Italy is home to some unconventional medicine
Today we see how you can target these receptors without the need to use any kind of cannabis.
I do spend time encouraging Monty’s 18-year-old big brother to avoid recreational drugs; so that is to declare my broader perspective on the issue. These drugs seem very popular among college students of every nationality, but according to my son particularly among those from countries where they cannot freely buy alcohol, like the US.
In today’s post we go back to look at PEA (Palmitoylethanolamide) which I proposed, and then rejected, as an autism therapy way back in 2014. PEA is widely used to treat neuropathic pain in Italy and Spain. PEA is a substance you already have in your body and it plays a role in inhibiting mast cells to degranulate, it is a PPARα agonist and it affects the Cannabinoid receptors CB1 and CB2.
I did recently come across PEA again when looking at case histories un-related to autism and I bought the identical product used in the case histories, and in the quantity required to make a genuine trial on myself.
My autism trial in 2014 did not show any effect, but I did not continue very long and I think I used the Dutch version, not the Italian product, naturally used in all the Italian research.
PEA does not cross the blood brain barrier well and is not absorbed well. There are prodrugs of PEA that do cross the BBB, but these are not commercially available.
We have nonetheless seen many times that reducing inflammation in the periphery does, perhaps surprisingly, affect the brain.
Another point to mention, since the gut microbiome is perhaps even more fashionable as cannabis, is that PEA does indeed modify the microbiome.
My old post from 2014: -
Human Growth Factors, Autism and the Centenarian Nobel Laureate
It turns out that from 2015 onwards Italian researchers started to look at PEA as an autism therapy. They have tested it in two different mouse models of autism and they have published case histories in humans.
PEA is big in Italy because the underlying research is Italian and the Nobel Laureate in my 2014 post was an Italian.
Italian medicine – where anything goes?
Our reader Tatjana has an Italian autism doctor. The only Italian autism clinician/researcher I ever contacted was Antonio Persico, but he was one of the few that did not reply.
Today we get a chance to read Italian autism research and many Europeans will be surprised how "American" these Italian doctors seem to be. The long-time followers of alternative medical therapies may recall Dr Bradstreet, the American DAN doctor who died from gun shots, he had some research pals in Italy and they are among the authors of one of the case studies.
Today we get a chance to read Italian autism research and many Europeans will be surprised how "American" these Italian doctors seem to be. The long-time followers of alternative medical therapies may recall Dr Bradstreet, the American DAN doctor who died from gun shots, he had some research pals in Italy and they are among the authors of one of the case studies.
For our North American readers, in most of the world there is only one kind of doctor, an MD, and they tend to be much more tightly controlled than in the US. For example, in the United Kingdom you will not find a single DAN doctor, or MAPS doctor. There used to one DAN type doctor from New Zealand and he was banned from seeing patients with autism.
Italy seems to be more Californian, as you will see if you read the doctors’ full case histories.
Palmitoylethanolamide (PEA) in mouse models of Autism
Highlights
· Autistic-like behaviour of BTBR mice are reversed by PEA through PPAR-α activation.
· PEA restores hippocampal BDNF signaling pathway and mitochondrial dysfunction.
· PEA improves central and peripheral inflammatory state of BTBR mice.
· PEA modulates gut microbiota composition in BTBR mice.
Abstract
Autism spectrum disorders (ASD) are a group of heterogeneous neurodevelopmental conditions characterized by impaired social interaction, and repetitive stereotyped behaviours. Interestingly, functional and inflammatory gastrointestinal diseases are often reported as a comorbidity in ASDs, indicating gut-brain axis as a novel emerging approach. Recently, a central role for peroxisome-proliferator activated receptor (PPAR)-α has been addressed in neurological functions, associated with the behaviour. Among endogenous lipids, palmitoylethanolamide (PEA), a PPAR-α agonist, has been extensively studied for its anti-inflammatory effects both at central and peripheral level.
Based on this background, the aim of this study was to investigate the pharmacological effects of PEA on autistic-like behaviour of BTBR T+tf/J mice and to shed light on the contributing mechanisms.
Our results showed that PEA reverted the altered behavioural phenotype of BTBR mice, and this effect was contingent to PPAR-α activation. Moreover, PEA was able to restore hippocampal BDNF signaling pathway, and improve mitochondrial dysfunction, both pathological aspects, known to be consistently associated with ASDs. Furthermore, PEA reduced the overall inflammatory state of BTBR mice, reducing the expression of pro-inflammatory cytokines at hippocampal, serum, and colonic level. The analysis of gut permeability and the expression of colonic tight junctions showed a reduction of leaky gut in PEA-treated BTBR mice. This finding together with PEA effect on gut microbiota composition suggests an involvement of microbiota-gut-brain axis.
In conclusion, our results demonstrated a therapeutic potential of PEA in limiting ASD symptoms, through its pleiotropic mechanism of action, supporting neuroprotection, anti-inflammatory effects, and the modulation of gut-brain axis.
Aims
Autism spectrum disorder (ASD) is a condition defined by social communication deficits and repetitive restrictive behaviors. Association of the fatty acid amide palmitoylethanolamide (PEA) with the flavonoid luteolin displays neuroprotective and anti-inflammatory actions in different models of central nervous system pathologies. We hypothesized that association of PEA with luteolin might have therapeutic utility in ASD, and we employed a well‐recognized autism animal model, namely sodium valproate administration, to evaluate cognitive and motor deficits.
Methods
Two sets of experiments were conducted. In the first, we investigated the effect of association of ultra micronized PEA with luteolin, co‐ultra micronized PEA‐LUT® (co‐ultraPEA‐LUT®) in a murine model of autistic behaviors, while in the second, the effect of co‐ultraPEA‐LUT® in a patient affected by ASD was examined.
Results
Co‐ultraPEA‐LUT® treatment ameliorated social and nonsocial behaviors in valproic acid‐induced autistic mice and improved clinical picture with reduction in stereotypes in a 10‐year‐old male child.
Conclusion
These data suggest that ASD symptomatology may be improved by agents documented to control activation of mast cells and microglia. Co‐ultraPEA‐LUT® might be a valid and safe therapy for the symptoms of ASD alone or in combination with other used drugs.
Palmitoylethanolamide (PEA) in human case studies
Introduction. Autism spectrum disorders are defined by behavioral and language atypias. Growing body of evidence indicates inflammatory mediators may contribute to the condition. Palmitoylethanolamide (PEA) is naturally occurring and has been available as a nonprescription medical food supplement in Europe since 2008. PEA has been tested in thousands of human subjects without any noted significant side effects. Here we report the first cases of the administration of PEA to two children with autism. Case Presentations. The first 13-year-old male child (Subject 1) presented with a total IgE of 572 IU/mL (nl < 200) and with low mature CD57+ natural killer cell counts (32 cells/µL; nl = 60–300 cells/µL) and with significant eczema and allergic stigmata. Expressive language, as measured by mean length of utterance, and overall autism severity as measured by the Childhood Autism Rating Scale, Second Edition, improved significantly. Atopic symptoms diminished. No side effects were reported. The second male child, age 15 (Subject 2), also displayed noticeable and rapid improvements in cognitive, behaviors, and sociability. Conclusion. Currently, there is no definitive treatment for autism condition. Palmitoylethanolamide could be an effective treatment for autism syndrome. We propose appropriate double-blind clinical trials to further explore palmitoylethanolamide efficacy and safety.
