From: firstname.lastname@example.org(Steven B. Harris) Subject: 5-HTP + B6 = Trouble; Doc Harris Presents Green Banana Award (was: US ban on tryptophan) Date: 29 Dec 1996 Newsgroups: sci.med.nutrition,sci.med,sci.pharmacy,misc.health.alternative, sci.life-extension,alt.support.depression Simon Friedman <email@example.com> wrote: Jack Challem wrote: > If you look around, you will find a few companies now selling tryptophan supplements to doctors in the US. The molecular structure is slightly different, basically just the immediate precursor molecule. I checked with my FDA contact, and he said yes, it's true.< >>You can also buy 5-hydroxytryptophan from at least 2 mail-order outlets that I know of. 5-HTP is the next step in metabolism from trypophan on its way to become serotonin. Simon<< ------------------------------------------------------------ Comment: Yes, and in fact 5-HTP needs only one more step to become serotonin-- a decarboxylation. The sequence is: Tryptophan --> 5-HTP --> Serotonin. An exactly analogous sequence is: Tyrosine --> L-DOPA --> Dopamine In both cases the end product neurotransmitter does not get across the blood brain barrier very well, but all of the precursor molecules above are transported by the brain's large neutral amino acid pump, and they get into the brain fine. Thus, if you are a Parkinson's patient who wants to raise dopamine levels, you must take L-DOPA, not dopamine. Similarly, it would do you no good to take serotonin-- you must take tryptophan or 5-hydroxytryptophan (5-HTP). Now for the complications. (Aren't there always complications in life?) The final reaction to the neurotransmitter in both the case of dopamine and serotonin, is decarboxylation, and the same enzyme (the aromatic L-amino acid decarboxylase) is involved in both conversions. This decarboxylase enzyme is present in the liver, and it acts in the case of L-DOPA to convert the compound to dopamine before it can make it into the brain (and if this happens, the L-DOPA is wasted). The decarboxylase enzyme uses B6 as a cofactor for this reaction, and for this reason a Parkinson's disease patient taking L-DOPA cannot take more than the RDA of B6, because doing so would act to neutralize oral L-DOPA too quickly. These days, almost all Parkinson's patients on L-DOPA take the drug in a combination with an artificial decarboxylase inhibitor, called Carbidopa (the combination is called Sinemet). But even with Carbidopa, Parkinson's patients are advised not to exceed a daily dose of B6 of 25 mg, since more will overwhelm the Carbidopa effect, and cause pharmacologic L-DOPA to be destroyed in the liver before it can get into the brain. Now, Carbidopa, because it acts on the same metabolizing enzyme in the liver, performs exactly the same preservative service for 5-HTP as for L-DOPA. For this reason, neurologists have experimented with giving Carbidopa to people who needed to take 5-HTP to raise brain serotonin (this in the days before selective serotonin re-uptake inhibitor antidepressants like Prozac were available). The problem today with 5-HTP-selling companies bypassing doctors and going to laymen, is that a lot of health enthusiasts with problems who are enthusiastically taking 5-HTP are NOT taking Carbidopa, but they ARE taking a lot of B6 in one form or another. Yet without Carbidopa, more than a few milligrams of extra B6 per day would be expected to insure that most dietary 5-HTP gets turned into serotonin before it can get into the brain. Alas, one company I know packages their 5-HTP in 50 mg capsules with 10 mg of B6. They do this ostensibly so that 5-HTP can be converted to serotonin in the brain. Duh. This insures that any 5-HTP will get converted to serotonin in the liver instead, and thus never make it to the brain. Vitamin B6 is the *LAST* thing you want in an 5-HTP product. At the very best, people who take B-vitamins with 5-HTP, or who take 5-HTP products with B6, waste their money. All this would be merely humorous (caveat emptor) were it not for some other facts. At worst, ignorant people fooling with 5-HTP actually risk their health, since serotonin in the peripheral blood is not benign. Serotonin causes not only harmless flushing and diarrhea, but people with serotonin secreting tumors (hindgut carcinoids) also have problems with fibrosis of the endocardium and valves in their right hearts, which can cause heart failure. This fibrosis is caused by the serotonin. This effect can also be seen with dietary intake of only modest amounts of serotonin, and there has actually been described in the medical literature a tribe of South Sea islanders with right heart fibrosis as a result of eating green banana mash (matuki), which poisons them with its serotonin content. No, I'm not making this up. The hydroxylation of tryptophan is a rate-limiting step in the peripheral production of serotonin, and one bypasses it at one's peril. How much does it take? Several hundred milligrams of 5-HTP taken per day, if converted to serotonin, would result in a urinary excretion of the serotonin metabolite 5-hydroxyindoleac- etic acid (5-HIAA) of several hundred milligrams also-- an amount well within the urinary excretion range of the average person with a serotonin producing carcinoid. Such a dose of 5-HTP certainly would result in a serotonin blood load comparable to that of green-banana-diet eating people who have serotonin-induced heart valve disease. Normally, people do not excrete breakdown products of more than 10 mg of serotonin metabolites per day. If you take one capsule per day of 50 mg 5-HTP with 10 mg B6, however, you would be expected to go to at least 50 mg per day of 5-HIAA in the urine. Less metabolism in the liver (less B6) would result in less 5-HIAA in the urine. If you are going to take 5-HTP, therefore, you probably need 5-HIAA urine monitoring, to figure out just how big a dose of systemic serotonin you're actually getting (and incidentally, how much 5-HTP you're wasting). See a doctor! For all the reasons outlined above, I am presenting those vitamin companies who sell 5-HTP with B6, or who sell it alone but don't warn their customers about 5-HIAA monitoring or B6 intake, a special award: the Green Banana Award. This honor is for those supplement-sellers who monkey around with people's health before consulting with some really good nutrition and medical specialists to make sure they don't f*&% up and hurt somebody. Hopefully, companies which receive the Green Banana Award will contemplate its message, and will thereby change their behavior in order to avoid some of the less-coveted awards which otherwise await them in the future: the Civil Damage Award, for instance, or even the All-Expense-Paid Guest of the Federal Government Award. Steven B. Harris, M.D.
