(NB: 5-HTP = 5-Hydroxytryptophan. 5-HT = serotonin. MAO = monoamine oxidase, and MAOI = monoamine oxidase inhibitor. 5-HT2A & C are serotonin receptor subtypes)
As a long standing 5-HTP advocate, I was a bit worried when I came across this page.
The author claims that oral 5-HTP is likely to cause cardiac fibrosis.
He notes that 5-HTP is readily converted to 5-HT in the liver by aryl amino acid decarboxylase, which is B6 dependent. He notes that this 5-HT will then pass up the portal vein to the inferior vena cava, and pass through the right side of the heart, where he claims it will cause fibrosis (scarring) of the valves. From here, it will go up the pulmonary artery to the lungs and be metabolized to 5-HIAA by pulmonary MAO. This action of MAO in the lungs makes venous samples for 5-HT poor tests for assessing 5-HT production from the GI tract or liver.
He compares this process with the production of 5-HT by gastrointestinal carcinoid tumors, which are known to produce large amounts of serotonin, and which are also correlated with a characteristic pattern of mostly right sided cardiac fibrosis (consisting of dense fibrous deposits - primarily on the tricuspid valve, but also occurring on the pulmonary valve, eventually leading to right-sided heart failure). He correctly notes that the degree of 5-HT production has been shown to be an important predictor of the progression of cardiac fibrosis.
He also comments on the histologically identical lesions found with drugs with 5HT2 agonist activity such as dexfenfluramine, fenfluarmine and other 5-HT2-preferring ergot drugs.
He claims that concomitant B6 supplementation will make this process worse, to the point where almost no 5-HTP will make its way to the brain to be converted to 5-HT.
![:\](https://bluelight.org/xf/BL_Images/Orig_Emoji/wrygrin.gif "wry grin :\")
...so, I’ve done a bit of reading. I’ve found that there are indeed 5-HT2B and 5-HT2C receptors known to exist in large amounts in human heart valves, and interaction of 5-HT with these receptors is known to cause fibroblast mitosis.
50 – 85% of an oral dose of 5-HTP is absorbed. Around 25% of this is broken down by hepatic aromatic L-amino acid decarboxylase (to 5-HT) before entering the bloodstream, so only 38 – 64% of the dose actually ends up as extra serotonin in the brain when 5-HTP is taken orally as a dietary supplement.
5-HIAA levels are going to correlate to total MAO activity – in the gut, liver, brain (5-HIAA is actively transported back across the blood-brain barrier for excretion) AND lungs. This means that urinary 5-HIAA levels may correlate poorly to portal vein 5-HT levels.
While around 25% of an oral dose of 5-HTP is going to be converted to 5-HT in the liver, I’d note that the liver also contains a large amount of MAO. I am unclear as to how much of this 5-HT made in the liver is going to reach the portal vein, but I suspect that it is a very small amount - 91% of carcinoid tumors associated with cardiac fibrosis have already metastasized either to the liver itself, or to parts of the body with venous drainage that avoids hepatic first pass metabolism before entering the right heart. As metastatic deposits derange liver architecture and inhibit liver function, I feel that this indicates that hepatic MAO activity is difficult to overwhelm in otherwise healthy individuals.
Additionally in normal individuals 80% of total body 5-HT comes from gastrointestinal enterochromaffin cells. This 5-HT will also make its way up the portal vein to the liver. Given that normal individuals do not develop cardiac fibrosis, this again suggests good hepatic MAO activity.
If decarboxylation happened proximal histologically to MAO concentrations, I suppose there could be a problem, but I think that this is relatively unlikely (if anyone has any info on this, it would be appreciated).
B6 is prevalent in the diet, and deficiency is relatively uncommon (although it can occur with anti-TB agent isoniazid, penicillamine and with estrogen+/-progesterone therapy – as in contraceptive agents). Thus normal people will have adequate B6 in their livers to assist the decarboxylase enzyme. This said, B6 is contraindicated in L-DOPA therapy without concomitant decarboxylase inhibition precisely because B6 increases the rate at which hepatic decarboxylase converts L-DOPA to dopamine.