2.2. Subject 1
He is a 13-year-old autistic male with a well-documented history of significant atopic illnesses. He was originally diagnosed with autism by a child neurologist at age of 21 months following a significant regression in child development noted after a viral-like illness with associated high fevers (up to 45.5°C) at age of 15 months. Chronic urticaria, eczema, allergic rhinitis, and asthma have been treated with a variety of antihistamines, montelukast, and topical and systemic steroids since age of 2 years with only temporary beneficial effects. Serum food allergy testing revealed IgE mediated responses to the following: corn, peanut, soybean, wheat, milk, rice, egg, and numerous other dietary proteins. Both skin prick testing and serum IgE inhalant allergy testing revealed similar patterns of significant reactions to most antigens tested including dust mites and nearly all grasses, trees, weeds, molds, and both domestic and farm animals. Both traditional desensitization with injectable antigens and sublingual immunotherapies have failed to reduce allergic stigmata and had no noticeable effects on the course of the child's autism. Total serum IgE testing on numerous occasions has been significantly elevated and at the time PEA was introduced; it was 572 IU/mL (nl ≤ 200). Despite the high total levels of IgE and multiple IgE reactants, blood eosinophils have remained in the normal range throughout. Serum vitamin D-OH25 levels remain deficient despite extensive efforts at oral supplementation, inferring a defect in absorption of fat-soluble nutrients. Serum vitamin D-OH25 levels were at 21 ng/mL at the time PEA was started.
Cellular immune markers reflected specific abnormalities with deficient mature CD57+ natural killer (CD57+ NK) cell counts 32 cells/μL (nl = 60–300 cells/μL), with a total white count of 6.3 × 103/μL. However, the percentage of lymphocytes was high at 58%, while neutrophils were underrepresented at 33%, and absolute lymphocytes were also elevated at 3.5 × 103 cells/μL. All other obtained typical cell indices were in the normal range.
The Childhood Autism Rating Scale, Second Edition (CARS-2) [21], was administered as part of a routine evaluation of the child's severity prior to a change that is his academic placement. Prior to PEA, CARS-2 scoring placed the child at 43.5 total (82nd percentile) with a verbal communication subscale of 3 out 4. A speech assessment was performed including a mean length of utterance (MLU) measurement. MLU is based on the linguistic concept of morphemes as the smallest component of speech [6]. Speech therapists use MLU as a routine assessment and, in this case, MLU was obtained prior to a change in school placement. MLU was observed to be 3.0 prior to PEA and this corresponded to an age equivalent of approximately 34-35 months (just under a 3-year-old level of speech).
2.3. Post-PEA Supplementation (Subject 1)
After the practitioner reviewed the medical literature and the therapeutic rationale with his parents, they treated the child with Normast 600 mg tablets (Epitech Group Srl, Milano, Italy). Normast is available without prescription in Italy and Spain and is classified as “Food for Special Medical Purposes” by the Health Authorities of European Union member states according to standards set forth under European Commission Directive 1999/21/EC.
Initially, 1/2 tablet (300 mg) was given orally with water twice daily on an empty stomach to this boy (a child capable of swallowing tablets). After a week with no observable negative effects, the dose was increased to 1 (600 mg) tablet twice daily. Subject 1's parents returned for assessment after one month of oral supplementation with PEA. They reported “remarkable” changes in his behavior and his expressive language. Specifically, they noted he was spontaneously joining a conversation and commenting on various things happening in the home. The parents also reported the schoolteacher and speech therapist inquired about what had changed and noted similar positive changes at school. Equally noteworthy was the significant reduction in tantrums, outburst, self-talking, and stereotypies. Further, nose-picking, asthmatic cough, allergy stigmata (dark circles under eyes and nasal itching), nasal edema, and both skin eczema and urticaria diminished clinically after a month of PEA administration. No adverse effects were noted.
Following these comments, we re-administered the CARS-2 test and noted a total score of 32 (representing the 28th percentile) whereas the starting score was 43.5 (net change 11.5 points and 54 percentiles less). The subscale for expressive language changed to 2 out 4 and represented significant and noticeable changes. Due to these observations, we suggested repeating the MLU assessment for further definition of the degree of language changes. Reassessment of MLU also changed significantly to 5.4 (approximately 58 month's age-equivalency). This represented a 2-year age gain in expressive language in only one month of supplementation with PEA.
Total serum IgE testing after PEA was introduced remained essentially unchanged at 567 IU/mL (nl < 200). Serum vitamin D-OH25 levels rose to 46 ng/mL after PEA was started (possibly due to better absorption). CD57+ natural killer (CD57+ NK) cell counts increased after PEA to 52 cells/μL (nl = 60–300 cells/μL), with a total white count remaining similar at 5.6 × 103/μL. Noticeably the percentage of lymphocytes reduced to 44%, and the other cell indices were also in the normal range.
2.4. Subject 2
He is an Italian 15-year-old male, whom developed normally for the first 2 years, but near 3 years of age, the child developed a progressive loss of previously acquired language, eye contact, and social interaction. Ultimately, this was diagnosed with autism spectrum disorder. At 6 years of age, he experienced his first partial complex epileptic episode, described as the sudden onset of unconsciousness with resultant loss of motor control. The child fell and struck his head although no apparent concussion occurred. He was eventually treated with sodium valproate. The last episode of epilepsy was in March 2006. No recurrent seizures have been reported. After this event the family initiated dietary restriction by eliminating gluten, casein, yeast, sugar, and soy, and they also began supplementation of a multivitamin and additional folic acid. He started diet restriction and vitamins since 2007 at age of 8 years and never stopped. Following these changes the child's overall tone and energy improved and sensory integration also became more appropriate.
The Autism Treatment Evaluation Checklist (ATEC) [22] test was administered as part of a routine evaluation of the child's severity prior to a change in his academic placement. The ATEC has been shown to correlate with the CARS test in domains of sensory/cognitive awareness, speech/language, and sociability [23]. Prior to PEA supplementation the ATEC total scoring was in the mild to moderate range, specifically 25 (a lower number is better): speech 6 of 28 points, sociability 3 of 40 points, sensory/cognitive 1 point (normal), and overall health/behaviors 15 of 75 points. Total serum IgE testing was in the normal range at 127 IU/mL (nl < 200). Serum vitamin D-OH25 levels were normal at 45.10 ng/mL at the time PEA was started. We conducted the observations until three months after treatment. The boy never stopped diet restrictions and multivitamin supplementation since 2007.
2.5. PEA Supplementation
After practitioner NA reviewed the medical literature and the therapeutic rationale with his parents, they treated the child with Normast 600 mg tablets (Epitech Group Srl, Milano, Italy). After three months of supplementation, ATEC total score reduced by half (12 (after) versus 25 (before) points). The individual scores in the separate domains were speech 4 points, sociability 1 point, sensory/cognitive 0 points, and overall health/behaviors 7 points (Figure 1, Table 1). Also shown for comparison in (Figure 1, Table 1) are the child's improvements in aggression and cognitive and behavioral skills. Language showed mild improvements. In addition, in this case, total serum IgE reduced by half (66.0 post compared to 127 IU/mL pre-PEA). No adverse effects were noted (i.e., nausea, fever, hyperactivity, sleep disorders, skin rash, allergic reactions, and gastrointestinal problems).
Dynamics on a scale of Autism Treatment Evaluation Checklist (ATEC) in Subject 2 autistic patient before (baseline) PEA supplementation and three months later. The purpose of the ATEC is to measure change in an individual due to various interventions, that is, the difference between the initial (baseline) ATEC scores and later ATEC scores
4. Conclusion
In this original report of two cases, we show PEA-mediated effects may be beneficial for treating core symptoms of autism. PEA is a well-studied, apparently safe even in the pediatric population, anti-inflammatory capable of regulating mast cells and modulating immune chemistry. It is manufactured in the EU and prepared under strict standards according to Good Manufacturing Practice (GMP). PEA also appears to be an atypical endocannabinoid, with additional anti-inflammatory effects mediated via the PPAR pathway. In the United States, recent prevalence data indicate greater than 2% of boys may have ASDs [35, 36]. Given the urgent need for safe and effective strategies for treating ASDs, we propose appropriate double-blind controlled clinical trials to explore further the potential for PEA efficacy and its safety.
Acknowledgments
This study is dedicated to the memory of Professor James Jeffrey Bradstreet who passed away on June 19, 2015. His contribution to this work is fundamental.
