"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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Cannabis treatment and autism continued

Consider this post talking about the findings reported by Lihi Bar-Lev Schleider and colleagues [1] on the topic of "the epidemiology of ASD [autism spectrum disorder] patients receiving medical cannabis treatment and to describe its safety and efficacy" an extension of other discussions on this blog (see here). Indeed, similar to the paper from Adi Aran et al [2] the name of research game was to look at 'real life experiences' of medicinal cannabis use 'for autism' in Israel (where medicinal cannabis use has been approved for some groups). I foresee this research area growing in months to come...

The focus of the Bar-Lev Schleider paper was CBD - cannabidiol - once again, a component of cannabis distinct from another compound, tetrahydrocannabinol (THC), which is described as being "the principal psychoactive constituent of cannabis." I say the focus was on CBD, but authors mention how: "The treatment in majority of the patients was based on cannabis oil containing 30% CBD and 1.5% THC."

Researchers relied on data "prospectively collected as part of the treatment program of 188 ASD patients treated with medical cannabis between 2015 and 2017." Said participants were an average age of around 13 years old, mostly male and all diagnosed with autism or ASD "in accordance with the accepted practice in Israel." Epilepsy was also mentioned in about 15% of cases, which is interesting in light of the increasing (media) focus on the use of medical cannabis 'for' certain types of epilepsy.

Results: I'm not entirely sure how outcomes with regards to safety and efficacy were actually collected. What I mean by this is that authors describe the use of "the global assessment approach" which meant asking questions like "How would you rate the general effect of cannabis on your child condition?" to participants' parents, but don't seemingly provide details on any specific validated questionnaires used. You might well ask if any such questionnaires exist at the moment with reference to the use of medicinal cannabis, but this doesn't really help matters. Bearing such an issue in mind, researchers reported that: "After six months of treatment 82.4% of patients (155) were in active treatment and 60.0% (93) have been assessed; 28 patients (30.1%) reported a significant improvement, 50 (53.7%) moderate, 6 (6.4%) slight and 8 (8.6%) had no change in their condition." 'Improvement in what?' you might ask. Well, various classes of behaviour are described including those implicated in daily activity - sleep, concentration on daily tasks - among other things. The authors also commented on how medicinal cannabis also seemed to have positively impacted on the occurrence of seizures too: "The improved symptoms at 6 months included seizures, of the 13 patients on an active treatment at six months 11 patients (84.6%) reported disappearances of the symptoms and two patients reported improvement."

And then to another important issue to consider when examining any kind of medicinal product: the presence of (adverse) side-effects. In this respect, we are told: "The most common side effects, reported at six months by 23 patients (25.2%, with at least one side effect) were: restlessness (6 patients, 6.6%), sleepiness (3, 3.2%), psychoactive effect (3, 3.2%), increased appetite (3, 3.2%), digestion problems (3, 3.2%), dry mouth (2, 2.2%) and lack of appetite (2, 2.2%)." Although most of these seem quite minor side-effects, it's still important to recognise them and the distress that they might bring particularly when 'digestion problems' *might* very well compound some already over-represented gastrointestinal (GI) issues already talked about with autism in mind (see here).

"Cannabis as a treatment for autism spectrum disorders patients appears to be well-tolerated, safe and seemingly effective option to relieve symptoms." That's the conclusion reached by Bar-Lev Schleider and colleagues on the basis of their findings. They do note how their results are based on "an observational study with no control group and therefore no causality between cannabis therapy and improvement in patients’ wellbeing can be established" which is important. Important too is the need for further discussions about the ethics of using something like medicinal cannabis in the context of autism [3] and then, if further hurdles are overcome, discussions about the hows-and-whys of a clinical trial or two. Indeed, speaking of clinical trials (see here)...

And as I write this [4] there's more, lots more [5]...

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[1] Bar-Lev Schleider  L. et al. Real life Experience of Medical Cannabis Treatment in Autism: Analysis of Safety and Efficacy. Scientific Reports. 2019: 9.

[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] Duvall SW. et al. Ethical Implications for Providers Regarding Cannabis Use in Children With Autism Spectrum Disorders. Pediatrics. 2019 Jan 4. pii: e20180558.

[4] Barchel D. et al. Oral Cannabidiol Use in Children With Autism Spectrum Disorder to Treat Related Symptoms and Co-morbidities. Front Pharmacol. 2019 Jan 9;9:1521.

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

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Cannabis treatment and autism

"This preliminary study supports [the] feasibility of CBD [cannabidiol]-based cannabis trials in children with ASD [autism spectrum disorder]."

That was the research bottom-line suggested by Adi Aran and colleagues [1] following their retrospective study of some "60 children with ASD and severe behavioral problems" who were given cannabidiol (CBD)-rich cannabis. They report that nearly two-thirds of parents/caregivers of those children in receipt of CBD-rich cannabis observed "much improved or very much improved" behaviour on the Caregiver Global Impression of Change scale, "a 7-point, caregiver rated scale, designed to assess how much the child's symptoms have improved (‘No change’, ‘Slightly improved’, ‘Much improved’, or ‘Very much improved’), or worsened (‘Slightly worse’, ‘Much worse’, or ‘Very much worse’) relative to the baseline state."

Cannabidol (CBD) is a component of cannabis. Distinct from tetrahydrocannabinol (THC) in terms of chemical arrangement, CBD is still thought to have some psychoactive properties, although perhaps not as 'detrimental' as THC [2]. Cannabis and CBD have been fairly big news lately as a consequence of the legalisation of such compounds for specific medicinal uses here in Blighty (see here).