Carboxylase inhibitors such as carbidopa are generally given with dopamine, as they reduce nausea produced by dopamine at D2 receptors on the blood side of the blood brain barrier. This implies that moderate amounts of dopamine manage to manage to avoid hepatic and pulmonary MAO after oral L-DOPA administration.
To summarize, 5-HT has a plausible mechanism for causing cardiac fibrosis, and evidence from carcinoid tumor patients and problems resulting from 5HT2 agonist appetite suppressants supports this role. The effect is going to correlate to 5-HT dose delivered to the right side of the heart. This dose is unable to be measured indirectly with urinary 5-HIAA levels, as these will be contributed to by pre-hepatic, hepatic and brain MAO (representing 5-HT that has not been exposed to the right side of the heart) as well as pulmonary MAO (representing 5-HT that has). Given normal enterochromaffin production of 5-HT and carcinoids distal to the liver generally does not cause fibrosis, it seems that hepatic MAO action is robust. However, experience with L-DOPA and carbidopa shows that some monoamine is able to get through.
The only way to really test this would be sampling portal venous 5-HT concentrations post oral 5-HTP dose. I don’t have full access to any research databases, but to the best of my searching ability, this has not been done.
However, weighing all the data, I would say that intermittent short-term use of 5-HTP is likely to be safe. I’m a little less sure re: daily use, but again, I think that moderate doses are also likely to be safe. Apparently 5HTP has been used in medicine in France and Italy for ~30 years - in some cases at very high doses (~2000mg / day) – without anyone noting cardiac side effects.
I’d suggest that 5-HTP would be best consumed with carbidopa, although sadly carbidopa is a little difficult to obtain. It has been used this way without ill effect in numerous medical trials in humans without ill effect. I note that your 5-HTP FAQ states that carbidopa is contraindicated with 5-HTP, and suggest that this is incorrect.
Phew. Any input would be welcome.
As a long standing 5-HTP advocate, I was a bit worried when I came across this page.
The author claims that oral 5-HTP is likely to cause cardiac fibrosis.
He notes that 5-HTP is readily converted to 5-HT in the liver by aryl amino acid decarboxylase, which is B6 dependent. He notes that this 5-HT will then pass up the portal vein to the inferior vena cava, and pass through the right side of the heart, where he claims it will cause fibrosis (scarring) of the valves. From here, it will go up the pulmonary artery to the lungs and be metabolized to 5-HIAA by pulmonary MAO. This action of MAO in the lungs makes venous samples for 5-HT poor tests for assessing 5-HT production from the GI tract or liver.
He compares this process with the production of 5-HT by gastrointestinal carcinoid tumors, which are known to produce large amounts of serotonin, and which are also correlated with a characteristic pattern of mostly right sided cardiac fibrosis (consisting of dense fibrous deposits - primarily on the tricuspid valve, but also occurring on the pulmonary valve, eventually leading to right-sided heart failure). He correctly notes that the degree of 5-HT production has been shown to be an important predictor of the progression of cardiac fibrosis.
He also comments on the histologically identical lesions found with drugs with 5HT2 agonist activity such as dexfenfluramine, fenfluarmine and other 5-HT2-preferring ergot drugs.
He claims that concomitant B6 supplementation will make this process worse, to the point where almost no 5-HTP will make its way to the brain to be converted to 5-HT.
...so, I’ve done a bit of reading. I’ve found that there are indeed 5-HT2B and 5-HT2C receptors known to exist in large amounts in human heart valves, and interaction of 5-HT with these receptors is known to cause fibroblast mitosis.
