"serum levels of certain endocannabinoids are substantially decreased in people with ASD"

The quote titling this post - "serum levels of certain endocannabinoids are substantially decreased in people with ASD [autism spectrum disorder]" - comes from the paper published by Adi Aran and colleagues [1]. It adds to previous study on this topic (see here) and continues a research theme from members of this authorship team where the word 'cannabis' is being discussed - in the peer-reviewed science domain - in the context of [some] autism (see here).

Distinct from the last time authors' research appeared on this blog talking about the feasibility of "Cannabidiol-Rich Cannabis" 'for autism' [2], the name of the research game this time around was to assess "the circulating levels of several endocannabinoids and delineate the correlations between their levels and disease characteristics in a large group of children with ASD and their matched controls with typical development." Researchers mention how previous studies in this area "were not designed to comprehensively characterize the involvement of the ECS [endocannabinoid system] in the pathogenesis of ASD" in quite a sweeping blow to some of the other research in this area.

So, endocannabinoids are part of a system that is involved in various important biological processes [3]. As the name suggests there's an overlap between 'endogenous cannabinoids' and some of the chemical components seen in cannabis that provides as good an answer as any as to why cannabis use/misuse is the continuing issue that it is in a population sense. Authors talk about their study focusing on various endocannabinoids: AEA (anandamide), 2-AG (2-arachidonoil-glycerol), AA (arachidonic acid), PEA (N-palmitoylethanolamine), and OEA (N-oleoylethanolamine). They report how said compounds in serum samples were "analyzed by liquid chromatography/tandem mass spectrometry in 93 children with ASD... and 93 age- and gender-matched neurotypical children." Please don't however get me started on the nonsense that is the word 'neurotypical' (see here). Various other behavioural, psychometric and demographic data were also collected and thrown into the statistical mix.

Results: "Serum levels of the main endocannabinoid AEA and its structurally related compounds OEA and PEA were lower in children with ASD versus age-, gender-, and BMI [body mass index]-matched control group of typically developed children." Nothing particularly new there, as the lower levels of anandamide for example, mimic those reported by Karhson and colleagues [4]. Researchers also mentioned how their findings *might* also have some other potential: "circulating AEA, OEA, and PEA might be used to identify a biologically homogeneous subgroup of ASD, predict response to treatments and adverse reactions to medications, and assist in the development of novel drugs that target specific core symptoms of ASD." Interestingly, some of these 'options' have already been explored [5] in humans and also some animal models [6] with autism in mind.

As to the biochemical *links* between the Aran findings and indeed, the ECS more generally with autism, well, there's still a way to go to decipher them all yet. There are clues emerging [7]; clues that intersect with other important autism-relevant concepts like inflammation among other things. I note also the authors mention how their findings "support the rationale in the ongoing and emerging clinical trials of CBD [cannabidiol] in ASD" (see here) and some results to come.

I'm well and truly [cautiously] interested...

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[1] Aran A. et al. Lower circulating endocannabinoid levels in children with autism spectrum disorder. Molecular Autism. 2019; 10:2.

[2] Aran A. et al. Brief Report: Cannabidiol-Rich Cannabis in Children with Autism Spectrum Disorder and Severe Behavioral Problems-A Retrospective Feasibility Study. J Autism Dev Disord. 2018 Oct 31.

[3] Lu HC. & Mackie K. An Introduction to the Endogenous Cannabinoid System. Biol Psychiatry. 2015;79(7):516-25.

[4] Karhson DS. et al. Plasma anandamide concentrations are lower in children with autism spectrum disorder. Mol Autism. 2018 Mar 12;9:18.

[5] Antonucci N. et al. Beneficial Effects of Palmitoylethanolamide on Expressive Language, Cognition, and Behaviors in Autism: A Report of Two Cases. Case Rep Psychiatry. 2015;2015:325061.

[6] Servadio M. et al. Targeting anandamide metabolism rescues core and associated autistic-like symptoms in rats prenatally exposed to valproic acid. Transl Psychiatry. 2016 Sep 27;6(9):e902.

