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.


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.


  1. Just a few random thoughts -

    First, there was a short case report a few years back about how altering the tryptophan concentration in a child with autism's diet led to improvements in the core symptoms of autism, including insomnia.

    Beretich, Guy R. 2009. “Reversal of autistic symptoms by removal of low-relative tryptophan foods: case report.” Medical hypotheses 73(5):856-7.

    Second, isn't melatonin also a pretty decent antioxidant? Which leads to ...

    Third, is it possible/plausible that enough melatonin is being created but that it is being used up for secondary purposes, such as an antioxidant, so there isn't enough left over to regulate sleep?

    Which, forth, couldn't a disregulation of sleep be partially responsible for some of the brain overgrowth/lack of pruning that is seen in some people with autism.

    And, finally (more of a rant), why aren't more people investigating this problem? If you want to talk one behavior of autism that causes more havoc than almost all of the other behaviors combined, it is sleep disruption. If you could help address sleep issues then you would improve the lives of countless children with autism and their parents.

  2. Thanks for the comment MJ.

    Interesting points indeed and random thoughts are always welcome:

    1. Yes. I am due to post an entry in the coming days focusing on the whole tryptophan - serotonin - melatonin cascade. Low levels of tryptophan - the starting material - alongside potential issues with some of the various enzymes (and their cofactors!) involved in the pathway seem to litter the autism research landscape. Not necessarily consistently though.

    2. Oh yes.

    3. Interesting hypothesis. I'm going to have a more detailed look at how melatonin is used and whether there is a degree of 'priorty' over its usage (particularly the antioxidant role, if issues with things like glutathione may also be present).

    4. Pruning is a much under-researched area in autism. I remember a few people talking about over-zealous pruning as potentially being related to disrupted peptide chemistry but your suggestion seems to tie in better with some of the data.

    5. Why indeed? Perhaps because everyone links melatonin with the sleep-wake cycle and forget that like just about every other compound/drug/metabolite, it might have lots of other important functions? Fair do, there is some good research coming out about melatonin as per the Research Autism entry:

  3. Hi, I wonder if people with autism (and anyone else, for that matter) are coached HOW to help their body produce melatonin naturally. Research i've seen states for a healthy human, people must sleep in a room so dark they cannot see their hand in front of their face. (in fact, they don't even need to be asleep--just being in a dark room is adequate especially between the hours of 2-4 AM. If fact, to be even clearer-- you can "trick" your body and use a sleeping mask so just your EYEs are in the dark--- and it works the same.) Light is the signal to the brain to shut off essential melatonin production. Dim red or amber disrupts melatonin the least; white light high in the blue spectrum disrupts the most... so even blue lights on a clock radio can disrupt the melatonin production. A streetlight filtering in through typical blinds or curtains is enough to shut off melatonin. Recommendations are to Turn OFF TVs, computers, iPhones, etc (which are all high in the blue spectrum) 1-3 hours before bedtime (or use blue-blocker glasses, or a red-colored filter over your screen-- a red plastic clipboard works in a pinch). Use night lights with dim red or amber bulbs placed low toward the floor in the hall or bathroom. Best way to start the day is enjoying breakfast near a sunny window (when the weather cooperates). So, as much sunlight/ bright light during the day... and dark-dark nights is a perfect recipe for normal, essential melatonin production in healthy humans.

    1. Thanks for the comment Audrey.

      It's an interesting thought about learning how to sleep and the various parts of the light spectrum. I note for example that quite a few of the Paleo followers (Stone Age diet if you will) talk about how sleep should done in as dark as you can get it.

      That being said, my understanding of the research on melatonin with autism in mind, suggests that we might be talking about something rather more 'fundamental' with regards to the biology (and genetics) of the sleep-wake cycle.