From: firstname.lastname@example.org(Steven B. Harris) Subject: Re: 5-HTP + B6 = Trouble; Doc Harris Presents Green Banana Award (was: US ban on tryptophan) Date: 30 Dec 1996 Newsgroups: sci.med.nutrition,sci.med,sci.pharmacy,misc.health.alternative, sci.life-extension,alt.support.depression In <email@example.com> firstname.lastname@example.org (Robert A. Walston) writes: >Does anyone else have information regarding 5-hydroxy tryptophan and >the heart fibrosis problem Dr. Harris discusses? I just ordered some >50 mg capsules (without B-6), and now I am hesitant to take them. >Would the same warning apply to tryptophan itself? Were all of us who >received such wonderful relief from insomnia from tryptophan before >the FDA took it off the market endangering our lives? If tryptophan >itself doesn't create excess serotonin in the bloodstream and 5HTP >does, then maybe I should have ordered pharmaceutical grade tryptophan >(available as a veterinary supplement) instead! Also, is there a real >risk from taking just 50 mg of 5HTP a night (and no supplemental B-6)? >Any information would be appreciated. > >-Bob Walston > The same warning does NOT apply to tryptophan, because the hydroxylation of tryptophan to 5-HTP is rate limiting, and happens essentially only in nervous system tissue. It's bypassing this by eating 5-HTP or serotonin which is the problem. Pure tryptophan is not dangerous. Whether taking 50 mg of 5-HTP will give you problems, I don't know, as I do not know what is the lowest dose of serotonin which has been reported to cause the cardiac fibrosis (I'll let you know after some further research). And also (again) whether all of a 50 mg dose of 5-HTP gets turned into serotonin in your liver, will depend on your vitamin status. If you don't take any supplements at all, you're in much better shape in this regard, than if you do. As I noted, the only way to really be sure is to do a 24 hour urine collection for the serotonin metabolite 5-HIAA (5-hydroxyindole acetic acid). Steve Harris, M.D.
From: email@example.com(Steven B. Harris) Subject: Re: Dumb Question? About Amino Acids prescription Date: Fri, 31 Oct 1997 Newsgroups: misc.health.alternative,sci.med.nutrition,sci.life-extension In <34588282.5FEC@voicenet.com> neiGHBor <firstname.lastname@example.org> writes: >> Somebody's going to get valve damage from 5-HT and sue Life >> Enhancement. And I imagine the defence is going to be: "How could WE >> have KNOWN??" >You mean 5-htp also right? Since that turns into 5-ht. How much 5-htp >would you consider safe? Is 50 mg per night with 10 mg b6 too much? > >Or maybe you meant 5-htp all along. Either way please tell me. Yeah, these abbreviations are not standardized, and I mix them up. 5-hydroxytryptAMINE (= 5-HT = serotonin) is what causes heart damage. Never eat it. It doesn't get into the brain anyway, since it's not transported by the large neutral amino acid transport system. 5-hydroxytrytophan (5-HTP) is what's sold as a serotonin brain precursor. It is taken up into the brain. If you could keep if from getting converted to serotonin in the liver, you'd be in great shape. Taking 10 mg of B6 a day, however, is going to get most of it converted to serotonin before it has a chance to get into the brain. 50 mg a day without carbodopa is too much, since most of it will get converted to serotonin, and 50 mg a day of "outside the brain" serotonin or so is about the amount associated wtih heart damage in carcinoid syndrome. Steve Harris, M.D.
From: email@example.com(Steven B. Harris) Subject: Re: 5-HTP doesn't seem to convert to 5-HT in the bloodstream, only in the brain. Date: Tue, 04 Nov 1997 Newsgroups: alt.dreams.lucid,misc.health.alternative,sci.life-extension In <345E6576.firstname.lastname@example.org> neiGHBor <email@example.com> writes: >But that study said that even when they put tryptophan in the blood, >5-htp levels in the blood rose. >Does tryptophan turn into 5-htp in the blood only when high amounts of >tryptophan are put into the bloodstream? Otherwise shouldn't lots of >5-htp be entering the brain in people with a normal diet? I think this is correct-- otherwise normal tryptophan eating would cause increases in 5-HTP and 5-HT and urine 5-HIAA (as in the paper). But none of this happens to normal people, who excrete less than 10 mg/day of 5-HIAA, and don't have to be careful to eat low tryptophan diets (for instance) when being checked for carcinoid by urine 5-HIAA levels (they do have to avoid bananas and pinapples, though!). All in all, the paper you cite is a strange one, and I cannot explain the results. Must be some odd effect of super massive tryptophan loading. >In the study where they put tryptophan into the bloodstream, 5-htp >levels in the blood rose, so couldn't one look at the effect of diets >high in tryptophan instead? And wouldn't tryptophan with b6 be >dangerous also? As I say, it's never been seen with dietary tryptophan. This must be an odd effect of IV loading of massive amounts. >What do you think is more likley: > > That those Baganda banana mush eaters had high levels of >serotonin in the blood and that that is necessary for the danger. > >OR > > That even barely detectable increases in blood serotonin are >dangerous. I would guess, to tell the truth, that high levels of serotonin in the blood are actually necessary. Blood levels ARE elevated in the carcinoid (the rebuttal paper you cite disputes this, but the latest and best of all the carcinoid studies finds significantly elevated serotonin levels in carcinoid patients with fibrosis, vs carcinoid patients without it). Why didn't serotonin levels go up in the paper you cite? I suggested not enough B6. Perhaps more important, however, is the fact that serotonin will be made from 5-HTP in the liver, and THIS serotonin may not make it though the lungs, which destroy it with monoamine oxidase (to turn it into 5-HIAA), so it never gets to a peripheral vein to be measured as serotonin/5-HT. Thus, the serotonin exists ONLY in the circuit between liver and lungs. Unfortunately, that circuit contains the right heart, which is where the valve disease is in carcinoid, and in serotonin eaters. And that's why the disease is NOT in the left heart, and why urine 5-HIAA levels are a better correlate of heart disease than peripheral serotonin levels, which don't reflect right heart levels when the serotonin comes from liver or gut. So don't pay too much attention to this paper (or, rather, to the conclusions that the 5-HTP sellers draw from it). Interestingly, the valve disease is apparently due to serotonin stimulation of myofibrocytes, which proliferate and go crazy, and make the valves stiff. The process in serotonin-associated valve disease is histopathologically identical to that seen in fenfluramine, ergotomine, and methylsergide valve disease. These latter drugs are one and all serotonin receptor agonists. But fenfluramine and dexfenfluramine aren't susceptable to the lung monoamine oxidase system, and so they (perhaps no surprisingly) produce valve disease on both sides of the heart. This is all an interesting story, some of which has become untangled in just the last few months. Perhaps I should write all this up again for posting here on Usenet. Steve Harris, M.D.
