What's with 5-hydroxytryptophan (5-HTP)?

I might have said it before so please do excuse the repetition, but the aromatic amino acid tryptophan has been of some interest to me down the years. Like most people who have heard or know about tryptophan, the connection with serotonin (5-hydroxytryptamine or 5-HT) seems to be the big attraction when it comes to this very important amino acid and its pretty important effects on biology and daily life.

Putting serotonin slightly to one side for this post, I instead want to talk about another player along the tryptophan - serotonin pathway, 5-hydroxytryptophan (5-HTP) and various lines of study to this important intermediary compound in what is admittedly, a slightly disjointed post.

I was brought to this post by two factors:

• An interesting comment in a LinkedIn discussion about how issues with the production of melatonin observed in some cases of autism might tie into other findings in autism in relation to issues with tetrahydrobiopterin (BH4) for example. Without trying to make connections where there may not be any, it got me thinking about the whole tryptophan - serotonin - melatonin pathway in a little more detail.
• A curious paper which I stumbled upon a while back by Emanuele and colleagues* suggesting that the symptoms of romantic stress defined as "... a recent romantic break-up or reported recent romantic problems" might benefit from a brief dose of 5-HTP both behaviourally and biologically. Curious I know, and not necessarily relevant to this blog; but nevertheless it brought me back to 5-HTP.

Before your eyes start to glaze over and you reach for the 'click away' button, it is probably best if I start at the beginning and briefly show you how things usually go with regards to tryptophan, serotonin and melatonin. So in my very best handwriting (yes, you can perhaps see why I didn't ace certain school exams) and with no expense spared... see figure 1.

Figure 1: Bless you tryptophan.

In short:


L-Tryptophan is converted to 5-HTP via the enzyme tryptophan hydroxylase, TPH which relies on the cofactors of iron and BH4 for optimal functioning. Keep this cofactor thing in mind.

5-HTP is then converted to serotonin (5-HT) and onwards to various other compounds including 5-hydroxyindoleaceticacid (5-HIAA).

The conversion of 5-HT to melatonin is via the intermediate compound, N-Acetlyserotonin (NAS).

Just before anyone mentions, I have only included the TPH enzyme in my schematic and not the other enzymes involved in the various other reactions so as to keep it simple.

Hopefully you can see from my scribbles the central role tryptophan plays in this important metabolic process and how little issues with components in the pathway can potentially have knock-on effects for downstream metabolites.

So to the title of this post: "What's with 5-hydroxytryptophan?". Well, potentially quite a bit.

The first time I heard about 5-HTP was with reference to the collected data on the potential therapeutic use of the compound in cases of depression as per the Cochrane Review by Shaw and colleagues** (full-text). As per nearly every Cochrane Review I've ever read, the text reads something like, a few trials showing possible effects from [5-HTP] supplementation on depressive symptoms but not enough rigorous study to be able to form a suitable opinion. Don't believe me... well, see the Cochrane Review for GFCF diets for autism (here). Anyway, mention also of the fact that antidepressants already exist to 'treat' depression probably accounts for the drop in research interest in this area in recent years. That and possibly 'peak X' (see here for more details).

Where next?

Sleeping aid. Looking again at the magnificent figure offered to accompany this post, one could perhaps see how sleep could be affected by 5-HTP purely based on melatonin featuring some way down the pathway. The evidence.. well let's just say it needs improving despite some initial attempts (here and here). Additional evidence on any direct effect from 5-HTP administration on melatonin levels is even more scant.

Fibromyalgia. Heading into some pretty interesting territory here with again a dearth of recent investigations on this topic. Caruso and colleagues*** reported some interesting results from a double-blind, placebo-controlled trial of 5-HTP in fibromyalgia (FM) suggestive of positive effects to be had. Other, less controlled trials, also seemed to indicate some improvements in FM symptoms although with side-effects reported. Other than that, reviews and sprinklings of speculation.

Finally autism. Not much more to say aside from the very limited research on 5-HTP supplementation does not (so far) support any resounding changes to presented symptoms as per the paper by Sverd and colleagues****. Evidence has been presented to suggested that 5-HTP administration seemed to do a very good job at raising blood serotonin concentrations in males with autism (here). Whether this finding is (a) transferable to the majority and (b) might relate to issues with the availability of tryptophan as a starting material (in plasma and urine) or indeed the function of TPH (cofactor availability?) are still matters of speculation.

The Red Hot Chili Peppers @ Paul Whiteley

I'm just about done with 5-HTP for now. As per previous posts, the main caveat is that no medical advice or endorsement of anything is given or intended. Hopefully knowing a little bit more about 5-HTP after this post and how we should perhaps not be closing the research door on it just yet, would you be interested to learn that the gut microbiota might very well have an important effect on the serotonergic system*****? Accepting that bacteria and 'the microbiome' is a research area on the rise, one wonders whether 5-HTP might also have a hand in this process.

To finish, the Red Hot Chili Peppers rocked the SoL yesterday evening and so here is one of their finest... Higher Ground. And to the woman sat behind me who told me to sit down... it's a rock concert.

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* Emanuele E. et al. An open-label trial of L-5-hydroxytryptophan in subjects with romantic stress.
Neuro Endocrinol Lett. 2010; 31: 663-666.

** Shaw KA. et al. Tryptophan and 5-Hydroxytryptophan for depression. Cochrane Database Syst Rev. 2002: CD003198

*** Caruso I. et al. Double-blind study of 5-hydroxytryptophan versus placebo in the treatment of primary fibromyalgia syndrome. The Journal of International Medical Research. 1990; 18: 201-209.

**** Sverd J. et al. Effects of L-5-hydroxytryptophan in autistic children. J Autism Child Schizophr. 1978;8: 171-180.

***** Clarke G. et al. The microbiome-gut-brain axis during early life regulates the hippocampal serotonergic system in a sex-dependent manne. Molecular Psychiatry. June 2012.
DOI: 10.1038/mp.2012.77