50 – 85% of an oral dose of 5-HTP is absorbed. Around 25% of this is broken down by hepatic aromatic L-amino acid decarboxylase (to 5-HT) before entering the bloodstream, so only 38 – 64% of the dose actually ends up as extra serotonin in the brain when 5-HTP is taken orally as a dietary supplement.
5-HIAA levels are going to correlate to total MAO activity – in the gut, liver, brain (5-HIAA is actively transported back across the blood-brain barrier for excretion) AND lungs. This means that urinary 5-HIAA levels may correlate poorly to portal vein 5-HT levels.
While around 25% of an oral dose of 5-HTP is going to be converted to 5-HT in the liver, I’d note that the liver also contains a large amount of MAO. I am unclear as to how much of this 5-HT made in the liver is going to reach the portal vein, but I suspect that it is a very small amount - 91% of carcinoid tumors associated with cardiac fibrosis have already metastasized either to the liver itself, or to parts of the body with venous drainage that avoids hepatic first pass metabolism before entering the right heart. As metastatic deposits derange liver architecture and inhibit liver function, I feel that this indicates that hepatic MAO activity is difficult to overwhelm in otherwise healthy individuals.
Additionally in normal individuals 80% of total body 5-HT comes from gastrointestinal enterochromaffin cells. This 5-HT will also make its way up the portal vein to the liver. Given that normal individuals do not develop cardiac fibrosis, this again suggests good hepatic MAO activity.
If decarboxylation happened proximal histologically to MAO concentrations, I suppose there could be a problem, but I think that this is relatively unlikely (if anyone has any info on this, it would be appreciated).
B6 is prevalent in the diet, and deficiency is relatively uncommon (although it can occur with anti-TB agent isoniazid, penicillamine and with estrogen+/-progesterone therapy – as in contraceptive agents). Thus normal people will have adequate B6 in their livers to assist the decarboxylase enzyme. This said, B6 is contraindicated in L-DOPA therapy without concomitant decarboxylase inhibition precisely because B6 increases the rate at which hepatic decarboxylase converts L-DOPA to dopamine.
Carboxylase inhibitors such as carbidopa are generally given with dopamine, as they reduce nausea produced by dopamine at D2 receptors on the blood side of the blood brain barrier. This implies that moderate amounts of dopamine manage to manage to avoid hepatic and pulmonary MAO after oral L-DOPA administration.
To summarize, 5-HT has a plausible mechanism for causing cardiac fibrosis, and evidence from carcinoid tumor patients and problems resulting from 5HT2 agonist appetite suppressants supports this role. The effect is going to correlate to 5-HT dose delivered to the right side of the heart. This dose is unable to be measured indirectly with urinary 5-HIAA levels, as these will be contributed to by pre-hepatic, hepatic and brain MAO (representing 5-HT that has not been exposed to the right side of the heart) as well as pulmonary MAO (representing 5-HT that has). Given normal enterochromaffin production of 5-HT and carcinoids distal to the liver generally does not cause fibrosis, it seems that hepatic MAO action is robust. However, experience with L-DOPA and carbidopa shows that some monoamine is able to get through.
The only way to really test this would be sampling portal venous 5-HT concentrations post oral 5-HTP dose. I don’t have full access to any research databases, but to the best of my searching ability, this has not been done.
However, weighing all the data, I would say that intermittent short-term use of 5-HTP is likely to be safe. I’m a little less sure re: daily use, but again, I think that moderate doses are also likely to be safe. Apparently 5HTP has been used in medicine in France and Italy for ~30 years - in some cases at very high doses (~2000mg / day) – without anyone noting cardiac side effects.
I’d suggest that 5-HTP would be best consumed with carbidopa, although sadly carbidopa is a little difficult to obtain. It has been used this way without ill effect in numerous medical trials in humans without ill effect. I note that your 5-HTP FAQ states that carbidopa is contraindicated with 5-HTP, and suggest that this is incorrect.
Phew. Any input would be welcome.
Sorry for the OT, but I'm a curious cat! Meow! %)
