Introduction

5-hydroxytryptophan (5-HTP) is the immediate precursor to serotonin (5-HT, 5-hydroxytryptamine). Serotonin plays an important role in regulation of mood, appetite, body temperature, and the secretion of various hormones. While serotonin does not readily cross the blood brain barrier, serotonin precursors such as L-tryptophan and 5-HTP do. Supplementation with these precursors increases both central and peripheral levels of serotonin, and 5-HTP is generally seen as superior because it bypasses the rate-limiting step of serotonin synthesis (tryptophan hydroxylase) and absorption is not dependent on dietary factors [1]. 5-HTP also crosses into the CNS more easily, as L-tryptophan is limited by transporter availability and other factors [2].

Appetite suppression

One of the common uses of 5-HTP is as an appetite suppressant. 5-HTP administration to both humans and animals decreases food intake [3-4]. When given to rats in large amounts, 5-HTP decreased food intake by 68.9% [5]. Four clinical trials in overweight or obese humans have found 5-HTP to decrease food intake and consequently cause weight loss [6-7]. In a double-blind, placebo-controlled trial conducted by researchers at the University of Rome, 20 obese women were given 300 mg 5-HTP or placebo three times daily for six weeks of unrestricted diets followed by six weeks in which subjects were instructed to consume 1200 calories daily. The 5-HTP group experienced significant weight loss during both periods, and caloric intake was markedly reduced (1879 vs. 3220 calories during spontaneous eating, with a further reduction to 1268 calories during the second period) [7]. In another double-blind, placebo-controlled study on 20 overweight type II diabetes patients, subjects given 5-HTP had significant reductions in energy intake and body weight compared to plaecbo [6]. Although these dosages are large, it is presumable that lower doses of 5-HTP will also suppress appetite, albeit not as dramatically.

What’s remarkable about 5-HTP’s appetite suppressant effects is that it they are macronutrient-specific. It’s almost common knowledge that carbohydrate intake can make us sleepy by insulin assisted transport of tryptophan to the brain, leading to increased serotonin levels. Often when people are nervous, they crave carbohydrates, possibly due to their serotonin elevating properties. Thus, carbohydrate craving can be viewed as a deficit in serotonin [8]. Such a theory is supported by the observations in weight loss studies with 5-HTP, where carbohydrate calories were reduced, but not protein or fat calories [6]. Thus, 5-HTP could be helpful for those on low-carbohydrate diets.

There have been multiple mechanisms postulated for this effect of 5-HTP supplementation. Dieting causes a significant decrease in serotonin levels [7]. Serotonin may help suppress food intake by acting at serotonin receptors and by altering levels of certain hormones. 5-HTP induces the release of Corticotropin Releasing Factor (CRF), which increases energy expenditure while simultaneously decreasing energy intake [9]. Agonists of 5-HT1B, 5-HT2A, and 5-HT2C receptors such as DOI and mCPP cause appetite suppression in rats, an effect that may be due to actions at both central and peripheral serotonin receptors [4, 10].

While serotonin is the anti-carbohydrate neurotransmitter, norepinephrine is the “carbohydrate craving” neurotransmitter through its action on alpha-2 adrenoreceptors [11]. This often seems counterintuitive, as noradrenergic drugs are used for weight loss. However, stimulation of alpha-2 adrenoreceptors by norepineprhine or other agonists causes a decrease in serotonin synthesis which leads to carbohydrate craving [12]. This partially explains the synergistic effect on anorexia that yohimbine (an alpha-2 antagonist) produces with noradrenergic drugs. This observation also underlines the importance of serotonergic enhancement when using noradrenergic drugs (such as ephedrine) for dieting.

Studies in rodents indicate that 5-HTP administration causes a significant increase in the hormone leptin [3, 13]. Leptin plays an imporant role in the regulation of appetite and other physiological processes, and various factors can alter leptin secretion. 5-HTP administration results in significant increases in insulin, corticosterone, and prolactin levels, and all of these hormones can increase leptin levels [13]. The present animal research indicates that the the effect of 5-HTP on leptin levels are insulin-dependent, while the role that 5-HTP-induced increases in corticosterone plays seems to be minor [3, 13]. Future research should further define the mechanisms by which 5-HTP increases leptin levels.

