NAC for autism: a case study

NAC or N-acetlycysteine has appeared a couple of times on this blog in relation to both autism (see here) and schizophrenia (see here). Not bad for a compound which more readily finds a home in modern medicine following paracetamol (acetaminophen) overdose or as a consequence of its mucolytic properties.

As one might imagine, the autism link is of particular interest to this blog, focused specifically on the findings of Hardan and colleagues* when it came to putting NAC to the [albeit preliminary] experimental test. The results by the way were encouraging for at least some parts of the presentation of childhood autism with the promise of more to come.

As a sort of follow-up to the Hardan paper, I'm talking today about a case report offered by Ghanizadeh & Derakhshan** (open-access) highlighting a little more individual detail following the use of NAC with an 8-year old boy diagnosed with autism. I know the word 'case report' sends a shudder down many a scientific shoulder, but as I've said quite a few times before, we ignore the N=1 in autism at our peril given the wide, wide heterogeneity present and all that associated comorbidity to contend with. Real personalised medicine you might say.

If I have managed to persuade you to listen to the rest of my ramblings on this paper and topic, there are a few important points to make about/from the Ghanizadeh paper:

• From the description provided, the child in question seemed quite floridly autistic with the important add-ons of hyperactivity and inattention present from an early age. Although we aren't told what exactly it means, the authors note: "His laboratory examination was unremarkable".
• Oral NAC (800mg per day) was begun as part of another trial by the authors to counteract nail-biting***. As unusual as it might sound, mail-biting has been a focus of some NAC research coincident to the presence of anxiety.
• Indeed, the boy's nail-biting behaviours did seem to subside alongside the installation of NAC but perhaps of greater interest were the reports that "there was a marked reduction in his autism symptoms 30 days after the onset of NAC administration". OK so this report did come from the boy's parents, and without causing any offence, the issue of objectivity might come into play.
• The types of 'changes' reported however were in core areas such as his verbal skills, social interaction and a quite unusual preoccupation with having his hair cut (I say unusual because a visit to the barber or hairdresser described by many parents about their child with autism, is often characterised by entirely the opposite reaction).
• Aside from "a mild abdominal pain" the authors importantly say that "nothing worsened after the administration of NAC" which I take to indicate that side effects were minimal over the course of the intervention.

I should have perhaps mentioned at the beginning that there is some sound logic why NAC might have some effect on cases of autism. The amino acid cysteine as well as containing sulfur, so potentially tied into to that most forgotten areas of autism research sulfur chemistry (see here), is also the precursor to another important compound, glutathione. I know my regular readers are probably getting a little bored of me going on about this 'elephant in the room' and in particular that glutathione overview paper by Main and colleagues (see here) but a possible link is a possible link.

I was also interested to read the authors' discussions on how NAC might also have the ability to decrease "high glutamate levels". As any good biochemist will tell you, glutathione, which is dependent on cysteine, is a tripeptide which also incorporates the amino acids glycine and glutamate into its triadic manufacture. From that point of view, circumstances where any of the three amino acids were low or not optimally biologically available might affect the production of glutathione. If that happens to mean you have low cysteine levels, glutathione would be low but also this might mean levels of glutamate or glycine could be higher as a result of not being used up to make glutathione. Glutamate is another compound finding some significant interest with regards to autism and conditions presenting with autistic symptoms.

Reiterating that the Ghanizadeh paper is a case report, I do find there to be some interesting observations reported. With my speculating hat on, I do wonder whether that link with nail-biting and onwards anxiety suggested for NAC might also be part and parcel of the effect observed in this case given the quite considerable link suggested between autism and anxiety (see here)?

And by the looks of things NAC is in the research ascendancy perhaps even with a prophylactic effect****...

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* Hardan AY. et al. A randomized controlled pilot trial of oral N-acetylcysteine in children with autism. Biol Psychiatry. 2012 Jun 1;71(11):956-61. doi: 10.1016/j.biopsych.2012.01.014.

** Ghanizadeh A & Derakhshan N. N-acetylcysteine for treatment of autism, a case report. J Res Med Sci. 2012 Oct;17(10):985-7.