Aran et al report findings suggesting that further controlled research is required in this area. They observed that among their 60 children (50 boys and 10 girls with an average age of 12 and 10 years respectively) taking on average between 4-5 "drugs for behavioral problems", quite a high proportion were still being treated with cannabis "≥ 6 months from treatment onset." Perhaps also importantly, a third of children received less medications or lower dosage of medication following their "cannabis treatment."

I will however add in a word or two of caution following the Aran observations. First, although there is a lot of discussion and hype around the use of medicinal cannabis and various diagnoses / conditions / labels, one still has to remember that this is a drug, and a drug of abuse at that. This mirrors the chatter about another substance of abuse being potentially indicated in the context of autism (see here). Aran et al also talked about some adverse effects noted in their cohort ("sleep disturbances (14%) irritability (9%) and loss of appetite (9%)") including: "One girl who used higher tetrahydrocannabinol [THC] had a transient serious psychotic event which required treatment with an antipsychotic." Others have also independently warned about medical cannabis use [3] citing ASD as one example. What this information imply is that alongside any potential studies of cannabis or specific compounds derived from cannabis with autism in mind, one needs to also keep a focus on the potential downsides to its use as well as any positives...

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[1] 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.

[2] Pierre JM. et al. Cannabis-induced psychosis associated with high potency "wax dabs". Schizophr Res. 2016 Apr;172(1-3):211-2.

[3] Bou Khalil R. Why Is It Important to Protect Children with Mental Disorders from Medical Cannabis? J Dev Behav Pediatr. 2015 Nov-Dec;36(9):766.

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Cannabidiol for drug-resistant seizures in Dravet syndrome

"Cannabis drug cuts seizures in children with severe epilepsy in trial" went one of the headlines referencing the results published by Orrin Devinsky and colleagues [1]. Accompanied by an editorial talking about 'real data, at last' [2] on how a chemical component of cannabis - cannabidiol - might be rather useful for some forms of drug-resistant seizures in Dravet syndrome, there is quite a bit of enthusiasm about these latest findings added to other results from this authorship group (see here). The trial details for their latest results can also be found on the ClinicalTrials.gov website (see here).

Dravet syndrome is something that I had previously heard of in light of some connections being made with the presentation of autism or autistic features [3]. Indeed, in these days of the plural autisms (see here) and adherence to the old 'we don't know what causes autism' mantra (see here), there is still quite a bit more investigation needed on autism appearing alongside known genetic or metabolic conditions and what this might mean for prevalence estimates of autism for example.

Dravet syndrome (DS) - also called severe myoclonic epilepsy in infancy (SMEI) - is primarily characterised by a severe type of epilepsy present in early infancy that continues accompanied by a progressive decline of other developmental functions. Such a regression accompanying seizures has attracted some autism researchers' attention (see here) in view of the clinical profile of DS not being a million miles away from that seen in other instances of autistic regression (see here). This also bearing in mind that autism and epilepsy are also not unstrange bedfellows (see here).

In the latest study Devinsky et al set about testing the possible effectiveness of cannabidiol in cases of DS under the gold-standard - double-blind, placebo-controlled - conditions. Some 120 children and young adults diagnosed with DS were randomly allocated to receive "either cannabidiol oral solution [GWP42003-P] at a dose of 20 mg per kilogram of body weight per day or placebo" over a 14 week period. I should also mention that this was pharmaceutical grade cannabidiol. Researchers primarily focused on seizure frequency between the two groups but did also look at important issues such as the instances and types of adverse events (AEs).

As per the headlines, the results suggested that cannabidiol did seem to be quite effective at reducing the frequency of seizures in the treated group compared to controls. Over 40% of those in receipt of the active medication showed at least a 50% decrease in seizure frequency over the course of study. Perhaps a little worrying were the observations that around a quarter of those in receipt of the placebo also showed a similar pattern of reduction (and why this finding just escaped statistical significance for the group taking the active medicine). Results also showed a pattern of possible 'super-responders' to cannabidiol intervention: "The percentage of patients who became seizure-free was 5% with cannabidiol and 0% with placebo."

But then there were the AEs also identified. So: "Adverse events that occurred more frequently in the cannabidiol group than in the placebo group included diarrhea, vomiting, fatigue, pyrexia, somnolence, and abnormal results on liver-function tests. There were more withdrawals from the trial in the cannabidiol group." This also is a bit of worry, particularly if cannabidiol is something that needs to be constantly taken to maintain any seizure-reducing effects.

On the whole these are interesting findings in need of greater research scrutiny. I will reiterate that this was a controlled study using pharmaceutical grade cannabidiol, so one has to be careful not to assume that either the findings or the intervention will be successful or available to the general population. This is a particularly important point in these days of talk about medicinal cannabis use and condition such as epilepsy (see here) for example.

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[1] Devinsky O. et al. Trial of Cannabidiol for Drug-Resistant Seizures in the Dravet Syndrome. N Engl J Med. 2017 May 25;376(21):2011-2020.

[2] Berkovic SF. annabinoids for Epilepsy - Real Data, at Last. N Engl J Med. 2017 May 25;376(21):2075-2076.

[3] Li BM. et al. Autism in Dravet syndrome: prevalence, features, and relationship to the clinical characteristics of epilepsy and mental retardation. Epilepsy Behav. 2011 Jul;21(3):291-5.

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Devinsky O, Cross JH, Laux L, Marsh E, Miller I, Nabbout R, Scheffer IE, Thiele EA, Wright S, & Cannabidiol in Dravet Syndrome Study Group. (2017). Trial of Cannabidiol for Drug-Resistant Seizures in the Dravet Syndrome. The New England journal of medicine, 376 (21), 2011-2020 PMID: 28538134