From: firstname.lastname@example.org(Steven B. Harris) Subject: Re: 5-HTP doesn't seem to convert to 5-HT in the bloodstream, only in the brai Date: Wed, 05 Nov 1997 Newsgroups: alt.dreams.lucid,misc.health.alternative In <3345.7247T705T914@CAN_THE_SPAMescape.ca> sgb@CAN_THE_SPAMescape.ca (Syd Baumel) writes: >No, the textbooks say that's the largest fraction in the body as a whole. >To quote from a 1986 pharmacology textbook: "In humans, about 90 percent >of the total serotonin in the body is in enterochromaffin cells in the >gastrointestinal tract; the remaining 10 percent is primarily in the >platelets and brain." As for the 10 mg figure, that's roughly how much >serotonin there is in the entire body, including the CNS's 10%, according >to a scholarly review on serotonin in Drug Topics, October 10, 1994. >Mind you, I don't know to waht extent that 90% in the GI wall is normally >segregated from the rest of the body; if it is, then the difference >between 1 or so mg of serotonin normally present in the rest of the body >and the 50 to 900 mg that the therapeutic dose range of 5-HTP could >achieve is immense and perhaps, as you argue, more than the body can >safely cope with. I'm astonished if it's really true that the stomach neurons have 10 times more serotonin than the brain (I shall check). If the whole system has only 10 mg in it, that's a turnover of the whole pool in 24 hours, since that's about how much is metabolised. Hmmm. >>> In light of the research in which high blood levels of 5-HTP seemingly >>> didn't translate into high blood levels of serotonin, is it possible, >>> perhaps, that the the platelets act as a buffer, soaking up excess >>> plasma serotonin? > >> You don't get high blood levels of serotonin if you take blood after >>it's already been through the lungs. > >That's a good point -- darn it ;-) (yes, I read your follow-up post to >neiGHBor after I posted the message you replied to here). But you still >leave hanging the question of whether the platelets could come to the >rescue. Fenfluramine is a serotonin releaser and reuptake inhibitor, >actions which the body may have a harder time counteracting than merely >having to keep a surge of serotonin in the liver from running amok. Do >you know if fenfluramine also releases serotonin from platelets? I >assume it at least prevents serotonin's reuptake by those platelets. If >it does both, locally in the heart, lungs, etc., we're dealing with a >much more pernicious influence than 5-HTP could possibly be. A good thought (since I throught of it also <g>), but it seems not to be the case. Mice given dexfen have LOWER serotonin levels in blood generally. Dexfen is a plenty good enough S2 agonist on its own, without having to do it's other reuptake and release tricks (which is probably what makes it a long lasting anorectic, when pure SSRI antidepressants generally work only temporarily-- harder to adapt to something that is also a pure agonist). If you give a mouse an overdose of Dexfen, you know what happens? Death by acute pulmonary hypertension and resp arrest in about 15 minutes. The stuff acts directly on lung capillaries via smooth muscle S receptors. And there's that fact that heart lessions with dexfen, like those with the serotonin agonists methylsergide and ergotamine, are bilateral. You don't see that in carcinoid UNLESS the lesions are bronchial and serotonin is making it into the left sided circulation via pulmonary veins. >But that doesn't mean that I'm ready to let 5-HTP off the hook. >Considering how popular it's becoming, there's a crying need for research >to be done to confirm or refute these concerns. Not just the heart, but >the lungs and perhaps skin tissue of people taking 5-HTP for any length >of time should be examined for signs of fibrotic hardening/thickening. Yes, and the sort of peritoneal fibrosis seen in carcinoid and chronic serotinergic agonist drug toxicity (not SSRIs). >Given the fenfluramine experience, a large sample size wouldn't be >necessary, at least as far as the heart damage is concerned -- in fact, >any doctor who prescribes it to more than a handful of patients could >potentially come up with useful data. > >Syd Yep. Steve
From: email@example.com(Steven B. Harris) Newsgroups: misc.health.aids,misc.health.alternative,sci.med,sci.med.pharmacy Subject: Re: 5-HT and Heart Risk (was: Vitamin Vultures (was Re: Life Extension HIV protocol) Date: 3 Dec 1998 18:57:58 GMT In <firstname.lastname@example.org> "kean" <email@example.com> writes: >Steve Harris, said: ><(for example, they don't sell 5-HT because of me), but otherwise their >supplement division is planned and run by other folks.> > > >If you don't mind me asking, why did you not want them to sell 5-HTP? > >Maureen in Mukilteo Comment: 5 hydroxytryptophan or 5-HTP (but not so much tryptophan) is converted in the liver to 5-hydroxytryptamine/serotonin (5-HT), which is not something you should have a lot of in your blood (it's nice to keep it behind the blood brain barrier). Chronic use of drugs that act on serotonergic receptors on cardiac myocytes (ergotomine, methylsergide) have been known to cause fibrosis and pulmonary hypertension from vessel constriction, and also (more dangerously) a hypertrophic proliferation of endocardial cells that causes valve problems. Serotonin itself does all this if it gets into the blood in quantity, and people with (carcinoid) mid-gut tumors that dump serotonin into the blood, sometimes get this kind of (easy to diagnose on autopsy) valve disease. As ALSO do West Africans who eat too much matoki, a green banana staple full of serotonin. (That pretty much does it for the argument that the carcinoids are making something else which causes the valve problems-- if they do, it's something also in green bananas BESIDES serotonin. Which would be something that would rack up as up there with the worst bad coincidences in medicine to date; and that's not all--- read on) Not long ago there was a diet drug called fenfluramine which was (among other properties) a direct serotonin agonist (as shown by its ability to cause instant overdose death in animals by pulmonary hypertension), just like the ergot drugs and serotonin itself-- but not like SSRI antidepressants that raise serotonin levels only indirectly, and then only in th brain, not the blood (they actually lower levels in blood). Fenfluramine caused pulmonary hypertension, and -- surprise-- myocyte proliferative valve disease. "Gosh," said the doctors and the FDA--- "who would ever have guessed it would do THAT?" Duh. Fenfluramine is off the market. But 5-HTP (unregulated by the FDA right now becaues it appears in bananas and can therefore be claimed to be a food supplement) is typically recommended to be given in doses about equivalent to the serotonin amounts excreted into the blood in people with carcinoid tumors who get heart disease (50 mg a day). If most of the ingested supplement 5-HTP is turned into serotonin/5-HT before it can be taken up by the brain (which can't take up serotonin directly), then there are potential problems. Extra B6 and no carbidopa (the way 5-HTP is often given) should exacerbate this premature liver metabolism. If people taking 5-HTP for years for depression or sleep eventially come down with cardiac disease, I know a lot of people who will say "Gosh, who could have guessed this danger"? I've been going on about it on the net, and even managed to get a mention of the problem in a popular book (Ray Sahalian's book on 5-HTP). But he doesn't mention my name, and he doesn't look carefully at the arguments. Poor research on that. I think he'll be one of the ones screaming the loudest if the worst happens. Steve Harris, M.D.