*** Ghanizadeh A. et al. N-acetylcysteine Versus Placebo for Treating Nail Biting, A Double Blind Randomized Placebo Controlled Clinical Trial. Antiinflamm Antiallergy Agents Med Chem. 2013 May 6. [Epub ahead of print]

**** Beloosesky R. et al. Prophylactic maternal N-acetylcysteine in rats prevents maternal inflammation-induced offspring cerebral injury shown on magnetic resonance imaging. Am J Obstet Gynecol. 2013 Mar;208(3):213.e1-6. doi: 10.1016/j.ajog.2013.01.023.

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Ghanizadeh A, & Derakhshan N (2012). N-acetylcysteine for treatment of autism, a case report. Journal of research in medical sciences : the official journal of Isfahan University of Medical Sciences, 17 (10), 985-7 PMID: 23826003

That recent metabolomics study on autism (part 2)

Consider this a part-two to my previous post introducing the paper from Dr Xue Ming and colleagues* on metabolomics, amino acids and gut bacteria with autism in mind. It's going to be another micropost (sort of!) given that quite a bit of the background has already been discussed previously.

So straight to the paper:

• As expected, the study from Yap and colleagues** (including Prof. Nicholson) was the template for undertaking this study.
• Spot urine samples were collected from 48 children diagnosed with DSM-IV autism; in some cases confirmed by the gold-standards that are ADOS and ADI, and compared with 53 matched asymptomatic controls.
• Alongside the various screening measures, a gastrointestinal [disorder] GI severity scale was used to ascertain the presence of GI dysfunction. (verified in 29/48 children with autism).
• Mass spectrometric analysis of the urine sample, blah, blah, blah, and out of a total of 391 metabolites, confirmed metabolites, located in samples, 82 of them were altered between autism and control samples.
• Amino acids et al: several amino acids were significantly lower in the autism group including glycine, serine and the alanines. Taurine also featured. Indeed quite a few of the gamma glutamyl amino acids were also reduced in the autism group with a link to GI disorders potentially suggestive of issues with gamma glutamyl transpeptidase.
• Gut bacterial metabolites: some really interesting stuff here and very much influenced by the presence of GI problems or not. Of particular note, "significantly increased levels of 2-(4-hydroxyphenyl)propionate and taurocholenate sulfate" and reduced levels of 3-(3-hydroxyphenyl)propionate and 5-aminovalerate.
• Mention is also made of some of the gut bacterial findings previously made with autism in mind, and even the possibility of gut hyperpermeability (leaky gut) as influencing the absorption of metabolites. Think back to Paul Patterson' recent announcement on mice, leaky gut and gut bacteria.

A couple of quick observations. Taurine: OK, more an organic acid than an amino acid. Found to be significantly lower in the autism group results compared with controls in this study, but by contrast, elevated in the Yap study. One could argue that there were participant geographical differences (Ming: USA vs. Yap: Australian/Swiss) which might reflect genetic, dietary or environmental differences across different geographical groups. It's interesting to note also that in the Yap paper they noted that "taurine concentrations were hypervariable in the autism group". That and the differences across analytical technologies (Ming: mass spec vs. Yap: NMR). Autisms not autism? Who knows?

Lower urinary glycine and indeed N-acetylglycine were also picked up in the autism group of the Ming study. I don't want to make too much of this at the moment but perhaps will throw in two possibly relevant things: (a) that very interesting paper from Andrew Clayton on autism, aromatic amino acids and gut bacteria (see this post) which talked about benzoic acid and hippuric acid and the link with glycine and (b) the very interesting area of glycine and sleep (see this post). I'm not making any value judgements bearing in mind the focus on urinary glycine not plasma levels of glycine, so just putting it out there.

There's not too much more to say on the the Ming paper apart from being a really interesting piece of research and with a strong requirement for independent scientific replication. That and given the focus on comorbid GI conditions appearing alongside some cases of autism, perhaps a lot more inspection into the root causes and management of them. Indeed look no further than the special Pediatrics supplement on autism for quite an interesting opinion paper*** on this topic with some pretty big hitters as part of the authorship group.

And rest.

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* Ming X. et al. Metabolic perturbance in autism spectrum disorders: a metabolomics study. J Proteome Res. October 2012.

** Yap IK. et al. Urinary metabolic phenotyping differentiates children with autism from their unaffected siblings and age-matched controls. J Proteome Res. 2010; 9: 2996-3004.