Patient History
The participating physician who brought to our attention the patient for this study is part of our group's collaborative clinical network. This male child was born at term with natural spontaneous delivery [39 weeks + 6 days with an Apgar index between 8 and 10] and was found to have Tetralogy of Fallot, which was corrected surgically at the age of 3 months without complications. As is typical with autism, physical, and mental development appeared normal during the first few years of life. At the age of 28 months febrile episodes occurred, which were treated with antibiotics and nonsteroidal anti-inflammatory drugs. In April 2005, the parents reported three febrile episodes in succession characterized by inflammation of the upper respiratory tract; these were treated with oral antibiotics and nonsteroidal anti-inflammatory drugs and with paracetamol to control hyperpyrexia. At this time, over the course of 30 days, behavioral changes suddenly emerged: the child began to show rejection behavior of strangers with weeping and escape responses toward other children of same age; hyperactivity with constant running; changed eating behavior with refusal of food and limiting the choice only to 3–4 kind of aliments; up to 7–8 bowel movements per day; loss of acquired verbal skills, avoidance of gazing at people, and appearance of motor stereotypes. Approximately 30 days after onset of the first episode of fever, the child was admitted to the day hospital at the Pediatric Neuropsychiatry Clinic of Saint Gerardo Hospital—Monza, where a diagnosis of “delay of verbalization and socialization” with suspected autism was made. The child lives with his family in a provincial town, far from sources of industrial pollution. The mother (36 years old at time of childbirth) did not take any medications during pregnancy with the exception of supplementation with folic acid, iron, calcium, and magnesium; amniocentesis was performed at week 16 without complications and the remainder of the pregnancy followed a regular course. A genetics analysis of the patient was not performed, although there was no family history of autism.
Protocol with Co‐UltraPEA‐LUT®
The child was 10 years old when this study began. After diagnosis of ASD the child underwent 6 months of psychotherapy with his parents, without benefit. Psychomotor and speech therapy produced some benefit on behavior. A gluten‐free/casein‐free diet and vitamin supplements led to a rapid improvement in sleep–wake behavior and eye contact. However, vitamin supplements in particular, at doses far exceeding their daily recommended allowance, were suspended almost immediately due to worsening of hyperactivity and stereotypical behaviors. From time to time, the patient underwent homotoxicological‐homeopathic therapy with favorable results, especially with regard to mercury detoxification and treatment with probiotics.
Given the involvement of brain inflammation in the development of ASD, as well as the presence of activated mast cells 19, we undertook a therapy with the anti-inflammatory and mast cell modulating agent co‐ultraPEA‐LUT®, at a dose of 700 mg+70 mg b.i.d. (Glialia® microgranules, Epitech Group SpA, Italy) for 1 year. During the study period (May 2012–2013), the child continued the gluten‐ and casein‐free diet. The patient was evaluated before treatment, after ~5 months and ~12 months using the ATEC questionnaire (http://www.autism.com/index.php/ind_atec_report) and by a quarterly questionnaire administered to the child's teachers for the assessment of motor stereotypic behaviors (http://www.stress-cocchi.net/Autism10-it.htm). The ATEC questionnaire is sensitive enough to measure changes in the child's condition and consists of four subgroup scales: Scale I. Speech/Language/Communication (14 items—scores can differ from 0 to 28), Scale II. Sociability (20 items—scores can differ from 0 to 40), Scale III. Sensory/Cognitive Awareness (18 items—scores can differ from 0 to 36), and Scale IV. Health/Physical Behavior (25 items—scores can differ from 0 to 75). The four subgroup scores can be utilized to calculate a total score (total scores can range from 0 to 180). The scores are estimated according to the reply and corresponding subscale. The higher the subscale and total score, the more impaired is the patient. The lower the subscale and total score, the less impaired the patient. The stereotyping behavior was evaluated, before, during, and after 12 months by means of a five‐step scale of intensity as follows:
0 = symptom or behavior not present; 1 = rarely present and not linked to particular situations; 2 = present only in precise moments (e.g., before sleeping); 3 = present if the child is not actively involved in the environmental situation; 4 = very present and difficult to interrupt.
In addition to cognitive, behavioral, and motor symptoms, the child experienced an elevated frequency of night‐time enuresis, independent of time of year, general conditions or diet. This problem is often present in autistic children over five years of age 43.
Clinical data
Clinical Assessment of an Autistic Patient Treated with Co‐ultraPEA‐LUT®
Co‐ultraPEA‐LUT® treatment was well tolerated by the patient. Evaluation using the ATEC test revealed a decrease of scores (both total score and subgroup scores), indicative of an improved behavioral outcome of about 23%. The most evident effect over time appeared in the sociability subgroup, where the score decreased from 24 to 13 (Table 1). Co‐ultraPEA‐LUT® reduced most indices of hyperactivity, as demonstrated by reduction in motor stereotypies which from the very beginning were present only rarely or at precise moments (Table 2).
Table 1. ATEC scores in response to PEA‐LUT® treatment in a 10‐year‐old child with ASD
Autism treatment evaluation checklist
|
Time (months)
| ||
0
|
5
|
12
| |
I. Speech
|
24
|
23
|
21
|
II. Sociability
|
24
|
22
|
13
|
III. Sensory/Cognitive
|
31
|
29
|
26
|
IV. Health/Physical/Behavior
|
24
|
22
|
19
|
Total
|
103
|
96
|
79
|
Table 2. Motor stereotypy changes in response to PEA‐LUT® treatment in a 10‐year‐old child with ASD
Motor stereotypies
|
Time (months)
| |||
0
|
4
|
8
|
12
| |
Rocking
|
3
|
3
|
2
|
1
|
Head banging
|
0
|
0
|
0
|
0
|
Flapping tremor
|
4
|
3
|
2
|
2
|
Fingers movements
|
4
|
3
|
2
|
3
|
Walking on Tip‐Toes
|
0
|
0
|
0
|
0
|
Skill stereotypies (e.g., quickly turning a knife on a table)
|
1
|
2
|
3
|
3
|
Vocal stereotypy (unmotivated screaming, frog noise, grunts)
|
4
|
3
|
2
|
1
|
Clinical improvement, as highlighted by the questionnaire results, coincided with significant progress in cognitive behavior as observed by parents and teachers. The patient is, in fact, now more able to understand simple commands and execute them with ease; eye contact is much improved and the child's behavior far more affectionate. Unfortunately, no significant progress in speech profile has been observed until now.
In the described case report, chronic co‐ultraPEA‐LUT® reduced behavioral alterations of a child with ASD. Our observations are consistent with the results obtained after treatment with ultra micronized PEA, administered alone, in two children suffering from autism spectrum disorder 59. It is important to point out that children with autism experience a higher incidence of anxiety, particularly social anxiety, than children with other developmental disorders or with a normal development 60. Anxiety in children with ASD is related to sensory over‐responsivity and gastrointestinal problems, suggesting that these pathological states represent interconnected phenomena, sharing common underlying mechanisms mediated by mast cell and microglia activation. Our data suggest that ASD symptomatology may be improved by agents documented to control activation of mast cells and microglia. These results, while pointing to co‐ultraPEA‐LUT® as a valid and safe treatment in the autism symptoms—alone or in combination with other drugs—clearly need to be confirmed in a larger number of cases. The proof‐of‐principle study presented here encourages further investigations.
Palmitoylethanolamide modes of action
· PPARα agonist
· Indirect activation of cannabinoid receptors CB1 and CB2, which will affect microglial activation (M0, M1 M2) as explained in this previous post:
· Modification of gut microbiota
· Mast cells stabilization, via PPARα
The effects of the PEA are due to its interaction with several pathways: at first, it reduces, via the peroxisome proliferator-activated receptor alpha (PPARα), the recruitment and activation of mast cells at sites of nerve injury and the release of pro-inflammatory mediators from these cells [3, 4]; secondly, it inhibits the microglia activation and the recruitment of mast cells into spinal cord after peripheral nerve injury, as well as following spinal neuroinflammation or spinal cord injury [5, 6]. In the beginning, PEA was also supposed to be an agonist of the cannabinoid type II receptor (CB2) [7]; subsequently, in their research, Sugiura et al. have demonstrated that PEA has just a very low affinity for this receptor [8], clarifying why CB2 antagonists do not inhibit some of its anti-inflammatory effects [9]. Anyhow, PEA indirectly activates CB2 and the cannabinoid receptor type 1 (CB1) [10], down-modulating fatty acid amide hydrolase (FAAH), the enzyme responsible of the degradation of the anandamide (AEA), a CB1 agonist [11].