From: firstname.lastname@example.org(Steven B. Harris) Newsgroups: sci.med Subject: Re: 5-HTP (was: Ignorant Steve B. Harris) Date: 23 Feb 1999 00:23:59 GMT In <email@example.com> firstname.lastname@example.org writes: >> In all cases where valve problems are associated with high blood >>serotonins, the daily amounts of serotonin released into the >>bloodstream needed to do the nasty [deed] (judged by urine metabolites) >>is about 50 mg a day. > > Egad! You mean my love of chocolate could lead to MVP? Nooooo! Don't think there's much in chocolate. That's phenylethylamine. >On a more serious note (and more lines to keep up with netiquette), >has anyone done a correlation between taking tryptophan and pulmonary >hypertension and/or cardiac valve problems? MAOIs? Conceivably, >someone could be doing a lot of damage to themselves with the wrong >diet while on an MAOI or if they take tryptophan as, say, a natural >(read organic) sleep aid. > >Pete Womack, MT(ASCP). No, probably not. Tryptophane, at least if uncontaminated, is probably pretty safe. Even the FDA agrees, since they still (very covertly) approve it being added to infant formulas. But their excuse for taking it off the market due to contamination some years ago (a problem now fixed) continues to be an excuse for a more restrictive policy. You know: remember when that airliner bound for France was supposedly blown up by a bomb a couple of years ago? Which got us all those restrictions about having to show a driver's licence before you can fly, so that some computer somewhere has a record of everywhere you've traveled by air, and when? Well, turns out the airliner was never proved to have been anything other than a mechanical failure (of what sort never determined, but probably a fuel tank explosian). But-- guess what-- you still have to show that driver's license and answer those questions. And the sniffers that sniff for nitrates now can be built to sniff for anything. Coming soon: ID necessary to travel by bus. And smart highways which tell what cars go where and when. Enjoy. In any case, to return to the subject, tryptophan is not metabolized to serotonin peripherally to any large extent, because the rate comitting step or for that is the 5-hydroxylation, done by an enzyme found in neural tissue (I think perhaps exclusively). The chemists have bypassed this regulatory step with 5-HTP. Serotonin is supposed to be confined behind your blood brain barrier, where 99% or something of it is. A little leaks out of neural tissues in your gut and gets taken up by platelets, and performs a few odd functions, but mostly, it's not supposed to eaten in large quantities, and the same goes for the neural precursor 5-HTP (since your liver then easily converts this to serotonin, which does your brain no good since it cannot get in). Steve Harris, M.D.
From: email@example.com(Steven B. Harris) Newsgroups: sci.med Subject: Re: 5-HTP (title respectfully changed) Date: 23 Feb 1999 00:54:33 GMT In <firstname.lastname@example.org> email@example.com (Shapere) writes: >In article <firstname.lastname@example.org>, >email@example.com(Steven B. Harris) writes: > >>Because it gets turned into serotonin in your liver, and dumped into >>your blood (depending on your B6 status, in part). Same enzyme does >>the job which does it for L-dopa (so it goes to worthless dopamine >>before it can get across the blood brain barrier). Your system is not >>built to handle much serotonin in the blood. SSRI's don't increase >>serotonin levels in blood (only in the brain), but fenfluramine, as >>well as methysergide and ergotomine, are all direct serotonergics (as >>shown by their direct pulmonary hypertension on toxicity studies). > >I have a question...can you reassure me and provide a good rationalization for >why MAOIs wouldn't do this too? (I mean, since MAO is *everywhere*.) Is there >no serotonin whatsoever outside the CNS (under normal conditions)? Very little. Though you have to count neuroendocrine-like cells in the gut (enterochromafiin cells) as CNS (they really aren't, but act in many of same ways). So ar as your blood and tissues go, there's just a scosh that leaks out of such neurons and neuron-like cells, in the gut. Serotonin is metabolized by MAO, so in theory, your levels could go up with an MAO inhibitor, indeed. Don't know if this has been described (another medline search required). Such drugs have yet to be associated with heart valve problems, so my guess is that you're okay unless you eat too many green bananas (ie, they are a staple in your diet). >How extensively is 5-HTP usually metabolized by the liver, anyway? That depends entirely on your B6 status, and how much your decarboxylase enzymes are occupied by other jobs. So I can't say. So far as I can tell, nobody has yet done the critical experiment of measuring urine 5-HIAA (the ultimate serotonin metabolite) in the urine of people taking 5-HTP. For people experimenting with the stuff, it might be a good idea, though. >>But serotonin does more than just cause pulmonary hypertension. It >>also causes direct proliferation of myocytes, which grow where they are >>not supposed to, and cause heart valve deformities. > >That's interesting...I suppose serotonin syndrome could cause mitral valve >prolapse too, then? More rarely. Serotonin per se mostly does not make it through the lungs (where it's metabolized), which is why left heart problems are rare in serotonin eaters and in gut-carcinoid tumors, (unless, interestingly, you actually have tumor metastases in the lungs). No, I have no idea what effect MAO inhibitors have on that. Interestingly, a lot of the serotonin-agonist left heart pathology is due to non-serotonin chemicals which ACT like serotonin, but are not metabolized in the lungs. Fenfluramine being one. >(Nobody ever found a murmur or anything until after I'd had CSS (4/97) - >I'd never made the connection. Interestingly, I never had panic attacks >before then either.) > >Any recommended reading on this subject? (Bearing in mind that I'm just a >clueless pre-med?) > >-elizabeth None that I can put my finger on. Somebody needs to write a review of the various ways of getting serotonin-agonist valve syndrome. I had to put my own synopsis together from a number of rare and rather unlikely sources (the Matoki-eater heart pathology literature is all from the 50's and 60's). The fact that such a review has not been done is probably one reason why a lot of people still don't quite believe in this pathological mechanism. Even after fenfluramine. Steve Harris, M.D.