Insomnia

Research in humans is still largely lacking for this purpose. An open study found that 600 mg 5-HTP increased REM sleep by 20 minutes in normal subjects, with a smaller effect with 200 mg [7]. There are theoretical reasons for a benefit, as high amounts of serotonin can cause tiredness (and other serotonergic agents such as trazodone are used to treat insomnia), and 5-HTP also increases melatonin levels by increasing serotonin, an effect that is more pronounced in the dark [21]. Preliminary human research and research with tryptophan indicates that 5-HTP may be of use in patients with obstructive sleep apnea [1, 22].

Side effects and precautions

In clinical trials, the most commonly reported side effects are nausea and gastrointestinal distress, and less commonly headaches and sleepiness [14, 17]. The nausea problem may be resolved by starting with a low dose and moving up, and even when large doses are used (900 mg/day), the problem diminishes with time [7].

Some of the hormonal effects of 5-HTP supplementation may not be desirable, although the relationships are complex. For example, 5-HTP increases cortisol secretion in healthy humans at doses as low as 100 mg [17, 26]. 5-HTP also causes an increase in prolactin concentrations in both animals and humans [3, 27]. These effects may be due to stimulation of 5-HT1A, 5-HT1C, 5-HT2, and possibly other 5-HT receptors [27-28]. The implications of these effects in the context of 5-HTP supplementation are not well known.

5-HTP should not be used along with prescription antidepressants without medical supervision or careful monitoring, as interactions are likely. 5-HTP potentiates the effects of SSRI's [29]. Serotonin syndrome is a concern, although a 12-month study of 200 mg 5-HTP along with an MAOI reported no incidences [7]. However, adverse reactions to the combination of tryptophan and Prozac have been reported [2], and serotonin syndrome has been reported with tryptophan and MAOI combinations [7].

Another concern is Eosinophilia-Myalgia Syndrome (EMS). This affected many users of tryptophan supplements in the late 1980's and resulted in multiple fatalities, and although it has been debated whether it was due to the tryptophan itself or a product impurity [14], contamination is now known to be the cause. Since 5-HTP is usually produced through extraction from plant sources, the same problem is not a likelihood. Two cases of EMS-like symptoms have been reported in patients taking 5-HTP; one was before product contamination was identified in 1990, and in the other case, product contamination was confirmed [7]. HPLC analysis has found some commercial preparations of 5-HTP to be contaminated, but it is unknown if this is the same contaminant that caused EMS [30]. For this reason, it is advisable to use 5-HTP from a brand with high product quality standards (such as the Meridian Naturals brand).

Note: A few people have contacted me bringing up a concern voiced by a Dr. Steven B. Harris. According to Dr. Harris, 5-HTP supplementation is potentially dangerous because highly elevated levels of serotonin in the periphery have been linked to heart problems and other cardiovascular problems. Dr. Harris also says that the issue is greater when vitamin B6 supplements are taken because this catalyzes the conversion of 5-HTP to serotonin. As far as I know, Dr. Harris' contentions are unpublished, unreferenced, and have been voiced by no one other than himself. While researching for this article, we encountered no references to cardiovascular events following 5-HTP supplementation in either the primary or review literature. There also didn't appear to be any references to an interrelationship between vitamin B6 and 5-HTP supplements, although there is one report where monkeys were injected with amounts of vitamin B6 magnitudes higher than the amounts in oral supplements, and an increase in serotonin levels follows. While elevated levels of serotonin, or any other neurotransmitter, or pretty much any substance, can be harmful, it is important to first establish the concentrations at which they are harmful and whether or not a certain drug leads to those concentrations before drawing conclusions. As is the case with any supplement, one should always consult a doctor before taking 5-HTP if they have any condition or are taking any other prescription drugs, and discontinue use at first sign of an adverse reaction. -David

Recommended dosage

5-HTP is highly bioavailable, and about 70% reaches the bloodstream [7]. The half-life of 5-HTP is short (approximately 90 minutes [17]), so it should be taken three or more times daily if possible. It can be taken with or without food. The typical dosage is usually 50-100 mg three times daily, or for insomnia, 100-300 mg is taken before bed.

If you have any questions or comments regarding this article, please email dvdtlsn@bulknutrition.com.