Several studies focused on the use of PEA in a multitude of chronic pain conditions. For example, it can have a beneficial effect like adjuvant for the treatment of the low back pain [12] or it was used alone for chronic pain management in critically ill older patients, where the use of traditional analgesics can lead to high risk of adverse effect [13]. Encouraging results have been shown in the treatment of non-surgical radiculopathies with an ultra-micronized formulation of PEA [14] and the combination therapy with alpha-lipoic acid to reduce chronic prostatitis/chronic pelvic pain syndrome [15].
Now to Cannabis
The autism research on cannabis is rather light on the science, but it does exist.
Cannabinoid receptors
Before the 1980s, it was often speculated that cannabinoids produced their physiological and behavioral effects via nonspecific interaction with cell membranes, instead of interacting with specific membrane-bound receptors. The discovery of the first cannabinoid receptors in the 1980s helped to resolve this debate.[7] These receptors are common in animals, and have been found in mammals, birds, fish, and reptiles. At present, there are two known types of cannabinoid receptors, termed CB1 and CB2,[1] with mounting evidence of more.[8] The human brain has more cannabinoid receptors than any other G protein-coupled receptor (GPCR) type.[9]
Cannabinoid receptor type 1
CB1 receptors are found primarily in the brain, more specifically in the basal ganglia and in the limbic system, including the hippocampus [1] and the striatum. They are also found in the cerebellum and in both male and female reproductive systems. CB1 receptors are absent in the medulla oblongata, the part of the brain stem responsible for respiratory and cardiovascular functions. CB1 is also found in the human anterior eye and retina.[10]
Cannabinoid receptor type 2
CB2 receptors are predominantly found in the immune system, or immune-derived cells[11] with the greatest density in the spleen. While found only in the peripheral nervous system, a report does indicate that CB2 is expressed by a subpopulation of microglia in the human cerebellum.[12] CB2 receptors appear to be responsible for the anti-inflammatory and possibly other therapeutic effects of cannabis seen in animal models.[11]
Cannabidiol
Cannabidiol (CBD) is non-psychotropic. Recent evidence shows that the compound counteracts cognitive impairment associated with the use of cannabis.[15] Cannabidiol has little affinity for CB1 and CB2 receptors but acts as an indirect antagonist of cannabinoid agonists.[16]
There is now strong evidence that CBD treats chronic pain, and it is used by many in the form of a topical oil treatment
Tetrahydrocannabinol (THC) is one of at least 13 cannabinoids identified in cannabis. THC is the principal psychoactive constituent of cannabis. With chemical name (−)-trans-Δ⁹-tetrahydrocannabinol, the term THC also refers to cannabinoid isomers.
The actions of THC result from its partial agonist activity at the cannabinoid receptor CB1 (Ki = 10 nM[19]), located mainly in the central nervous system, and the CB2 receptor (Ki = 24 nM[19]), mainly expressed in cells of the immune system.[20]The psychoactive effects of THC are primarily mediated by the activation of cannabinoid receptors, which result in a decrease in the concentration of the second messenger molecule cAMP through inhibition of adenylate cyclase.[21
We know that we can use CB1 and CB2 to shift microglia away from the M2 state. In the post below:
I extracted this section to remind readers: -
Molecules to Skew M2 Polarization of Microglia
7.1. Endocannabinoids and Cannabinoid Receptors
Based on these results, it is strongly suggested that 2-AG-CB1 axis contributes to polarization and maintenance of M1 microglia, while 2-AG-CB2 axis acts as a switch from M1 to M2 polarization of microglia (Figure 4). CB2 agonists are known to induce phosphorylation of AMP-activated protein kinase (AMPK), suggesting that the CB2 plays an important role in AMPK-mediated anti-oxidative and cytoprotective effects [119,120,121]. Furthermore, 2-AG is reported to activate PPAR-γ in M2 macrophages [122]. Thus, AMPK may be one of key signal molecules for the switch to M2 polarization. Besides endocannabinoids, adiponectin and ghrelin can induce down-stream signal transduction of their receptors via AMPK and therefore these molecules may be involved in skewing M2 polarization of microglia
Very recent cannabis in autism literature: -
Real life Experience of Medical Cannabis Treatment in Autism: Analysis of Safety and Efficacy
There has been a dramatic increase in the number of children diagnosed with autism spectrum disorders (ASD) worldwide. Recently anecdotal evidence of possible therapeutic effects of cannabis products has emerged. The aim of this study is to characterize the epidemiology of ASD patients receiving medical cannabis treatment and to describe its safety and efficacy. We analysed the data prospectively collected as part of the treatment program of 188 ASD patients treated with medical cannabis between 2015 and 2017. The treatment in majority of the patients was based on cannabis oil containing 30% CBD and 1.5% THC. Symptoms inventory, patient global assessment and side effects at 6 months were primary outcomes of interest and were assessed by structured questionnaires. 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. Twenty-three patients (25.2%) experienced at least one side effect; the most common was restlessness (6.6%). Cannabis in ASD patients appears to be well tolerated, safe and effective option to relieve symptoms associated with ASD.
Side Effects
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%).
Out of 23 patients who discontinued the treatment, 17 (73.9%) had responded to the follow-up questionnaire at six months. The reasons for the treatment discontinuation were: no therapeutic effect (70.6%, twelve patients) and side effects (29.4%, five patients). However, 41.2% (seven patients) of the patients who discontinued the treatment had reported on intentions to return to the treatment.
Cannabis as a treatment for autism spectrum disorders patients appears to be well-tolerated, safe and seemingly effective option to relieve symptoms, mainly: seizures, tics, depression, restlessness and rage attacks. The compliance with the treatment regimen appears to be high with less than 15% stopping the treatment at six months follow-up. Overall, more than 80% of the parents reported at significant or moderate improvement in the child global assessment.
The exact mechanism of the cannabis effects in patients with ASD is not fully elucidated. Findings from ASD animal models indicate a possible dysregulation of the endocannabinoid (EC) system11,12,13,14,15,16 signalling behaviours, a dysregulation that was suggested to be also present in ASD patients17. Mechanism of action for the effect of cannabis on ASD may possibly involve GABA and glutamate transmission regulation. ASD is characterized by an excitation and inhibition imbalance of GABAergic and glutamatergic signalling in different brain structures18. The EC system is involved in modulating imbalanced GABAergic19 and glutamatergic transmission20.
Other mechanism of action can be through oxytocin and vasopressin, neurotransmitters that act as important modulators of social behaviours21. Administration of oxytocin to patients with ASD has been shown to facilitate processing of social information, improve emotional recognition, strengthen social interactions, reduce repetitive behaviours22 and increase eye gaze23. Cannabidiol was found to enhance oxytocin and vasopressin release during activities involving social interaction16.
Two main active ingredients (THC and CBD) can have different psychoactive action mechanisms. THC was previously shown to improve symptoms characteristic to ASD patients in other treated populations. For example, patients reported lower frequency of anxiety, distress and depression24, following THC administration, as well as improved mood and better quality of life in general25. In patients suffering from anxiety, THC led to improved anxiety levels compared to placebo26 and in dementia patients, it led to reduction in nocturnal motor activity,violence27,28 behavioural and severity of behavioural disorders29. Moreover, cannabis was shown to enhances interpersonal communication30 and decrease hostile feelings within small social groups31.
In our study we have shown that a CBD enriched treatment of ASD patients can potentially lead to an improvement of behavioural symptoms. These findings are consistent with the findings of two double-blind, placebo-controlled crossover studies demonstrating the anxiolytics properties of CBD in patients with anxiety disorder32,33. In one, CBD had a significant effect on increased brain activity in the right posterior cingulate cortex, which is thought to be involved in the processing of emotional information32, and in the other, simulated public speaking test was evaluated in 24 patients with social anxiety disorder. The CBD treated group had significantly lower anxiety scores than the placebo group during simulated speech, indicating reduction in anxiety, cognitive impairment, and discomfort factors33.