From: firstname.lastname@example.org(Steven B. Harris) Newsgroups: sci.med,misc.health.alternative,sci.med.pharmacy,sci.life-extension Subject: Theoretical Dangers of 5-HTP (was Re: [Fwd: L-5-hydroxy Tryptophan question]) Date: 7 Apr 1999 14:06:10 GMT email@example.com in Message-ID: <firstname.lastname@example.org> states: In article <3709FFBA.1BF8403E@thegrid.net>, email@example.com wrote: > Go to http://www.dejannews then to Power Search, then enter HTP-5 in the subject column and firstname.lastname@example.org in the poster's colum and this newsgroup in the newsgroup column. You'll get them.< >I did this. I got 37 posts. I sampled about 15 at random. Not a single citation in one of them, nor even a reference to an author. Harris makes a few allusions to serotonin conversion in the liver. >Did a Medline search on (5-HT or 5-HTP) and liver and convert. Got two articles, one using yeast, one in rats, neither partic- ularly relevant to the topic at hand. >Did another Medline search on (5-HT or 5-HTP) and liver and B6. One citation, about leucine, and only tangentially about seroton- in, but only about brain serotonin, not serum serotonin. >I've done all this before, with different Medline searches, and can find no citations to the things that Dr. Harris is talking about. He won't provide any references, just uncited essays. >I'm still waiting for citations. If Dr. Harris is basing his speculation about heart problems from 5-HTP supplementation, he *must* have some references. Greg Nigh Student, National College of Naturopathic Medicine (http://www.ncnm.edu), for whom I do not pretend to speak. ------------------------------------------------------------- _____________________________________________________________ Comment from Harris: I have lots of references, but do not have all of them at hand at this very moment. However, let me suggest that you naturopathic students learn to use MEDLARS a little more creatively. The thing is a computer program and it doesn't know what you're trying to ask or find out, and it won't spoon feed you. It's not safe to do a couple of text word searches off the top of your head, and conclude that I, or anybody else in biomedicine, must therefore be talking out of my hat. If you do that, I'm probably going to rub your nose in it when I get around to it. If you're having a problem finding papers which show that 5-HTP administration raises serotonin blood levels a lot (and levels of the serotonin metabolite 5-HIAA a lot also), I have included 5 of them below, all human studies. They aren't the only ones out there, but these have this information in the abstract itself. Now, go back and find them (and the others) yourself, on medline. I leave this as an exercise for the student, because I'm not going to spoonfeed you, either, so long as you decide not to act like a student. If you persist in being unpleasant, grasshopper, you get the up-your-nose treatment instead. DANGERS OF 5-HTP For those joining this debate late, the subject is what nastiness serotonin-agonist drugs (drugs which act directly on serotonin receptors), and of course serotonin itself, do to the heart. It has been known for some time that serotonin causes proliferation of cardiac myocyte cells, and that such a proliferation appears to be what causes the syndrome of stiffening, thickening, whitening, and dysfunction of heart valves in people taking serotonergic agonists such as methylsergide and ergotamine (identical pathology in these cases). Exactly the same odd and distinctive pathology as an effect of a drug was recently discovered (surprise) in the serotonergic agonist dexfenfluramine, which problem caused it to be removed from the market. This may have been a shock to the public, but The Powers That Be knew very well beforehand that dexfenfluramine was a direct serotonin agonist (and not just a brain active neuronal re-uptake inhibitor, which it is, also), since it has long been known to have direct serotonin-like vasoconstrictive effects in the lungs, as do all drugs in this direct agonist class. For example, injection of an overdose of dexfenfluramine in mice causes death in minutes from acute pulmonary hypertension, something that will never happen with Prozac or Zoloft (which raise serotonin levels in the BRAIN, not the blood-- and even then not for weeks). And the FDA knew very well, long before the valve thing (duh...) that dexfenfluramine occasionally caused pulmonary hypertension in humans, too. The rest should have been pretty much a yawner when it finally showed up. But as we heard, it just shocked the FDA. Who knew?, they said. Well, a few people guessed, and did say. So why was the stuff kept on the market for so long? First, because many of these FDA folks are apparently idiots (see my discussion of government). The FDA does not exactly hire the top researchers in the country. Second, because nothing else worked, long term, in this class, for weight loss, and there was a lot of economic push to keep the fen in fen-phen. For some reasons not well understood, appasta- tic neurons adapt to the high serotonin levels caused by SSRIs, and the weight loss effects caused by them disappear about the time they really start to work on depression. And probably this isn't coincidence, since the same slow receptor changes probably mediate both effects. But since dexfenfluramine had another and more direct action, its effects were harder to turn off. Nevertheless, it's now gone off the market. People don't want to get thin as in _The Thin Man_. Are we out of danger as regards this odd valve syndrome caused by serotonin-acting drugs? Well, consider that cardiac myocytes weren't designed by Mother Nature to proliferate in response to dexfenfluramine. They respond to natural serotonin in development, and possibly also to it as a trophic and injury repair factor in platelets, when small amounts of damage occur, and platelets adhere to the site (platelets take up serotonin from the blood and are loaded with it-- they dump it on anything they stick to). And there are two separate lines of evidence that excess (supra-physiologic) blood serotonin itself causes this same valve syndrome. First, the very same syndrome is seen in people with midgut carcinoid tumors, that secrete serotonin into the blood. And it is seen only in the right side of the heart, consistent with serotonin being oxidized in the lungs and not reaching the left heart (the exception is when tumors have metastasized to the lungs and thus bypass them). Not all studies have shown that the amount of serotonin secreted by such tumors correlates with serotonin blood levels and urine serotonin metabolites (5-HIAA), but the largest and more carefully done ones DO find a signific- ant correlation. That's hard to ignore. Correlation is not causation, to be sure, but on the other hand, as in the case of smoking and lung cancer, we do have a mechanism, and many other disparate examples. Nevertheless, there are a few diehards in