We've received a few calls lately with questions regarding the safety of 5-hydroxytryptophan (5-HTP). We decided that the simplest, most complete and most direct way to answer these questions specifically is to do so in a Question & Answer format. What follows is an item by item response to some of the myths floating around:
Q: Does serotonin circulating in the body cross the blood-brain barrier?
A: Not to any significant degree. Because of the size of the serotonin molecule, it cannot readily cross the blood brain barrier. Therefore, it is necessary to ensure that adequate levels of serotonin are produced in the brain to prevent serotonin deficiency problems.
Q: Is 5-HTP converted to serotonin (decarboxylated) before it crosses the blood brain barrier? Do we end up with serotonin in the blood and peripheral tissues but not in the brain?
A: Some is, some isn't. Some of the tryptophan in your diet - the upstream mother precursor - gets converted to serotonin in the brain, and some becomes serotonin in your blood and peripheral tissues. Studies have shown that 5-HTP taken orally by itself also increases serotonin levels in the brain.1 And, as is the case with tryptophan, production of serotonin from 5-HTP is divided - some 5-HTP is converted to serotonin in the periphery (before reaching the brain), and some is converted in the brain.2 Whatever the percentage split, 5-HTP has been shown (see Issue # 27) to compare favorably to Prozac and other SSRIs for alleviating depression. This is attributed to 5-HTP's ability to increase levels of serotonin in the brain.
Q: I understand that when Europeans take 5-HTP, they take it with a peripheral decarboxylase inhibitor, such as carbidopa or benserazide. Does this mean that carbidopa must be used to get desirable results when taking 5-HTP?
A: No, quite a few studies have been done with 5-HTP in humans in which the 5-HTP was given with nothing else. 5-HTP works as well (if not better) when used without peripheral decarboxylase inhibitors.3Moreover, side effects have been found to be greater with peripheral decarboxylase inhibitors than without. A review of the scientific literature found that 5-HTP given alone had better results (249/389 subjects were found improved) than when 5-HTP was used with a peripheral decarboxylase inhibitor (93/176 subjects). This represents a significant superiority of 21% (64% vs 52.9%) for 5-HTP alone over 5-HTP with a peripheral decarboxylase inhibitor.
Q: Does vitamin B6 cause 5-HTP to rapidly convert into serotonin before it even reaches the brain? Does this mean you don't get an increase of brain serotonin?
A: No, actually quite the opposite. In one notable study on rats, vitamin B6 deficiency was deliberately induced. It was discovered that very little serotonin was produced in the rat brain when deficient in B6.4
In other experiments with monkeys and rats, the presence of ample amounts of B6 - even to the point of "moderate excess" - increased production of serotonin (in the brain) from 5-HTP by up to 60%.5,6 Once again, it is clear that 5-HTP raises brain serotonin levels - with or without carbidopa or benserazide, and with or without vitamin B6. But the evidence indicates that it's better to take 5-HTP without carbidopa or benserazide and with vitamin B6.7
Q: I've heard that the elevation of blood serotonin levels (caused by taking 5-HTP) can cause coronary artery spasm, abnormal platelet aggregation, and increased risk of death by sudden heart attack.
A: That would certainly be a concern, if it were true. However, we could find nothing in the scientific literature to support these contentions.
Q: People with a particular (and rare) type of serotonin-secreting tumor called hindgut carcinoid, also have various heart problems, such as fibrosis of the endocardium and right heart valves, and heart failure. Should they avoid 5-HTP?
A: That's also pretty scary - until you consider the fact that these conditions have nothing to do with 5-HTP. This rare disease (carcinoid) is associated with extremely high serotonin levels (much, much higher than are obtainable by taking recommended doses of 5-HTP). It's true that this disease, in a very few instances, is associated with the heart problems mentioned above. However, nobody who has studied carcinoid thoroughly would jump to the conclusion that 5-HTP or another serotonin precursor might cause it! There is no evidence to support an initiatory role for serotonin in hindgut carcinoid or any other disease, nor to justify the contention that 5-HTP can cause the kinds of dramatic increases in serum serotonin levels associated with carcinoid tumors. Furthermore, even if 5-HTP caused huge increases in serum serotonin levels - which it has not been demonstrated to do - there is no evidence that this, in itself, would be harmful or that it could increase heart valve problems.8 In fact, in cats, 5-HTP-induced serotonin production has been found to reduce vulnerability to ventricular fibrillation.9 (One caution, however, for anyone with this rare type of carcinoid tumor: Since there is a statistical correspondence between serum levels of serotonin and valvular heart disease in some patients with carcinoid tumors (19 out of 604 in the Duke study),10 it is inadvisable at this time for those with carcinoid cancer to take supplemental 5-HTP.)