[7] Brigida AL. et al. Endocannabinod Signal Dysregulation in Autism Spectrum Disorders: A Correlation Link between Inflammatory State and Neuro-Immune Alterations. Int J Mol Sci. 2017;18(7):1425. Published 2017 Jul 3.

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Plasma anandamide concentrations are lower in children with autism

The findings reported by Debra Karhson and colleagues [1] piqued my interest for two primary reasons. First, they detail "the first empirical human data to translate preclinical rodent findings to confirm a link between plasma anandamide concentrations in children with ASD [autism spectrum disorder]." Second, authors also report on the use of a gold-standard technique when it came to their analyses: the development and use of "a LC-MS/MS [liquid chromatography-tandem mass spectrometry] method to quantitatively analyze AEA [anandamide] concentrations in small volumes of banked plasma with short sample preparation time and high sample repeatability."

OK, the basis for the Karhson study was the 'increasing interest for ASD' examining the endogenous cannabinoid or endocannabinoid system. This is a system, an internal system, that comprises of quite a few compounds, enzymes and receptors that play "important roles in central nervous system (CNS) development, synaptic plasticity, and the response to endogenous and environmental insults" [2]. Yes, as the name suggests, there is an 'overlap' between some of the workings of the endocannabinoid system (ECS) and components of a certain drug of abuse but that doesn't insinuate anything at the present time.

Anandamide (AEA) is a sort of messenger molecule that is part of the ECS. It shares some chemical characteristics with the active compound found in cannabis, leading quite a few commentators to talk about AEA in terms of being a 'pleasure' or 'bliss' molecule. It does not however, have the 'staying power' of its molecular companion; chemically-speaking being fairly readily degraded in the body. Indeed, of the many biological roles and functions linked to AEA and the ECS more generally, I'd in particular, like to direct your attention to some of the science-so-far literature in relation to pregnancy (see here). And, no, that does NOT mean that smoking marijuana during pregnancy is a good thing...

The authors highlight how the ECS is a research area rising in relation to autism (and associated diagnoses) based, quite extensively, on animal models of autism and all the associated 'issues' that this carries (see here). So: "despite the promise of these preclinical data, no studies to date have investigated AEA concentrations in humans with ASD." They sought to remedy that situation.

Results are reported based on the LC-MS/MS analysis of plasma samples provided by some 59 children with autism and 53 not-autism controls. As per my continued interest in all-things mass spec when specifically applied to autism research, I was encouraged by the use of a "commercially available stable isotope-labeled AEA-d8" being used as an internal standard, and the fact that the lower limit of detection for AEA was in the femtogram range. In short, authors were able to train their system to specifically look for AEA and were able to get down to some really quite low levels of detection.

"Two significant findings were observed: (1) plasma AEA concentrations significantly differentiated ASD cases from controls, such that children with lower AEA concentrations were more likely to have ASD, and (2) AEA concentrations were significantly lower in ASD compared to control children." I don't really need to say much more than that, aside from adding in another quote: "These results, although preliminary, corroborate preclinical evidence that AEA signaling may be impaired in patients with ASD."

The question of what these findings actually mean is still unanswered. It should for example, be noted that the Karhson results in real people were based on the analysis of plasma samples, where previous animal work has tended to be a little more 'invasive' in terms of the tissue types looked at (e.g. in the brain). The authors also mention that further investigations need to give due credit to the idea that autism rarely exists in some sort of diagnostic vacuum (see here), and some of these 'comorbidities' could very well influence the results obtained [3].

Further studies on this topic are very much required.

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[1] Karhson DS. et al. Plasma anandamide concentrations are lower in children with autism spectrum disorder. Molecular Autism. 2018; 9: 18.

[2] Lu H-C. & Mackie K. An introduction to the endogenous cannabinoid system. Biological Psychiatry. 2016;79(7):516-525.

[3] Romigi A. et al. Cerebrospinal fluid levels of the endocannabinoid anandamide are reduced in patients with untreated newly diagnosed temporal lobe epilepsy. Epilepsia. 2010 May;51(5):768-72.

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