cardiology who propose that other bad things from carcinoid tumors are doing the dirty deed. Like bradykinin. Except that in the 1950's and early 60's (second line of evidence) this syndrome was ALSO described in matoki eaters in West Africa. Matoki is a kind of green banana used as a dietary staple in these populations, which get this same odd right sided valve disease, which looks as though they all have carcinoid tumors or are taking dexfenfluramine. Except they aren't. But it just so happens that matoki contains the largest amount of serotonin of any natural food. Not bradykinin, or dexfenfluram- ine or ergotamine, etc. And the levels of serotonin metabolite 5-HIAA in the urine of this population are about the same elevated levels (50 mg a day) as carcinoid patients who develop right heart valve disease. Nobody else gets this much from a natural food. At some point the coincidences start to pile up. No, scientists haven't been able to reproduce this in animals. But they haven't been able to reproduce lung cancer by cigarette smoke, either. Do we in the West eat serotonin? No, not much. Serotonin isn't even a good dietary supplement to raise levels in the brain, because it doesn't cross the blood brain barrier, which transports amino acids and their analogs. Serotonin is a simple amine and lacks the carboxyl group to look like an amino acid. So nobody sells it as a dietary supplement. Tryptophane, the amino acid, does get into the brain and raise serotonin after being hydroxylated to 5-hydroxytryptophan (5- HTP), then decarboxylated by the aryl amino acid decarboxylase in the brain, which is B6 dependent. But tryptophane was taken off the market by the FDA due to contamination problems about a decade ago, and hasn't been seen since. It's still added to baby formula, so the FDA must figure the problems with manufacture have been fixed. But they aren't about to give you the power to mess with your brain serotonin levels. Who do you think you are, anyway? Tryptophane isn't converted to much serotonin in blood (toxic stuff there!) because the body wisely puts the committed step enzyme, the 5-hydroxylase, behind the blood brain barrier, where any serotonin made doesn't leak out again to nail your heart. So tryptophane is a natural food, but a safe one, when pure. Alas, with tryptophane gone, health food stores now 5-HTP in place of it, with the idea that you can do that 5-OH step yourself in a chemlab, and not in your neurons, to get serotonin. And they get away with it as a "food supplement," because there is some 5-HTP in bananas, too (though not much). The problem is that unlike tryptophane, 5-HTP really DOES raise blood levels of serotonin, since the liver contains a good aryl decarboxylase (also B6 dependent) which turns 5-HTP to serotonin in varying amounts and dumps it into your blood. From where it cannot get into your brain, and thus no doubt chews on your heart valves some before you can metabolize it in the MAO systems in your lungs, into 5-HIAA. If metabolized in the liver to any large extent, amounts of 5-HTP being given for depression and other problems are enough to easily give the critical toxic 50 mg a day of 5-HIAA which marks people at risk for valve disease. And there is reason to believe that it is metabolized to a large extent, especially if you take B6 (actually included in some 5- HTP supplements, go figure). We know serotonin levels go way up in blood on 5-HTP, and that's from liver metabolism. And so do 5-HIAA levels, and that's from metabolism of serotonin which never made it too your brain. And we know the situation with liver decarboxylation of 5-HTP should be expected to be much the same as for people with Parkinson's disease who take L-DOPA. L- DOPA is an amino acid analog (a hydroxylated tyrosine) which is decarboxylated in the liver by the *very same aryl decarboxylase that 5-HTP uses*, into dopamine (rather than the counterpart serotonin) before IT can get into the brain. That's a side effect, and something you don't want to happen. This dopamine is stuck, also, and just hangs around raising your blood pressure and doing nothing good. So these people with Parkinson's who take L-DOPA must take liver carboxylase inhibitors (carbidopa, as in Sinemet) and stay away from too much B6. I think even the naturopaths have gotten this far. But not to the next step, which is that it follows that, at minimum, people taking 5-HTP should for the same reasons also do these things that Parkinson' patients do (take carboxylase inhibitors and no B6). Except that few do. And few monitor their uninary 24 hour 5-HIAAs to see how much they are converting to toxic serotonin outside the brain, either. But yet this is a widely available lab test, which any large lab will do (it's a medical test for carcinoid tumors, but can as easily see green banana craving and 5-HTP mis-metabolism.) My guess is that we are headed for the same problems with 5-HTP that we had with dexfenfluoramine, and that these will be used as an excuse to further regulate the supplement industry, just as happened with tryptophane. I would suspect a giant plot to do this, in fact, if I thought these people at the FDA were that sophisticated. But they aren't. They're merely ignorant and overworked and arrogant, and the healthfood people are greedy and arrogant, and the consumer-- well, the consumer had better be on the nets, these days. Or be very, very conservative about new health food products. These days you may not die of a misprint, as Twain said, but from lack of biochemistry knowledge and ability to search medline. Scary, but there you are. And since your doctor never learned any nutrition, you won't get any help there. And it doesn't look like the naturopaths are taking up the slack, if Mr. Nigh and the rest of the yokels I see writing pamphlets in health food stores are any indication. 5-HTP is naturopathy's answer to Prozac, don't you know-- and they're not going to give it up easily. For the same reasons doctors didn't give up dexfenfluramine. So it looks bad all over, in the complicated future. The bottom line is that if you don't read, read, read, you're going to suffer, suffer, suffer. Probably best in that case to hoe your beans and try to simplify, simplify, simplify. As for the naturopaths, I suggest they rethink 5-HTP some. It's going to hurt when it hits. When physicians got caught by dexfenfluramine, they had the FDA to blame, which in turn was mighty lax about letting the public know how much evidence was in the literature beforehand to predict the kind of problem they eventually had. Golly, they said, who would've thunk it? The journalists didn't exactly go pull out 1960's articles on matoki and pore over textbooks of cardiology about carcinoid tumor. So everybody had somebody or something to blame, and they got away with it. Naturopaths, by contrast, have nothing-- and won't get away with it. The FDA won't back them on 5-HTP, because the FDA will never approve it. So naturopathy