Saturday, 9 June 2012

Melatonin and autism updated

I've covered some of the research on autism, sleep and melatonin previously on this blog. That post was a gentle introduction to to the topic of melatonin which I've decided to upgrade with this latest offering.

Perhaps an introduction first?

Melatonin is an interesting compound synthesized in the pineal gland from another interesting compound, serotonin (5-HT). The intermediate compound formed, N-acetylserotonin (NAS), is itself something which could really do with a lot more investigation given some suggestion of an anti-depressant effect among other things.

I could tell you all about the sleep-wake cycle connection of melatonin but aside from that there are also some other interesting activities of the compound, for example with regards to antioxidants as per this review by Hardeland & Pandi-Perumal* (full-text) from a few years back. I was particularly interested in the connection between melatonin and that old favourite glutathione but am not going to dwell on it.. OK, but not too much.

So what's the story with regards to autism and melatonin?

Well, quite a bit. Generally speaking(!) levels of circulating melatonin and some of its metabolites are noted to be on the low side in cases of autism as per the meta-analysis by Drs Rossignol and Frye**. Even more recent research*** looking at both daytime and night-time levels of the main metabolites of melatonin, 6-sulphatoxymelatonin, confirmed issues with melatonin production to be present in cases of autism. Interestingly also linking production issues with degree of symptom severity.

Why might melatonin production be aberrant in cases of autism?

The big question and I'm afraid that I don't have a big answer. There are a few possibilities: issues with the pineal gland or suprachiasmatic nucleus (the master clock centre), issues with serotonin or the starting material tryptophan, issues with the various reactions in the metabolism of melatonin (or precursors)... take your pick bearing in mind this list is not exhaustive.

I find it particularly interesting that (a) there might be a sensory-perceptual link to the production of melatonin which might be related to melatonin issues in some cases of autism, and (b) acetylation and methylation are required steps in the metabolism of melatonin. I might be making mountains out of molehills again but it strikes me that some people on the autism spectrum aren't exactly flush when it comes to methylation. Just speculating of course.

Supplementation?

Again with the very important caveat about not giving medical advice, melatonin does seem to have quite a good record when it comes to at least some cases of autism spectrum conditions and a few other diagnoses. Sleep and the regulation of sleep is the obvious target of melatonin, which itself can have some pretty important influence on presented behaviour.

Two quite recent trials extended the good news about melatonin: this one from Malow and colleagues**** and this one from Cortesi and colleagues*****. Outside of the CBT data, I was particularly interested in the 'controlled-release' bit of the work by Cortesi and co. given the mechanics of variations in endogenous melatonin production. It strikes me that melatonin is an ideal candidate for some of the newer release technologies being looked at in the world of medicines; such that transdermal patches and the like might have something valuable to offer as per other trials. I might talk about patches and newer methods for medication delivery further at some point in the future.

Having said that, and bearing in mind that lots and lots of different 'medications' have probable biological actions outside of those just intended, melatonin might not be just acting on sleep. I recently read an interesting (and yet again, speculative) review article about melatonin as a molecular 'handyman' by Boga and colleagues****** which does get you thinking about the hows and whys. Even the concept of combination therapy seems to have reached melatonin research.

To finish, something rather sleepy from Mama Cass - 'Dream a little dream of me' (but not literally)... yawn.

* Hardeland R. & Pandi-Perumal SR. Melatonin, a potent agent in antioxidative defense: Actions as a natural food constituent, gastrointestinal factor, drug and prodrug. Nutrition & Metabolism. 2005; 2: 22
DOI: 10.1186/1743-7075-2-22

** Rossignol DA. & Frye RE. Melatonin in autism spectrum disorders: a systematic review and meta-analysis. Developmental Medicine & Child Neurology. 2011; 53: 783-792.

*** Tordjman S. et al. Day and nighttime excretion of 6-sulphatoxymelatonin in adolescents and young adults with autistic disorder. Psychoneuroendocrinology. May 2012.

**** Malow BA. et al. Melatonin for sleep in children with autism: a controlled trial examining dose, tolerability, and outcomes. JADD. December 2011.

***** Cortesi F. et al. Controlled-release melatonin, singly and combined with cognitive behavioural therapy, for persistent insomnia in children with autism spectrum disorders: a randomized placebo-controlled trial. Journal of Sleep Research. May 2012.

****** Boga JA. et al. Beneficial actions of melatonin in the management of viral infections: a new use for this "molecular handyman"? Reviews in Medical Virology. April 2012.