Image credit: https://www.ncbi.nlm.nih.gov/pubmed/27692695
5-Hydroxytryptophan (5-HTP) is an amino acid precursor of serotonin with an anti-depressant, anti-anxiety, sleep, and weight loss benefits, but with some caveats. Read this post to learn more about the proven health benefits and risks of supplementing with 5-HTP.
What is 5-HTP?
5-hydroxytryptophan (5-HTP) is an amino acid that serves as a precursor for the biosynthesis of serotonin and melatonin in the brain from the other amino acid tryptophan.
Currently, depression is hypothetically described as caused by having low levels of serotonin in the brain, although we still don’t understand exactly what causes depression (R).
5-HTP in supplement form is extracted from the plant Griffonia simplicifolia, an African shrub.
Health Benefits of 5-HTP Supplementation
1) 5-HTP May Help with Depression
Small clinical studies have shown that 5-HTP alleviates depression better than placebo. However, more large-scale and higher quality studies are necessary to confirm the safety and effectiveness of 5-HTP (R).
The antidepressant effects of 5-HTP are comparable to that of some antidepressants (R).
The combined treatment of 5-HTP and SSRIs seem to have strong synergistic effects on serotonin levels in rats and humans so that some clinicians recommend the use of slow-released 5-HTP in combination with SSRIs (R, R2, R3). However, additional clinical trials are required to demonstrate the safety and effectiveness of this approach, and combinations of 5-HTP and medications should only be used under medical supervision.
In a small clinical trial involving 52 healthy male subjects, 5-HTP and an SSRI enhanced serotonin levels by 35% and 100%, respectively. Together, however, they increased serotonin by 500% (R).
2) 5-HTP Helps with Panic Attacks and Anxiety
People who suffer from chronic panic attacks due to lower availability of serotonin in the brain found significant relief through supplementation of 200 mg of 5-HTP (R).
In human clinical trials, herbal extracts of 5-HTP were shown to activate GABA receptors or increase GABA levels, promoting a sense of relaxation and decreased anxiety (R).
3) 5-HTP Helps with Nightmares in Children
Children aged 3-10 who suffer from nightmares had a reduction of 93.5% after taking a supplement of 2 mg/kg every night before bed for a month (R).
4) 5-HTP Helps Reduce Appetite, Craving, and Weight Loss
Carbohydrates increase serotonin levels in the brain, and increasing serotonin levels, such as by supplementing with 5-HTP, can mitigate carbohydrate craving and appetite, thus helps with adherence to dietary interventions and weight loss (R, R2).
5) 5-HTP Supports Successful Dietary Intervention in Type II Diabetes
In a 2-week long clinical trial involving 25 overweight diabetic subjects given no dietary restrictions, subjects who received 5-HTP had reduced caloric, carbohydrate, and fat intake compared to placebo. Subjects who received 5-HTP also have reduced body weight, blood sugar, insulin, and HbA1C levels after 2 weeks, possibly due to changes in the diet (R).
6) 5-HTP Helps Improve Sleep Quality
In a person with a genetic mutation that caused serotonin deficiency, it resulted in a lack of a circadian rhythm and overeating. For this person, supplementation with 5-HTP restored a normal circadian rhythm and food intake (R).
Over long periods of supplementation, production of GABA receptors increased, which assisted with natural sleep cycles and the promotion of healthy sleep (R).
A small clinical trial demonstrated that the use of 5-HTP in combination with GABA significantly improved sleep quality in 9 subjects with sleep disorders, in comparison to placebo (R).
7) 5-HTP may Help Mitigate Neurological Symptoms of Phenylketonuria
5-HTP relieves neurological symptoms due to phenylketonuria in mice (R).
8) 5-HTP Helps Restore Serotonin Levels After a Spinal Cord Injury
In rats with simulated spinal cord injury, supplementation with 5-HTP restored normal levels of serotonin (R).
The absence of increased 5-HTP activity in the dorsolateral prefrontal cortex correlates with premenstrual irritability (R).
While it is possible that 5-HTP supplementation may help with premenstrual symptoms, there is currently no clinical study available to support this benefit of 5-HTP.
5-HTP Benefits Over Tryptophan
1) 5-HTP is Readily Made into Serotonin
The amino acid tryptophan is converted to 5-HTP before it is converted to serotonin. TPH1 and TPH2, the enzymes responsible for converting tryptophan to 5-HTP, are the slowest (rate-limiting) enzymes in serotonin production (R).