*** Coury DL. et al. Gastrointestinal conditions in children with autism spectrum disorder: developing a research agenda. Pediatrics. 2012; 130: S160-S168.

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Ming X, Stein TP, Barnes V, Rhodes N, & Guo L (2012). Metabolic Perturbance in Autism Spectrum Disorders: A Metabolomics Study. Journal of proteome research PMID: 23106572

Glycine as a sleep aid?

Sleeping beauty @ Paul Whiteley

When it comes to sleep and autism, or more specifically suggestions on how to improve sleeping patterns and sleep duration in cases of childhood autism, one compound crops up time and time again: melatonin.

I've talked about melatonin quite a bit on this blog; running through the current evidence for effect (here) and also speculatively discussing some of the ways and means that melatonin is made (here) and where the various findings on alterations in levels of the stuff in cases of autism might be derived from. 

All very interesting for the 'miracle' that is melatonin, bearing in mind that even melatonin supplementation might have a downside for some (including some pretty important drug interactions).

Having said all that, and again pronouncing my mantra: no medical advice given or intended, I was very interested to hear about another area of possible interest specifically with sleep in mind, supplementation with the amino acid glycine.

I don't know if you know or not but I'm a bit of a fan of amino acid chemistry and the myriad of ways that amino acids influence our health - somatic and psychiatric - and wellbeing. I've tended to focus quite a bit on the aromatic amino acids (tryptophan, tyrosine, phenylalanine) simply because of the various important links that have been made with for example serotonin (5-HT) chemistry and the in-born errors of metabolism such as PKU. I was also very interested in the whole branched-chain amino acids and rare cases of autism connection made quite recently.

Glycine is a little bit different in that it is categorised as a non-essential amino acid (i.e. the body can make the stuff itself); the body being capable of synthesising glycine from another amino acid serine (see here for a really small and complicated picture of how this happens).

The University of Wikipedia(!) reports that glycine is, quite importantly, also an inhibitory neurotransmitter; a point included in this overview by Bowery & Smart* (full-text) who also discuss the links with another important inhibitory neurotransmitter, GABA (see recent post). Mention of the words 'inhibitory' and 'GABA' immediately get me thinking about the sleep connection to glycine based on what an inhibitory neurotransmitter like GABA (and its receptors) has been suggested to be able to do.

Believe it or not, there is actually some peer-reviewed literature on the potential usefulness of glycine supplementation with sleep in mind. This paper by Bannai & Kawai** (full-text) is as good as any in outlining this fact, together with some speculation on the mode of action being linked to a lowering of body temperature normally experienced during sleep. Indeed the lead author, Makoto Bannai, seems to be quite interested in the whole glycine-sleep area as per another article*** suggesting that glycine supplementation might also cut down on perceived "daytime sleepiness and fatigue induced by acute sleep restriction" during a placebo-controlled trial. I hasten to add that this effect seemed independent of any findings related to melatonin.

Appreciating that quite a bit more research might need to be done on glycine and the link with sleep, I can't help but wonder whether glycine might also show some favour in cases of autism with sleeping issues. I stress that I am not advocating this or any other position without the appropriate medical advice and guidance. In view however of the speculations on glycine and body temperature - something also noted in cases of autism - and some very, very soft evidence on glycine supplementation and peripheral features like hyperactivity (here), one has to at least wonder whether more investigation is warranted.

Indeed bearing in mind that products such as dimethylglycine (DMG) and trimethylglycine (TMG) have already been discussed with autism in mind, could there be a greater effect over just altering stomach pH and the delivery of methyl groups to a potentially hypomethylating population?

To finish, somebody that I used to know? I dunno him but maybe you do.

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* Bowery NG. & Smart TG. GABA and glycine as neurotransmitters: a brief history. British Journal of Pharmacology. 2006; 147: S109-S119.

** Bannai M. & Kawai N. New therapeutic strategy for amino acid medicine: glycine improves the quality of sleep. Journal of Pharmacological Sciences. 2012; 118: 145-148.

*** Bannai M. et al. The effects of glycine on subjective daytime performance in partially sleep-restricted healthy volunteers. Frontiers in Neurology. 2012; 3: 61.

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Bannai M, & Kawai N (2012). New therapeutic strategy for amino acid medicine: glycine improves the quality of sleep. Journal of pharmacological sciences, 118 (2), 145-8 PMID: 22293292