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]. Because 5-HTP successfully increases serotonin levels, it has been used
for a variety of therapeutic purposes, primarily the treatment of depression
[1].
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.
Depression
The majority of the research on 5-HTP has focused on its possible use as
a treatment for depression. In 2000, the clinical research was thoroughly
reviewed by Meyers [2]. Many studies were conducted by a group of European
researchers in the 1970's and early 1980's. In one study 60% of depressed
patients given 5-HTP (200-3000 mg/day) improved while there were no improvements
in the placebo group. Another double-blind study with 200 mg/day of 5-HTP
indicated that it was more effective than placebo and almost as effective
as the tricyclic antidepressant clomipramine. In 1977, a double-blind study
was done with 5-HTP along with a drug to inhibit peripheral conversion to
serotonin, and it found this combination to be equally as effective as the
antidepressant imipramine. In both of these studies, 5-HTP was associated
with fewer side effects than the other treatment [7]. Seven open studies
were also conducted with positive results, however open studies are not good
indicators of antidepressant effectiveness. In the 1970's, several other
studies were also conducted in Japan in patients with various types of depression,
all with positive results, but once again these were open studies.
In more recent research, a 1991 double-blind study in Switzerland compared
300 mg 5-HTP to fluvoxamine (Luvox) and found them to be equally effective
in treating depression (although the results were in favor of 5-HTP, the
difference was not statistically significant [7]). Most of these studies
were in patients with major depression, although a double-blind study comparing
L-tryptophan with a tricyclic antidepressant indicated that it was effective
for mild and moderate depression, and it can be assumed that this benefit
would cross over to 5-HTP. However, results from studies comparing 5-HTP
with another antidepressant without a placebo group should be treated with
caution. Two small studies conducted in the early 1980s indicated additive
antidepressant effects with a combination of 5-HTP and tyrosine, a combination
that warrants further exploration. At present, the bulk of the evidence indicates
a benefit from 5-HTP supplementation in the treatment of depression, although
a 2002 meta-analysis emphasizes the need for more studies with better methodology
[14].
While it superficially makes sense that by increasing serotonin levels with
5-HTP would relieve depression, the antidepressant mechanism behind 5-HTP
(and the SSRI’s) is slightly more complicated and constantly evolving with
increasing research. An overactive HPA axis leading to increased cortisol
levels has always been a hallmark of clinical depression, a phenomenon which
can be reversed with successful antidepressant treatment [15]. Current
research suggests that antidepressants, such as 5-HTP, might directly influence
the normalization of HPA function and change the action of cortisol in the
brain [16]. Acutely, 5-HTP induces the release of CRF and subsequently
cortisol [17]. This would appear to exacerbate depressive symptoms,
but the serotonin system is subject to tightly regulated negative feedback,
especially when stimulated by 5-HTP [18]. Treatment with 5-HTP will
lead to decreases in corticosteroid receptors in the rat brain [19].
The adrenal stimulation produced by 5-HTP might also be directly helpful
to depression, as it raises Beta-Endorphin levels [20].
Insomnia
Although 5-HTP is commonly used for this purpose, research in humans is still
largely lacking. 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].
Other possible benefits
5-HTP may be useful in the treatment of chronic headaches, which have been
linked to low serotonin levels. In a trial with 124 subjects, 5-HTP decreased
the number of migraine headaches, but the difference was not statistically
significant, while another study in 48 elementary and junior high school
students indicated that 5-HTP reduced headache frequency by 70% compared
to 11% for the placebo group [7]. 5-HTP may also be useful in patients with
panic disorder as one placebo-controlled trial found it to reduce the panic
reaction to CO2 challenge in patients with panic disorder [23]. Studies have
also indicated miscellaneous benefits from 5-HTP supplementation in patients
with fibromyalgia [24]. Reductions in serotonergic tone are partially responsible
for cognitive deficits (memory loss) resulting from tetrahydrocannibinol
(THC, the active component in marijuana). When given to rats, 5-HTP
can significantly attenuate THC-induced memeory impairment [31].
Finally, 5-HTP is beneficial in animal models of Down syndrome and amyotrophic
lateral scleroris, opening the door for human research [25].
Side effects and precautions
In clinical trials, the most commonly reported side effects are nause 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 Now Foods 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 converstion 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.