What does the Harvard Medical School have to say about tinkering with CBD?
Cannabidiol (CBD) — what we know andwhat we don’t
CBD is commonly used to address anxiety, and for patients who suffer through the misery of insomnia, studies suggest that CBD may help with both falling asleep and staying asleep.
CBD may offer an option for treating different types of chronic pain. A study from the European Journal of Pain showed, using an animal model, CBD applied on the skin could help lower pain and inflammation due to arthritis. Another study demonstrated the mechanism by which CBD inhibits inflammatory and neuropathic pain, two of the most difficult types of chronic pain to treat. More study in humans is needed in this area to substantiate the claims of CBD proponents about pain control.
Is cannabidiol safe?
Side effects of CBD include nausea, fatigue and irritability. CBD can increase the level in your blood of the blood thinner coumadin, and it can raise levels of certain other medications in your blood by the exact same mechanism that grapefruit juice does. A significant safety concern with CBD is that it is primarily marketed and sold as a supplement, not a medication. Currently, the FDA does not regulate the safety and purity of dietary supplements. So, you cannot know for sure that the product you buy has active ingredients at the dose listed on the label. In addition, the product may contain other (unknown) elements. We also don’t know the most effective therapeutic dose of CBD for any particular medical condition.
The bottom line on cannabidiol
Some CBD manufacturers have come under government scrutiny for wild, indefensible claims, such that CBD is a cure-all for cancer, which it is not. We need more research but CBD may be prove to be an option for managing anxiety, insomnia, and chronic pain. Without sufficient high-quality evidence in human studies we can’t pinpoint effective doses, and because CBD is currently is mostly available as an unregulated supplement, it’s difficult to know exactly what you are getting. If you decide to try CBD, talk with your doctor — if for no other reason than to make sure it won’t affect other medications you are taking.
CBD for Anxiety
Conclusions
Preclinical evidence conclusively demonstrates CBD’s efficacy in reducing anxiety behaviors relevant to multiple disorders, including PTSD, GAD, PD, OCD, and SAD, with a notable lack of anxiogenic effects. CBD’s anxiolytic actions appear to depend upon CB1Rs and 5-HT1ARs in several brain regions; however, investigation of additional receptor actions may reveal further mechanisms. Human experimental findings support preclinical findings, and also suggest a lack of anxiogenic effects, minimal sedative effects, and an excellent safety profile. Current preclinical and human findings mostly involve acute CBD dosing in healthy subjects, so further studies are required to establish whether chronic dosing of CBD has similar effects in relevant clinical populations. Overall, this review emphasizes the potential value and need for further study of CBD in the treatment of anxiety disorders.
Conclusion
I think I would put PEA and CBD in the same category of possibly beneficial therapies.
THC, the key psychoactive constituent in cannabis, will of course improve features of some people’s autism, as would LSD.
Indeed, one post that I never completed was all about the new idea of micro dosing LSD. I thought it would appeal to our Dutch Aspie readers.
First ever trials on theeffects of micro dosing LSD set to begin
Some Silicon Valley creatives are vocal proponents of small daily doses of psychedelics to boost creativity and mental health. But can micro dosing with LSD really live up to the claims?
Participants will take the capsules over a short period, fill out questionnaires and conduct cognitive tests online during the course of the trial.
“The most exciting part of this is the trial’s design, developed by a collaborator in the US,” explained Dr Erritzoe. “Due to the nature of the design, we’re not expecting the findings to be as robust as a large-scale lab-based clinical trials, but if people follow the manual, we should see some interesting results.”
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| Add caption |
https://beckleyfoundation.org/plant-based-psychedelics/
Several of you have enquired about the closing date of the study. We don’t have an exact date yet, but we guarantee that the option to sign up will be open at least until 31st of October 2019.
Furthermore, we would like to let you know that Reddit user /u/Greg_5656 has created an accurate ‘how-to’ video on setting up the project. The video goes through the same steps as the manual, making it easier to follow along. Thank you Greg!
The Swiss have their own LSD clinical trial running: -
Will PEA give a benefit in your case of autism? Maybe it will, but I think you will need to give it a try for several weeks and make sure you use a product that contains what is says on the label.
Is PEA effective in its original application to treat neuropathic pain? Only sometimes; it works often enough for the Italians and Spanish, but it is no panacea. I think it is worth a try for neuropathy, there is a lot of evidence to support it.
There is no doubt that psychoactive substances will improve how some people with psychiatric disorders feel. In the 1960s at UCLA they were trialing LSD on people with autism.
The problem with these psychoactive substances is that long term use definitely can cause permanent damage. That is part of the reason why they were banned.
If you have untreatable epilepsy, it may be that a psychoactive substance can save your life, and so the choice is clear.
Should the clinic at Johns Hopkins, that treats extreme cases of autism with electro-convulsive therapy (ECT), be able to prescribe psychoactive substances like LSD and THC? I would say definitely yes.
Is Cannabidiol (CBD) going to help your case of autism? I think if anxiety is part of the problem, it very likely will help. Is it going to raise cognition like Bumetanide does in some people? I don’t think so.
Is Cannabidiol (CBD) a game changing autism therapy? I don’t think so, but every little does help.
Can Aspies make effective use of micro-dosing to manage any troublesome symptoms? Quite possibly.
Will big time CBD responders also respond to PEA? That, I would like to know.
Clearly some people taking PEA for neuropathy might get a similar benefit from CBD. If they took THC they would probably forget all about the pain.
I think the prodrug of PEA that crosses the blood brain barrier is interesting and I hope the Italians pursue it.
Hi Peter, I think BCP is part of the encocannabinoid system. You find it in copaiba oil and targets CB2 directly not undirectly as CBD and without the psychoactive effect. Do you think that could be similar to PEA?
ReplyDeleteValentina
Valentina, BCP does some interesting things, it affects CB2, PPAR gamma and PCC1alpha which triggers biogenesis of mitochondria. Its effect should overlap with PEA, but BCP should have effects that PEA lacks (and vice versa). PPAR gamma agonists may have side effects.
DeleteAlso concerning activated microglia, a provocative new study showing that prental allergen exposure (i.e. an immune reaction) causes female rats do become much more more male like, especially in cognitive development, while male rats to a lesser extent will become more female like in cognitive development:
ReplyDeletePress Release:
https://www.sciencedaily.com/releases/2019/03/190321130355.htm
Paper:
https://www.nature.com/articles/s41598-019-41258-2
In particular, an area of the hypothalamus was found in female rats with prenatal allergen exposure called the preoptic area, had a higher neuron count than is typical in female rats. One particular part of the preoptic area called INAH3 (Intermediate Nucleus of the Anterior Hypothalamus) is thought to mediate sexual identity as it is much smaller in females as well as homosexual men. The mechanism of action in the aforementioned study seems to be activated microglia causing major changes in brain development.
Now how is this relevant to autism? Well first here is a discussion on "gender identity" and the autistic population from earlier this year:
ReplyDeletehttps://www.spectrumnews.org/news/study-strengthens-autisms-curious-link-gender-variance/
On top of this, another curious study came out showing that African refugee women (women born in poor environments in African countries who resettled in the United States) have healthier pregnancy outcomes and healthier babies than native born United States children (controlled for race of course), which was very much contrary to the hypothesis of the investigators:
Press Release:
https://www.sciencedaily.com/releases/2019/03/190318132620.htm
Paper:
https://www.liebertpub.com/doi/10.1089/jwh.2018.7314
Now tying this altogether, one could easily blame pesticides (also linked, though weakly, to increased autism rates in a study this week), fetal alcohol syndrome (which can be misdiagnosed as autism), diabetes, and all of the other usual environmental suspects in increasing autism rates as well as increased gender dysphoria over the last several decades in the United States and the western world.
However, another aspect that may be overlooked here is the so-called hygiene hypothesis in that people spending more time indoors and in more sterile environments due to excessive cleanliness and use of antibiotics, may not be allowing their immune system to learn from a diverse array of environmental exposures so that the immune system can understand friend from foe. In a sense, this is like depriving children of human contact such as the famous cases of children from Romanian orphanages, except it is the human system that is devoid of being able to learn from its environment as well as from the microbial exposures of those who are around them.