will be caught by 5-HTP with their pants down and their fingers up their noses. And just about that time, the New England Journal of Medicine will be discovering why the health food hucksters should have known it biochemically all along. Due to our new experience with fen- phen, don't you know. And they'll be passing all this new insight on to the newspapers, so they won't have to read textbooks, something that journalists never ever do. Steve Harris, M.D. ABSTRACTS: J Clin Invest 1985 Oct;76(4):1485-90 Central serotonergic stimulation of aldosterone secretion. Shenker Y, Gross MD, Grekin RJ Serotonin stimulates aldosterone secretion both in vitro and in vivo, and serotonin antagonism decreases plasma aldosterone levels in patients with idiopathic aldosteronism. This study was designed to assess the effects of the serotonin precursor, 5-hydroxytryptophan (5HTP), upon aldosterone secretion in man, and to determine whether stimulatory effects of 5HTP are mediated through the central nervous system. Oral 5HTP, admini- stered as a single 200-mg dose, increased plasma aldosterone levels from 4.7 +/- 0.6 to 13.3 +/- 2.8 ng/dl in dexamethasone- -pretreated, normal volunteers. Peripheral inhibition of decar- boxylation of 5HTP, achieved by pretreatment with carboxydopa, 25 mg three times daily for 3 d, significantly increased the stimulatory effects of 5HTP on aldosterone levels (P less than 0.001). No change in aldosterone levels occurred in subjects who received placebo after pretreatment with dexamethasone and carboxydopa. Increased aldosterone was not accompanied by increases in plasma levels of renin activity, potassium, or ACTH. Plasma levels of 5HTP were markedly increased by carboxydopa pretreatment [indicating significant liver metabolism to serotonin in those not getting it], but peak plasma levels of serotonin were not significantly altered [by carbidopa, not by 5- HTP; papers below find both. Serotonin metabolism is fast enough and platelet uptake fast enough that differences in metabolites are all that are sometimes seen, and no difference in platelet free plasma]. Four patients with idiopathic aldosteronism all had an increase in plasma aldosterone levels after 5HTP administrati- on, whereas the response in four patients with aldosterone-produ- cing adenoma was variable. Incubation of isolated human and rat adrenal glomerulosa cells with serotonin resulted in increased aldosterone secretion by both sets of cells, whereas 5HTP was ineffective in stimulating aldosterone secretion in vitro. We conclude that central serotonergic pathways are involved in the stimulation of aldosterone induced by administration of 5HTP. This mechanism may be an important etiologic factor in the hypersecretion of aldosterone that occurs in patients with idiopathic aldosteronism. PMID: 2997280, UI: 86034589 ---------- Folia Psychiatr Neurol Jpn 1985;39(1):25-31 Endocrinological function in schizophrenic patients under haloperidol treatment: plasma PRL, HGH and 5HT levels after L-5HTP loading. Hoshino Y, Kaneko M, Kumashiro H, Tachibana R In order to examine 5HT metabolism in the hypothalamo-pituitary (HP) system of chronic schizophrenic patients taking haloperidol for a short or long period, chronological changes of blood 5HT, PRL and HGH were measured after an oral loading dose of L-5hyd- roxytryptophan (L-5HTP), a precursor of 5HT. The subjects consis- ted of 8 male patients with chronic schizophrenia, who were divided into the following two groups. The 1st group--4 patients taking haloperidol (5.6 mg/day) for 8 months on an average (short-term treatment). The 2nd group--4 patients taking halop- eridol (4.8 mg/day) for 7.5 years on an average (long-term treatment). The control group was made up of 9 healthy male volunteers. As a result, the basal level of blood 5HT in the 1st group was significantly higher than that in the control group. The blood 5HT levels in the 1st and 2nd groups showed an equally remarkable increase as compared with the control group. The basal level of plasma PRL in the 2nd group was significantly lowe than that in the control group. Moreover, in the 2nd group, an increase in the plasma PRL level after the loading was suppress- ed, but it showed less suppression in the 1st group. There was no significant difference in the basal HGH levels among the control, 1st and 2nd groups. After the loading, an increase in the plasma HGH was suppressed in the 2nd group, but the suppression was less in the 1st group. PMID: 3876974, UI: 86031640 ---------- Eur J Clin Pharmacol 1982;23(1):81-6 Human pharmacokinetics of long term 5-hydroxytryptophan combined with decarboxylase inhibitors. Magnussen I, Van Woert MH L-5-Hydroxytryptophan (5HTP) and its major metabolites 5-hydroxy- tryptamine (5HT) and 5-hydroxyindoleaceticacid (5HIAA) were measured in blood and cerebrospinal fluid from neurological patients receiving steady state treatment with 5HTP. There was accumulation of 5HT in blood platelets and 5HIAA in plasma in all patients, despite concomitant administration of the L-aromatic amino acid decarboxylase inhibitors, carbidopa and benserazide. There was no correlation between the 5HTP dose and the circulating concentrations of the aminoacid or its metabolit- es. Preliminary comparison of the biochemical and therapeutic effects of carbidopa versus benserazide suggest that 5HTP: carbidopa is superior to 5HTP: benserazide. A direct proportiona- lity between plasma 5HTP concentrations and the levels of 5HTP in the lumbar cerebrospinal fluid was found. The binding to serum proteins of 5HTP in the clinically relevant concentration range of 10 to 100 microM was investigated; 19% of circulating 5HTP was bound to serum proteins. 5HTP did not displace protein-bound tryptophan in serum. PMID: 6182005, UI: 83027497 ---------- N Engl J Med 1980 Oct 2;303(14):782-7 Development of a scleroderma-like illness during therapy with L-5-hydroxytryptophan and carbidopa. Sternberg EM, Van Woert MH, Young SN, Magnussen I, Baker H, Gauthier S, Osterland CK A scleroderma-like illness developed in a patient treated with L-5 hydroxytryptophan (L-5HTP) and carbidopa for intention myoclonus. The patient had high plasma kynurenine levels that remained high when the L-5HTP-carbidopa combination was discon- tinued, However, levels rose futher on drug rechallenge, suggest- ing that the drug unmasked an abnormality in one of the enzymes that catabolize kynurenine. Plasma kynurenine was also determined to be high in seven of 15 patients wth idiopathic scleroderma, but not in eight patients with intention myoclonus treated with L-5HTP and a decarboxylase inhibitor and in whom scleroderma did not develop or in 10 patients with Parkinson's disease treated wth L-dopa and carbidopa. Our data and studies in the literature suggest that two factors may be important in the pathogenesis of some scleroderma-like illness: high plasma serotonin and the abnormality associated with elevated kynurenine. Publication Types: Clinical trial