5-HTP is readily and freely converted to serotonin without biochemical inhibition.
2) 5-HTP Readily Crosses the Blood-Brain Barrier
Tryptophan competes with leucine, valine, tyrosine, and isoleucine to cross the blood-brain barrier (R).
5-HTP, however, does not compete with other amino acids to enter the brain.
5-HTP readily crosses the blood-brain barrier without receptors or channels.
Serotonin does not cross the blood-brain barrier, so serotonin outside of the brain (in the gut, platelets, heart, and liver) stays separate from serotonin in the brain.
5-HTP gets converted into serotonin both inside and outside of the brain.
3) 5-HTP is Only Made Into Serotonin
While tryptophan can be used for protein synthesis and turning into niacin, 5-HTP can only be used for converting into serotonin (R).
4) 5-HTP Bypasses Neurotoxic Tryptophan Metabolites
Tryptophan can be converted into kynurenic acid and quinolinic acid, which are involved in psychiatric disorders such as schizophrenia, anxiety, depression, and ADHD (R).
5-HTP is not directly converted into neurotoxic metabolites, but high levels of serotonin may indirectly increase these metabolites (R).
Risks and Side Effects of 5-HTP Supplementation
1) 5-HTP can Cause Nausea and Vomiting
Since serotonin in the digestive system controls gut movement, all interventions that increase serotonin levels, including 5-HTP supplementation and SSRI antidepressants, can cause nausea, vomiting, and diarrhea.
Slow-released 5-HTP may be better tolerated and less likely to cause side effects (R).
2) Long-Term Supplementation with 5-HTP can Deplete Dopamine, Norepinephrine, and Epinephrine
Long-term supplementation of 5-HTP can cause imbalances of these neurotransmitters, which can worsen neurological and psychiatric diseases. It is therefore recommended that 5-HTP supplementation is supervised by qualified clinicians and balanced with neurotransmitter precursors (R).
In cases where there is too much 5-HTP, it will reduce dopamine synthesis as a result of overwhelming the AAAD enzyme through competitive inhibition, leading to depletion of dopamine, norepinephrine and other neurotransmitters (R).
With increasing doses of 5-HTP, MAO activity increases. When this happens, MAO can then break down dopamine and cause it to decrease (R).
3) 5-HTP and Serotonin Syndrome
Serotonin syndrome explains a set of symptoms caused by very high levels of serotonin, which can be very serious and life-threatening (R).
Mild symptoms include shivering, sweating, tremor, restless limbs, and headache. Serious symptoms include hypertension, fever, mania, hallucination, and ataxia (R).
Serotonin syndrome is almost exclusively caused by SSRI and MAOI combinations, causing excessive levels of serotonin in the brain (R).
4) 5-HTP and Eosinophilia-Myalgia Syndrome
Eosinophilia-myalgia syndrome (EMS) is a disease causing severe, disabling, chronic muscle pain, skin symptoms, and other neurotoxic reactions which have affected over 1,500 people and caused at least 38 deaths. The FDA estimated that there are 10 EMS cases associated with 5-HTP worldwide (R).
It seems more likely that it is caused by a bacterial contamination in the supplement than tryptophan or 5-HTP itself. No new cases of supplement-related EMS have been reported since 1990 (R).
Other Side Effects
It is not possible to measure serotonin levels in a human brain without a brain biopsy. Indirect markers that are good indicators of serotonin levels in the brain are cortisol levels and blood or urinary HIAA levels (R, R2).
5-HTP Absorption and Elimination
5-HTP is rapidly absorbed in the upper intestine, with 50% of 5-HTP absorbed in 1.5 hours (R).
Elimination of 5-HTP is also rapid, with 50% absorbed in 2 hours (R).
Due to the rapid pharmacokinetics of 5-HTP, slow-release supplementation of 5-HTP may be more beneficial to maintain serotonin levels in the brain (R).
About 70% of ingested 5-HTP is found in the bloodstream (R).
Patients who take 5-hydroxytryptophan have severely decreased levels of P450 expression, (R).
200 mg is safe and beneficial for increasing serotonin levels in the brain, although some studies have shown safety and effectiveness when titrating doses up to 3 grams per day (R). Higher dosages increase the likelihood of side effects.