Growing up on a farm, as well as in rural areas, as well as having pets in the home are both associated with lower risks of lifetime allergies and it is interesting that women with allergy problems due to a poorly trained immune system may also be compromising the long-term health of their children, ironically by trying to protect themselves and their baby from "germs".
Add on top of that, the anti-vaccine trend and the irrational fear of "germs" many men and women have nowadays, and you have millions of American women potentially setting their future children up for disaster when they end up having children as their immune systems will not be properly trained and those children may be exposed to a hyperactive immune response in the mother. In other words, the choices your grandmother made in raising your mother, may have a strong impact on your health today.
By all accounts, African refugee women you would expect would have far worse pregnancy outcomes relative to American natives due to what we know about poverty and stress affecting children epigenetically thoughout their lifetime (including pregnancy) but the opposite seems to be true in this case, and so with respect to autism someone out there really needs to answer why so that young women can make intelligent choices about the environmental conditions and exposures they subject themselves with respect to the health of their babies.
Hi Peter,
ReplyDeleteCo-Ultra PeaLUT does not seem to be available here in the US. The company ships to many countries but not the US. Why is Glialia not available here and do you know how I might obtain it?
Thanks
Nancy
Nancy, some of the Italian on-line vendors also sell through Amazon.it marketplace.
DeleteIf you have a US Amazon account you automatically can use it on overseas Amazon sites. You go to Amazon.it and log on with your Amazon.com password.
I have used my Amazon account in 4 different countries. You usually get the option to be billed by Amazon in your home currency not the foreign currency.
Glialis is on Amazon.it
Then it is just a question of whether those vendors on Amazon.it will ship to North America.
If they won't ship to the US, contact a vendor directly.
There is a site farmasave.it you could contact them in English and ask if they can ship to the US.
PEA is a legal OTC supplement in the US, so you should have no problems with customs.
If given the choice, select regular Italian Post to avoid a huge bill for Fedex/UPS.
Nancy, if none of that works, contact me again.
DeleteHi everyone,
ReplyDeleteI just wanted to give everyone an update on our trial of KE4 (i.e. ketones).
First, the taste. In the video where the taste testers described it as "jet fuel", I expected it have a gasoline (petrol) taste, but this actually tastes like cherry cough syrup. I mix it with juice and no problems. It's not great, but it's fine.
Since my daughter seemed to improve with BHB salts at low doses, I decided to try this and we are a week in.
No challenges with taste, no tummy issues, and no complaints at all. At the same time, we haven't seen any obvious improvements I would attribute to the product, but it has only been about a week.
I'm using 5ml X 2.
Given that we're dealing with neurons, we're going to give this a full 3 months before we decide either way (and this should hold true for any new intervention).
Keep in mind that (1) it's very expensive for what you get and (2) they don't ship outside of the US. I have to use a reshipping service (there are many, like Shipito ) and if you're outside the US, you will too.
Hope everyone is doing well!
AJ
AJ, are you giving KE4 in addition to your previous BHB salts + C8, or as a replacement?
DeleteHi Peter,
ReplyDeleteHope all is well.
Peter, I'm giving KE4 in addition to the BHB salts + C8. I haven't changed a thing other than adding the KE4.
AJ
AJ, thanks for the update on KE4!
DeleteSince taste issues are a huge hindrance for us with KetoForce (very concentrated lime taste, which might work well for someone who likes orange juice and such, except my kid doesn't) I am looking into alternatives.
Preferrably it would be something than can be masked into applesauce, or a yoghurt smoothie, or maybe with peanut butter or lingonberry jam.
AJ, do you think any of the brands you use could live up to this description?
Those of you who have tried other things than KetoForce - any suggestions? It is of course a combo of amount and taste that matters, but I can't even get to 1 ml KetoForce/day since the taste just cuts through anything.
/Ling
Hi Ling!
DeleteHope all is well :-)
Ling, for us, my daughter, who is very "fussy" when it comes to new foods, is quite a trouper when I say something is "Medicine". She knows it's going to be yucky, and I do my best to mask the taste.
With everything we give her, we mix it in Pomegranate juice (POM) as she likes this and I think it masks some flavours. Having said that, if something is really sour, I would look to use something sweet (without much sourness) to mask it. To your point, I would mask it in applesauce or jam.
The other "keto" ester option was HVMN (and I learned of both KE4 and HVMN from Peter's posts). I don't know if HVMN is any better than KE4, I rolled the dice on KE4. HVMN can be found at https://hvmn.com/ketone
The only thing about either KE4 or HVMN is that they are so expensive for what you get. If this helps improve my daughter, then I will gladly pay for it, but we're definitely still trialing it and we can't say we have seen any clear improvements.
Having said that, what may not work for us may be a "cure" for someone else, as each of our kids' ASD is likely due to a different root cause (although there may be convergence points in relevant pathways).
So our secret is POM Pomegranate juice, as it already has an intense flavor that may somewhat mask other flavors, and it's healthy too.
I hope this helps, and have a great day Ling!
AJ
Hi AJ!
DeleteThe KetoForce is not very cheap either, especially with shipment to Europe. To me it is important to get an opportunity to trial if this is something that helps or not, and then I'll have a look at the long-term costs.
Also, we are into our second trial of C8, and I think there is some progress but it is a little bit early to tell and we have some confounding factors going on too so I will know better in a while.
There are few things that haven't worked tastewise before (krill oil, raw broccoli powder and KetoForce) but I am a bit burned by the experience with potassium citrate which made my daughter hate blueberry taste. We lost one of our routes of administration on that one. :-/
What is the taste of the CodeAge variant then?
/Ling
Hi Ling,
DeleteI think we're both affected by the shipping issues, although I'm sure I still have it easier in Canada than you in Europe.
To get KE4, I have to have KE4 ship it to a re-shipping service (since they don't ship directly to Canada).
I agree with you 100%, cost is of no consequence to us either, we will try anything that has a chance of working and is safe.
As far as taste, Codeage's C8 has very little taste, like a mild salad oil, and the Instant Keto has a mild chalky taste, so easy to mask. As they are salts though, it takes a lot to move the needle on ketones in the blood. That's why I decided to add the esters to the salts, but so far, no obvious improvement on the esters.
I really hope you can get some benefits from C8 / ketones. Any improvement is such a victory.
Have a great day Ling!
AJ
Hi AJ and Ling,
DeleteLing, I tried also KetoOS myself and found is as efficient as KetoForce. The taste is definitely better. Also, did you try KetoBlitz? It's the same company as KF an they claim it tastes better. I didn't try as it contains sodium benzoate, which is not tolerated here.
AJ thanks for the update and good luck with KE4. Perhaps you have already mentioned this before, but I can't recall: did you measure ketone levels with the urine strips while your daughter was on BHB/C8 only or now with the KE4 added?
Thank you for the information on re-shipping service. My KE4 has just arrived, but getting ketones from the US to where I live is sometimes really kind of adventurous quest. While it may result in meeting nice people, including researchers on ASD genetics curious about the ketone idea :) it is not really feasible long term.
Hi Agnieszka,
DeleteHope all is well and that like us in Canada, you're starting to get warmer spring-like weather.
Agnieszka, I actually had very high hopes for KE4 because we used relatively low dose C8 / BHB salts and we thought we saw some improvement, but we haven't seen much improvement at all yet with KE4.
With the C8 and BHB salts, the ketone strips didn't register a change at all. I haven't used the strips yet on KE4, but with the link Peter had kindly provided (i.e. https://ketosource.co/comparing-exogenous-ketones/ ) , I'm assuming 5ml X 2 would be significantly better than the C8 and BHB salts. I will do the ketone strips soon, it's just a bit of a hassle. My assumption was that if BHB was indeed helping at a super low dose with C8 and salts, that the 5ml X 2 of esters would show a noticeable improvement (but not yet).
Also, I'm so glad that my mention of re-shipping services was helpful! :) I really hope you get some benefits from KE4.
Have a great day Agnieszka!
