availability of its precursor tryptophan.

Tryptophan hydroxylase is the rate-limiting enzyme for production of serotonin

“[T]ryptophan hydroxylase, is the rate-limiting enzyme in neuronal serotonin synthesis.

Tryptophan hydroxylase enzyme inhibited by stress, insulin resistance, vitamin B6 or magnesium deficiency

“Tryptophan hydroxylase can be inhibited by numerous factors, including

• stress
• insulin resistance
• pyridoxine (vitamin B6) deficiency
• insufficient magnesium
• high dosages of tryptophan.

Aromatic L-Amino Acid Decarboxylase is the enzyme that converts 5-HTP to serotonin

“5-HTP is converted to serotonin by the enzyme aromatic l-amino acid decarboxylase (AADC)...

This same enzyme converts L-dopa to dopamine as well

“[This enzyme converts] L-DOPA to dopamine and 5-HTP to serotonin.

This enzyme works both inside and outside the brain

“This enzyme acts both in the periphery [throughout the body] and in the CNS [brain and central nervous system], meaning that ingested 5-HTP can be converted into serotonin in the periphery of the body.

Serotonin made from 5-HTP outside the brain is not available to the brain

“[Conversion of 5-HTP to serotonin that occurs outside the brain and central nervous system] cannot influence serotonin levels [in the brain and central nervous system] because serotonin is unable to cross the blood–brain barrier.

“Additionally, [this conversion outside the brain] depletes substrate levels, resulting in little 5-HTP reaching the brain.

The drug carbidopa prevents conversion of 5-HTP to serootonin outside the brain

“Administration of decarboxylase inhibitors [which inhibit this enzyme from converting 5-HTP to serotonin outside the brain] such as carbidopa blocks this peripheral conversion.

Vitamin B6 is necessary for this enzyme

“Pyridoxine (vitamin B6) is a cofactor for AADC [the enzyme that converts 5-HTP to serotonin] that has also been shown to regulate the levels of 5-HTP.

“In a paper describing the treatment and outcomes of patients with AADC deficiency [deficiency of the enzyme that converts 5-HTP to serotonin], all patients received pyridoxine [vitamin B6] supplementation; however, direct clinical benefit was not reported (Swoboda et al., 2003).

Vitamin B6 suggested to improve mood

“Nevertheless, supplemental intake of pyridoxine [vitamin B6] has been suggested to improve mood.

Low vitamin B6 derivative associated with depression

“A recent study found that low plasma levels of pyridoxal phosphate (the phosphate derivative of pyridoxine [vitamin B6]) were significantly associated with depression rating scale scores, suggesting that low pyridoxine [vitamin B6] levels may be related to symptoms of depression.

5-HTP causes serotonin syndrome at human equivalent of 7,000 to 14,000 mg for 154 pound human

“In rodents, 5-HTP induces a serotonin syndrome at dosages of 100–200 mg [per kg of body weight; this is the equivalent of 7,000 to 14,000 mg for a 154-pound human].

5-HTP combined with SSRI’s such as Prozac may cause serotonin syndrome at much lower doses

“This 5-HTP-induced syndrome is potentiated by SSRI’s. [This means that much lower doses of 5-HTP could cause serotonin syndrome when combined with SSRIs such as Prozac.]

SSRI’s antidepressant action predicted by its ability to induce serotonin syndrome when combined with 5-HTP

“Consequently, putative antidepressants can be tested for their degree of potentiation of the 5-HTP-induced syndrome. This test has been shown to have predictive validity for antidepressant action. In particular, it predicts the ability of the compound to inhibit serotonin re-uptake and the compound’s efficacy as an antidepressant.

Seven of 11 studies found 5-HTP superior antidepressant to a placebo

“Among the 11 [double-blind, placebo-controlled] studies, the authors reported that 5-HTP was superior to placebo in 7 of them.

Only 5 of the 7 studies were statistically significant; all studies were small

“However, the sample sizes in all these studies were quite small, and only 5 of these studies were able to show statistical significance. [This means that in the other 2, there was at least a 5 percent chance that the difference was due to random chance.]

“Investigators have also done at least 5 active comparator studies.

Seven of 11 studies found 5-HTP superior antidepressant to a placebo

“Two of these studies failed to show any difference between 5-HTP and the comparator, imipramine [Tofranil], or fluvoxamine [Luvox], while 2 determined that 5-HTP was less effective than tranylcypromine [Parnate] for treatment-resistant depression.

[Another way to say this is that 5-HTP was found to be as effective as the prescription antidepressants as Luvox and Tofranil, but less effective than Parnate.]

Neither 5-HTP nor 5-HTP plus carbidopa found effective in another study

“One compared 5-HTP alone versus 5-HTP and [carbidopa] a peripheral decarboxylase inhibitor, with neither group showing much improvement.

Difficult to determine if 5-HTP is an effective antidepressant

“Overall, it is difficult to draw any definitive conclusions regarding the efficacy of 5-HTP for depression, given the limitations [of the studies].