PMID: 6997735, UI: 81011891 ---------- Neuropsychobiology 1979;5(4):232-40 L-5HTP treatment and serum 5-HT level after L-5-HTP loading on depressed patients. Kaneko M, Kumashiro H, Takahashi Y, Hoshino Y Based on 5-HT hypothesis, L-5-HTP (150 or 300 mg/day) was given orally to 18 depressed patients. The global estimates were 2 very much improved; 8 much improved; 3 minimally improved, and 5 unchanged. The action of L-5-HTP was usually rapid. The elevation of the serum 5-HT level 1 week after L-5-HTP administration was relatively lower in the 5-HTP nonresponder group, compared with the responders. The chronological change of the serum 5-HT level in depressed patients after an oral loading dose of 3 mg/kg of L-5-HTP showed a gradual and slight elevation, compared with manic and normal groups. It seemed that the therapeutic effect of L-5-HTP on responders was related to lower 5-HT level in the brain for their pathogenesis, and that there was a metabolic disturbance of L-5-HTP into 5-HT in some depressed patients. PMID: 312470, UI: 79178849 ---------- N Engl J Med 1977 Jan 13;296(2):70-5 Long-term therapy of myoclonus and other neurologic disorders with L-5-hydroxytryptophan and carbidopa. Van Woert MH, Rosenbaum D, Howieson J, Bowers MB Jr We evaluated the therapeutic effect of L-5-hydroxytryptophan (L-5HTP), the precursor of serotonin (5-hydroxytryptamine), combined with carbidopa, a peripheral decarboxylase inhibitor, in patients with intention myoclonus and examined the serotonin metabolites in spinal fluid, blood and urine before and during therapy. In 18 patients with intention myoclonus due to anoxia or other brain damage, 11 derived more than 50% overall improvement during treatment with L-5HTP and carbidopa. Spinal- -fluid 5-hydroxyindoleacetic acid was 35% lower in patients with intention myoclonus than in controls (P less than 0.05). Therapy with L-5HTP and carbidopa increased the concentration of serotonin metabolites in urine and spinal fluid. We postulate that a deficiency of brain serotonin is causally related to intention myoclonus and that the therapeutic effect of L-5HTP and carbidopa may be due to the repletion of serotonin in regions of the brain where serotoninergic neurons have degenerated. PMID: 401457, UI: 77056277 ---------- Hiroshima J Med Sci 1976 Sep;25(2-3):135-40 On the tryptophan-serotonin metabolism in manic-depressive disorders. Changes in plasma 5-HT and 5-HIAA levels and urinary 5-HIAA excretion following oral loading of L-5HTP in patients with depression. Amamoto T, Sarai K PMID: 1088369, UI: 77187367 ----------
From: "Steve Harris" <sbharris@ix.RETICULATEDOBJECTcom.com> Newsgroups: sci.med.nutrition,sci.med Subject: Re: 5-HTP side effect Date: Thu, 7 Mar 2002 09:57:36 -0800 Message-ID: <email@example.com> Baron Blackfang wrote in message <7HCh8.41889$ZC3.firstname.lastname@example.org>... >I recently gave 5-HTP (5-hydroxytryptophan) a try as a sleep aid. I consumed >2, 50 mg caps twice a day. I didn't find any relief from insomnia, and I >found that my anxiety increased rather than decreased. > >5-HTP is supposed to be the active metabolite of tryptophan, which was used >in the past as an antidepressant until it was banned by the FDA. Do not take 5-HTP. It's converted (to variable extent) by the liver aryl amino acid decarboxylase to serotonin (5-HT or 5-hydroxytryptamine), which is a bad thing to have in your blood in large quantities. It causes cardiac myocytes to proliferate, and that causes proliferate valve disease (a problem seen in methylsergide overdose, old-time fenfluramine users, and victims of midgut carcinoid tumors that make a lot of serotonin). And, BTW, any serotonin that is made by the liver never gets into the brain, so it does you no good there. Some 5-HTP does get into the brain (the same transporter that gets tryptophan gets it in, but that doesn't work without the COOH group) and is converted to serotonin there. But you pay for that with serotonin made outside the brain, which you want strictly controlled. Free serotonin outside the CNS is nasty stuff. It causes instant vasoconstriction, which is one reason why platelets sop it up and store it as a sort of nature's wound vasoconstrictor anti-bleeding agent. An overdose, however, causes enough pulmonary vasoconstriction to cause pulmonary hypertension. Give an animal an overdose of serotonin and they die of pulmonary hypertension. The same is true of an overdose of fenfluramine-- death follows in minutes from that mechanism. Serotonin is also a growth factor for smooth muscle cells, which aids in wound healing when platelets dump it on small areas of damage. But again, too much of a good thing causes proliferation in smooth muscle cells where you don't want it, and that's the valve disease. There is some irony in the fact that tryptophan, which does not raise peripheral serotonin levels, and is a fairly safe way to raise brain serotonins, is illegal to sell without prescription. But 5-HTP, which bypasses the APUD cell enzyme that converts tryptophan to 5-HTP, is still available over the counter. SBH
From: "Steve Harris" <sbharris@ix.RETICULATEDOBJECTcom.com> Newsgroups: sci.med.nutrition,sci.med Subject: Re: 5-HTP side effect Date: Sat, 9 Mar 2002 15:43:31 -0800 Message-ID: <email@example.com> Alex wrote in message ... >"Steve Harris" <sbharris@ix.RETICULATEDOBJECTcom.com> wrote: > >> >> Do not take 5-HTP. It's converted (to variable extent) by the liver aryl >> amino acid decarboxylase to serotonin (5-HT or 5-hydroxytryptamine), which >> is a bad thing to have in your blood in large quantities. > >Steve, do you think there might be risks in taking one 50 mg capsule >of 5-HTP once a *week*? I would guess not. The average person with carcinoid heart disease is excreting around 50 mg 5-HIAA a day, as I remember from one study, suggesting that it takes around that much serotonin dumped into your blood to do this to you. In turn suggesting it's probably only people taking upward of 50 mg 5-HTP who are going to get into trouble. But who knows where there total safety limits are? >>I have read that B6 is needed for the conversion to serotonin, so I >take care *not* to mix it with a B6-containing supplement, to minimize >probability of conversion taking place in the gut on the bloodstream. >BTW, a brand of 5-HTP, I think from Nature's Way, comes with a hefty >dose of B6. I'd never buy it. It does seem the ultimate stupidity to put these together into a supplement. Duhhhhr (it's about like taking L-DOPA and B6 for your Parkinson's-- you're not gunna get much dopamine into your brain THAT way). But remember that if you take B6 at all, you're probably loaded with it. In other words, just because you take B6 today and 5-HTP tomorrow, that doesn't mean you're not getting as good conversion as your body can do. How long do you have to wait for B6 washout? I have no idea. Which is why it's best to limit the 5-HTP intake, unless you're going to regularly measure your urine 5-HIAA's. SBH