AJ
Hi AJ
DeleteI was just wondering which company do you use for re-shipping? I am in Ottawa and we sometimes get stuff shipped to the UPS store in Ogdensburg NY.
Hi Anon from Ottawa,
DeleteHope all is well! It's great to see fellow Canadians on the board!
I use Shipito - they will give you an address to use when buying items, and that address has a "suite" at their main address that differentiates you from others. Then, when your package arrives at Shipito, you get to choose which method (from many) you want to use and relevant pricing. I've used US post, and it has been running me around $30US.
Then, as you well know, we have to deal with our wonderful Canadian duties, which run me another $26 Canadian once the package arrives.
Best of luck!
AJ
Thanks AJ - I might try this re-shipping option next time for buying from the US. Hope all is well with you too!
Deleteus
Agnieszka & AJ - thank you for some taste descriptions!
DeleteIt is actually the KetoBlitz I have at home, and the taste is lime/jet fuel. ;-) If the regular KetoForce tastes worse I won't try that...
I just happened to learn that the keto diet can have a strong serotonergic or at least antidepressant effect, which make me think of my old serotonin hypothesis on language. I think also Clemastine can potentiate MAOIs (I have to check that up but I think it was mentioned on the leaflet).
/Ling
Thanks AJ for sharing the experience.
DeleteIt seems like different persons benefit from different mechanisms of exogenous ketones and it is not necessarily dose dependent. I've been using this treatment for over a year and still don't know which dose is optimal.
Hi Peter,
ReplyDeleteNeither amazon.it nor farmasave.it will ship to my home in he US.
Nancy
Nancy getting someone to ship it to the US is not a problem, but do the US Customs let you import supplements? I was just checking. Where I live importing supplements is no problem and I do it all the time. But some countries are very strict, they want the packaging and usage information in their language. They may seize the package and you lose your money.
DeleteMaybe it is best to check.
Hello Peter and community,
ReplyDeleteHope everyone is having a great Friday!
I spotted a recent paper I wanted to share with the community as I found it quite interesting, and maybe another piece of the puzzle.
https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0214198
"Results
The cluster analysis of ADI-R data revealed four ASD subgroups, including ASD with severe language impairment, and transcriptome profiling identified dysregulated genes in each subgroup. Screening via proteome analysis revealed 82 altered proteins in the ASD subgroup with severe language impairment. Eighteen of these proteins were further identified by nano-LC-MS/MS. Among these proteins, fourteen were predicted by IPA to be associated with neurological functions and inflammation. Among these proteins, diazepam-binding inhibitor (DBI) protein was confirmed by Western blot analysis to be expressed at significantly decreased levels in the ASD subgroup with severe language impairment, and the DBI expression levels were correlated with the scores of several ADI-R items.
Conclusions
By subgrouping individuals with ASD based on clinical phenotypes, and then performing an integrated transcriptome-proteome analysis, we identified DBI as a novel candidate protein for ASD with severe language impairment. The mechanisms of this protein and its potential use as an ASD biomarker warrant further study."
I have to admit, I hadn't run into DBI before (although I have run into IDH2 before), but I know for us, my daughter certainly has had (and still has) speech / language issues, and interestingly enough, has some unique concurrent strengths in terms of reading ability (early reader, although not necessarily fully understanding all content) and a love of (and I believe great ability) in music.
Could DBI and or IDH2 be a "convergence point" for different genetic mutations or non-genetic causes of ASD where language development is affected? This is certainly an interesting question, and for those of you who have a genetic diagnosis, it may be interesting to see if there are any connections in known pathways between your mutated gene of interest and these genes.
Have a great Friday and a great weekend everyone!
AJ
Thank you AJ! I will certainly look into this paper and see if there is something to be learned for me or all of us. :-)
Delete/Ling
"The scientists are now testing CBD (cannabidiol) as a prophylactic to prevent schizophrenia from even emerging... A single 600-milligram dose of CBD given to these patients, scientists at Kings College London have found, can partially normalize regions of the brain that have been shown in fMRI visualizations to become dysfunctional during schizophrenic episodes."
ReplyDeleteFrom this quite interesting article about CBD:
https://www.nytimes.com/interactive/2019/05/14/magazine/cbd-cannabis-cure.html?utm_source=pocket-newtab
LG
This comment has been removed by the author.
ReplyDeleteWe are currently having good results from Oleamide but I have not found much from others posting yet about its use and effect in autism. I find it to be superior to melatonin in resolving sleep latency and quality. My son no longer has active/awake dreams - he is quiet and still at night. Therapists at school are reporting he is calmer and less stemmy. I am noticing his ability to control his moods seems to have improved. We cannot use CBD oil because it causes gut issues and IBS for both me and my son when taken. The oleamide however seems far superior in its action anyway. I am not convinced it is solely due to sleep improvement, there are studies showing multiple actions including on microglia. As well as useful treatment for anxiety and depression. I am convinced there is potential here but wish there was more written about it.
ReplyDeleteHi,
DeleteThanks for this info! Sleep has been an issue for us for as long as I can remember. My daughter will stay up as long we would let her stay up, so we use Melatonin to at least get her to sleep, but her quality of sleep doesn't seem great as she is an incredibly light sleeper. So Oleamide is definitely next on my list of items to try.
Something of interest did happen recently to us - we had taken our daughter off Melatonin for a while as she had stared falling asleep at a reasonable time without it, and we had introduced Quercetin in the meantime, then she started to have difficulty falling asleep at a reasonable time so we reintroduced Melatonin and we saw some good improvements that we hadn't seen with Q alone or with Melatonin alone - but the two together seem to be making some good improvements for us.
Finally, and especially since you have added what I think is a good comment, would you kindly able to include a nickname at the end of your comments when on Anonymous mode (as I do)? This way we know who to attribute the comments to.
Thanks!
AJ
Hi everyone,
DeleteSince my original response to the anonymous post on Oleamide above, I've done some additional research and Oleamide seems like a very interesting molecule. Depending on one's specific needs, here are a few key papers I've found:
1. A Cannabinoid Receptor-Mediated Mechanism Participates in the Neuroprotective Effects of Oleamide Against Excitotoxic Damage in Rat Brain Synaptosomes and Cortical Slices
https://link.springer.com/article/10.1007%2Fs12640-019-00083-1
2. Identification of P2Y receptors involved in oleamide-suppressing inflammatory responses in murine microglia and human dendritic cells
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6395661/
3. Polygonatum Sibiricum Rhizome Promotes Sleep by Regulating Non-Rapid Eye Movement and GABAergic/serotonergic Receptors in Rodent Models
https://www.sciencedirect.com/science/article/abs/pii/S0753332218313325?via%3Dihub
4. Antiepileptic and Neuroprotective Effects of Oleamide in Rat Striatum on Kainate-Induced Behavioral Seizure and Excitotoxic Damage via Calpain Inhibition
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5702338/
There are many others (the above is a sampling of some of the ones I found most interesting).
It may be helpful to some, depending on underlying issues.
Have a great day everyone!
AJ
AJ, did you ever try Oleamide? I'm thinking of trying PEA but these two substances are often mentioned as a group of compounds. If you have any input except the above you have my ear. (If anyone else has any input that would of course also be of interest. :-) )
Delete/Ling
Hi Ling!
ReplyDeleteI've bought Oleamide and it's in my possession now, but since I recently added Butyrate, I wanted to use that for a good 8 weeks (to see its effect) before trying something else.
My biggest hope for Oleamide would be a good night's sleep. We use Melatonin which helps her fall asleep, but she doesn't stay asleep all night, and is an incredibly light sleeper. I think Oleamide may be more helpful in the falling asleep part of the equation than the staying asleep part, but I'm willing to trial it just incase
In the past, I did also trial PEA, but found no impact from that.
Have a great day Ling!
AJ
I'm having a great night here instead AJ, plastered to the screen. ;)
DeleteMay I ask you for a link or brand name to the PEA that didn't make any change for you? Why do you think Oleamide could work (I got the impression these substances were somewhat similar)?
Anyway, I found that article above on P2Y receptors useful, thanks for that. Adding clemastine for P2X7 looks tempting, is this available for you?