5-HTP plus L-tyrosine more effective antidepressant than either 5-HTP or L-tyrosine alone

[Note: A book called “Amino Acids in Psychiatric Disease” notes that one study found that combining 5-HTP plus the amino acid L-tyrosine, which is the precursor to dopamine, adrenaline and noradrenaline, was more effective for depression than either 5-HTP or L-tyrosine alone.]

Lack of efficacy is common in antidepressant studies

“One might question whether these positive studies should be ‘cancelled out’ by the negative studies listed. However, it is common for antidepressant studies not to demonstrate superiority to placebo, even trials with large sample sizes.

Lack of efficacy occurred in half of antidepressant studies involving prescription antidepressants

“In 51 adequate and well-controlled trials submitted by pharmaceutical companies for U.S. regulatory approval, drugs eventually approved as antidepressants fail to demonstrate statistical superiority to placebo roughly half of the time.

70% of 5-HTP absorbed

“[5-HTP] can be taken as a dietary supplement and is well absorbed from an oral dose, with about 70% ending up in the bloodstream.

DOSE: 5-HTP studies have used 20 to 3,250 mg per day, most using 200 to 300 mg per day

“The doses used in the studies [of 5-HTP] ranged from 20 to 3250 mg/day, with the majority administering 5-HTP at doses between 200 and 300 mg/day, regardless of whether carbidopa or another medication was coadministered.

DOSE: 5-HTP studies have used 20 to 3,250 mg per day, most using 200 to 300 mg per day

“Among the published studies of 5-HTP for depression, many did not report the dosing schedule.

“Of the studies that did report a dosing schedule,
- 3 used a 2-times-per-day schedule,
- 4 used a 3-times-per-day schedule, and
- 1 used a 4-times-per-day schedule (Kline et al., 1964).

5-HTP given 3 times per day may be best for depression

“Perhaps coincidentally, those that used [3 times per day] dosing appeared to have better efficacy results.

HALF-LIFE: 4 Hours

“The half-life of 5-HTP is relatively short [4.3 hours].

TIME TO REACH MAXIMUM CONCENTRATION: 1-2 Hours

“[The time it takes to reach a] maximal concentration [in the blood] is 1–2 hours.

Fewer adverse effects if divided into 3 doses rather than 2

“Compared with [twice a day] dosing, for any given total daily dose, [three times a day] dosing should tend to reduce the risk of adverse events.

Warning: Minimize risk of serotonin syndrome if used with SSRI’s such as Prozac

“It is especially important to minimize the risk of serotonin syndrome if 5-HTP is to be coadministered with SSRIs or other serotonergic antidepressants.

Giving 5-HTP with carbidopa increases blood levels 14-fold

“In a recent study of healthy volunteers, the addition of carbidopa resulted in a 14-fold increase in 5-HTP plasma levels.

It isn’t clear whether or not carbidopa increases 5-HTP’s efficacy

“Efficacy studies have been conducted both with and without the addition of a peripheral decarboxylase inhibitor [carbidopa]. However, there seems to be no consensus as to whether the addition increases the effect of 5-HTP.

ADVERSE EFFECTS: Most common are gastrointestinal, nausea, vomiting, diarrhea

“The most common adverse effects of 5-HTP are gastrointestinal and include nausea, vomiting, and diarrhea.

ADVERSE EFFECTS: Less common are headache, insomnia, palpitations

“Less commonly, headache, insomnia, and palpitations can occur.

Fewer adverse effects when carbidopa given with 5-HTP

“A study comparing 5-HTP to 5-HTP plus a peripheral decarboxylase inhibitor [carbidopa] found that [gastrointestinal] side effects were dose dependent and that they occurred more frequently in patients receiving 5-HTP alone.

[Note: At least one study found more side effects in patients given carbidopa along with 5-HTP than those given 5-HTP alone.]

Adverse effects due to 5-HTP being converted to serotonin in the gut

“[These adverse effects] may be due to peripheral conversion of 5-HTP to serotonin, which increases gut motility. Such conversion is blocked by [carbidopa].

Gastrointestinal adverse effects usually moderatne and often disappear with continued use

“In either case, [gastrointestinal] effects are usually moderate and often lessen or disappear once a steady dosage is achieved.

5-HTP given intraveneously can cause confusion, anxiety and memory problems, less common with oral doses

“Intravenous administration of 200 to 300 mg of 5-HTP can induce confusion, memory impairment, and symptoms of behavioral activation (primarily anxiety). These effects are generally much more rare with oral doses, particularly at lower doses.

[I’ll finish this later…]

REFERENCE

Turner E, Loftis J, Blackwell A. Serotonin a la carte: supplementation with the serotonin precursor 5-hydroxytryptophan. Pharmacol Ther. 2005 Jul 13.

AUTHOR’S CORRESPONDENCE

Erik Turner
Mental Health Division
Mood Disorders Research Center
Portland VA Medical Center
3710 SW US Veterans Hospital Rd
Portland, OR 97239, USA
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Articles on the same subject can be found here:

• 5-HTP (5-Hydroxytryptophan)

• Tofranil (imipramine)