Q: It has been reported that a tribe of South Sea Islanders gets right heart fibrosis from eating green banana mash because the green bananas poison them with serotonin. Should I be concerned?
A: The story of these South Sea islanders is complex, and nobody is really sure what is going on yet. Yes, it is true that bananas, especially certain types, contain high serotonin levels. But when high serotonin diets have been examined in the literature, elevations of serum serotonin have not been consistent or on the order of that seen in carcinoid patients.11
Q: Is 5-HTP safe only if you regularly test your 5-HIAA urine levels and make sure they remain normal?
A: 5-HIAA is a metabolite of serotonin, so this test would tell you if you had high blood levels of serotonin. However, there is no evidence that taking 5-HTP can drive your serotonin levels to the many multiples characteristic of carcinoid patients.
Q: Would aspirin and magnesium reduce the risk of 5-HTP causing a heart attack?
A: Aspirin and magnesium will probably reduce your risk of a heart attack in general. But once again, there is no reason to think that 5-HTP might cause a heart attack.
Q: Could some people suffer from a lethal serotonin overload?
A: There is no evidence of this.
Q: What about published studies which indicate that tryptophan does not convert into serotonin in the blood, but 5-HTP does?
A: Most of the tryptophan and 5-HTP in your diet converts to serotonin in your blood. It is estimated that only about 1 to 2% of your total serotonin crosses the blood-brain barrier and enters brain cells.
Q: Is it true that 5-HTP will not work for most people and could be deadly to others?
A: This is in total contradiction to the vast amount of published data. The studies indicate a very high responsiveness to 5-HTP. There is no evidence that 5-HTP has ever been deadly to anyone. Furthermore, there is no theoretical reason for suspecting this. By the way, there are nearly 5,000 papers referencing 5-HTP in the electronically referenced literature.
Boranic M, Pericic D, Poljak-Blazi M, Sverko V. Suppression of the immune response by drugs interfering with the metabolism of serotonin. Experientia 1984;40:1153-1155.
Takahashi S. Reduction of blood platelet serotonin levels in manic and depressed patients. Folia Psychiat Neurol Jap. 1976;30:475-486.
Zmilacher K, Battegay R, Gastpar M. L-5-hydroxytryptophan alone and in combination with a peripheral decarboxylase inhibitor in the treatment of depression. Neuropsychobiology 1988:20-28- 33.
Dakshinamurti K, LeBlancq WD, Herchl R, Havlicek V. Nonparallel changes, in brain monoamines of pyridoxine deficient growing rats. Exp Brain Res. 1976;26:355-366.
Hartvig P, Lindner KJ, Bjurling P, Langstrom B, Tedroff J. Pyridoxine effect on synthesis rate of serotonin in the monkey brain measured with positron emission tomography. J Neural Trans 1995;102:91-97.
Dakshinamurti K, Sharma SK, Bonke D. Influence of B vitamins on binding properties of serotonin receptors in the CNS of rats. Klin Wochenschr 1990;68:142-145.
Siow YL, Dakshinamurti K. Effect of pyridoxine deficiency on aromatic L-amino acid decarboxylase in adult rat brain. Exp Brain Res. 1985;59:575-581.
Jacobsen MB, Nitter-Hauge S, Bryde PE, Hanssen LE. Cardiac manifestations in mid-gut carcinoid disease. Eur Heart J 1995;16:263-268.
Lehnert H, Lombardi F, Raeder EA, Lorenzo AV, Verrier RL, Lown B, Wurtman RJ. Increased release of brain serotonin reduces vulnerability to ventricular fibrillation in the cat. J Cardiovasc Pharmacol 1987;10:389-397.
Robiolio PA, Rigolin VH, Wilson JS, Harrison JK, Sanders LL, Bashore TM, Feldman JM. Carcinoid heart disease: Correlation of high serotonin levels with valvular abnormalities detected by cardiac catheterization and echocardiography. Circulation 1995;92:790-795.
Hoshino Y, Kaneko M, Takahashi Y et al. Serum serotonin levels of normal subjects in physiological state and stress conditions. From the viewpoint of aging, circadian rhythm, ingestion of diet, physical exercise, sleep deprivation and alcohol ingestion. Jpn J Psychosom Med 1979;19:283-293.