/Ling
Back from serious testing of Palmitoylethanolamide.
ReplyDeleteIt's really weird, but it induces refusal to eat, and possibly gut pain (unclear communication). Happened three times, within a couple of days.
I haven't seen this effect described anywhere, and I can't make any sense of it. Happy for input/insights!
/Ling
Hi Peter,
ReplyDeleteI did a CBC (complete Blood Count) for my son. We got low neutrophils(26.7%) and high lymphocytes(60%) everything else is in the normal range. He has regressive autism and I did try Dr. Kelleys cocktail for like 6 months but no positive changes.
He had regressive autism after a bacterial infection at 2 years. What does the low nuetrophil and high lymphocyte count point to. The report says viral/bacterial infection and I am sure its due to the bacterial infection.
I am commenting on the PEA post as this paragraph mentions some corelation with PEA supplementation:
"Cellular immune markers reflected specific abnormalities with deficient mature CD57+ natural killer (CD57+ NK) cell counts 32 cells/μL (nl = 60–300 cells/μL), with a total white count of 6.3 × 103/μL. However, the percentage of lymphocytes was high at 58%, while neutrophils were underrepresented at 33%, and absolute lymphocytes were also elevated at 3.5 × 103 cells/μL. All other obtained typical cell indices were in the normal range."
Any suggestion to maybe try out PEA or something else might be helpful.
Thanks
Adam, your son currently has a reduced neutrophil-lymphocyte ratio. This is saying something, but is seems that your son may not be typical for autism. In the small study below they found that increased neutrophil-lymphocyte ratio predicts autism.
DeleteIn autism nearly always both extremes exist, which is why averages are meaningless.
You might want to recheck in future that he always has a reduced neutrophil-lymphocyte ratio, before you over-think his results.
PEA is very safe and it does help some people, albeit a minority. No harm in trying it, perhaps you have discovered a biomarker for responders.
Does increased neutrophil-lymphocyte ratio predict autism spectrum disorder?
https://www.researchgate.net/publication/333163099_Does_increased_neutrophil-lymphocyte_ratio_predict_autism_spectrum_disorder
Objective: Although autism spectrum disorder (ASD) is one of the most studied neurodevelopmental disorders, its etiology has not been fully elucidated. A growing body of evidence suggest the role of neuroinflammation in the etiology of ASD. Neutrophil to lymphocyte ratio (NLR) and platelet to lymphocyte ratio (PLR) are markers of systemic inflammation. In this study, we aimed to evaluate NLR and PLR in children with ASD comparison to healthy controls.
Methods: We reviewed the medical files of children with ASD in the ages of 2 to 5. The ASD group were consisted of drug-naïve 64 children who had complete blood count within a month of assessment. Age and sex matched 64 healthy children without any psychiatric disorders were recruited from the healthy child outpatient unit of the hospital.
Results: NLRs were significantly higher in ASD. Children with ASD had significantly higher neutrophil counts but lower platelet and lymphocyte counts compared to those of healthy controls. NLR was found to be a predictor of ASD.
Conclusions: Increased NLRs support the hypothesis of the involvement of neuroinflammation in the under-lying physiopathology of ASD. Even though recent evidence is not enough to suggest that in young children increased NLR levels may be used as screening and early intervention predictor, it should be kept in mind and may inspire new studies. Further longitudinal studies with larger sample size and homogeneous groups regarding the age and subtypes may clarify the inflammatory involvement in ASD
Peter, we did another CBC and got the same results low RDW 11.7% normal range is (12.1 - 16..9) 30% neutrophils (normal range is 45-40) and 60.5% lymphocytes (normal range is (40-45) (again a low NLR) other markers for eisonophils, basophils, monophils, platelets, are within normal range (our pediatrician is ignoring this). What is this saying ?
DeleteThe ESR is also within normal range. Do you think a CRP will help ?.
I did some research and low RDW means MB-12 and folate deficiency. I'll do some research on how B-12 and folate can effect lymphocytes and neutrophils before overthinking alot. Some insights from you might be helpful.
THanks
Adam, it is best to discuss the results with your doctor. It is easy to over-interpret results, so best ask someone with plenty of experience.
DeleteMany people with autism have some "odd" lab results. Sometimes this is due to their diet, sometimes it is a downstream consequence of their autism, sometimes you are never going to find out.
Often the best way forward is to try some safe interventions and see what helps. Sometimes testing may point the way forward, but clearly more often it does not.
There are some interventions that are shown in the research to help certain sub-populations. It is a growing number and I would just make a list and work through it. Call it educated trial and error. Crude, perhaps but it is effective.
I just ordered Normast from Epitech, should be here by 25-30th January.
ReplyDeleteIf you happen to find something on low NLR ratio on the internet please share it here.
I could not find anything on the internet regarding low NLR except the study you have cited above in your post. If you happen to find something please do share.
Thanks
Hi Peter, I wrote about TRAPPC4 and we found the compound S-Palmitoylcysteine. PEA has a similar formula and I am curious evidence supports a decrease in inflammatory cytokines, assisting with mitochondrial dysfunction at 30mg/kg, and improves hypocampal BDNF signalling.
ReplyDeleteHi all, just got done reading all of this information. Very interesting. I have a near four-year-old autistic son, who I guess falls under regressive ASD as he was developing normally until around 1.5 years old, then when he started to learn how to walk totally lost ability to speak, eye gaze avoidance, etc. Went from a normal happy child to having tantrums often, and sleep became very poor (still is).
ReplyDeleteHe is in early preschool for services, and has made some progress, but is still behind for his age. I came across anandamide mentioned as being low in people with ASD, and so researching that, lead to the next rabbit hole of PEA, and now I guess also oleamide for sleep as we have been trying melatonin with mixed results. Melatonin at 0.3mg-0.5mg will knock him out, but he wakes up at 4 or 5 AM, or still wakes up every three hours like he did before. Giving more than 0.5mg will result in screaming, to what we think is from nightmares. We can only guess, as he can’t tell us with his nonverbality.
We have lost so much sleep, money, and sanity from dealing with all of this the last two years. I’m seeing PEA available on Amazon but I’ve no idea what a good brand is.
Any help is appreciated!
Mike
PEA is quite widely used by doctors in some countries (Italy, Spain etc) and they often use a product called Normast. There are much cheaper products sold on Amazon. Are they as effective? who knows. Some people claim only the more expensive products do any good.
DeleteIn reality, in autism all kinds of broadly anti-inflammatory substances seem to help in specific people. High bioavailable Curcumin is an example.
Many drugs that have shown effect in autism are anti-inflammatory, ranging from steroids to statins, to drugs normally used for T2 diabetes (pioglitazone etc).
Try PEA and see if it helps. It does help some people with autism, but not others.
Thanks Peter, we will try some things out, especially oleamide. Just had another rough night-bed by 7:30pm with melatonin, but woke up screaming/crying at 11, 2, and up for the day at 5am.
ReplyDeleteWhat I’m mostly finding in research is about trying to limit FAAH, though I’m only really finding about how to do so through specific substances from food, like kaempherol, though for that the best sources are things not many kids will eat, like leafy greens. He’ll eat most of the fruits, though we try to limit sugar as he doesn’t handle a lot of carbs at a time well. Dark chocolate for anandamide seems to help him at school but it’s a very temporary boost.
Mike
Cbd oil decreases the permeability of the GI tract and BBB.
ReplyDeletehttps://www.sciencedirect.com/science/article/abs/pii/S0006899321004431
https://www.frontiersin.org/articles/10.3389/fphar.2021.641210/full#:~:text=Interestingly%2C%20CBD%20has%20been%20shown,maintenance%20of%20intestinal%20epithelial%20barrier.
Hi!
ReplyDeleteIf looking where to buy PEA I recomend the Epitech portfolio. They have participated in some trials and are funded by the UE. https://www.epitech.it/items/linea_neuroscienze/all/en
If looking for CBD, I recomend buying bulk directly to producers. As a reference I've recently got a 400 euros/kg price for 3th party tested CBD. MOQ was 1 kg. Shelflife is 2 years. Production was within EU.
Kind regards,
Daniel