Cannabinoid Biosynthesis
January 28, 2022
Cannabis sativa and its use in fighting cancer – Piauhy Labs
February 11, 2022Scientific information for healthcare professionals
Author : Dr.Elmo Resende, Ph.D
| Director of R&D - Piauhy Labs
Cannabis sativa and its use in the treatment of Autistic Spectrum Disorder
Autism is a psychiatric problem that is usually identified in childhood, between 1 year and a half and 3 years, although the initial signs sometimes appear in the first months of life. The disorder affects the child's communication and the ability to learn and adapt.
It is a developmental disorder that causes problems in people's language, communication, social interaction and behavior.
Autism — or Autism Spectrum Disorder (ASD), as it is technically called — is a health condition characterized by impairments in three important areas of human development: socio-emotional skills, shared attention, and language. Currently, science speaks not only of one type of ASD, but of many different types, which manifest themselves in a unique way in each person.
ASD is a multifactorial disorder for which the causative mechanism is not completely known. A study showed that 97% to 99% of ASD cases have a genetic cause, with 81% hereditary. Scientific work, with 2 million individuals from five different countries, also suggests that 18% to 20% of cases have a somatic (non-hereditary) genetic cause. And the remainder, approximately 1% to 3%, must have environmental causes, due to exposure to intrauterine agents — such as drugs, infections and/or trauma during pregnancy.
The term “Autism Spectrum Disorder” started to be used as of 2013, in the new version of the Diagnostic and Statistical Manual of Mental Disorders, official publication of the American Psychiatric Association, the DSM-5, when four diagnoses were merged under code 299.00 for ASD: Autism, Childhood Disintegrative Disorder, Pervasive Developmental Disorder Not Otherwise Specified, and Asperger's Syndrome. Science and experts can better assess and study the degrees of autism from this consideration of spectra.
In other words, this means that it is a condition that changes from person to person. So, depending on the spectrum, autism can be milder or more dysfunctional. This is variable.
ASD is a complex developmental disorder that manifests itself at the behavioral and social level.
Signs usually appear during early childhood and affect a person's ability to communicate and interact with other people. Most children with ASD are similar to others, but exhibit different behavior, performing strange and incomprehensible activities.
- Do not point at objects to show interest.
- Do not look at objects when another person points at them.
- Not being interested in the people around you.
- Avoid eye contact and want to be alone.
- Having difficulty understanding other people's feelings or talking about your own feelings.
- Seem not to know when people talk to them, but respond to other sounds.
- Being very interested in people, but not knowing how to talk, play with or relate to them.
- Repeat or echo words or phrases that are said to them.
- Have difficulty expressing your needs using typical words or movements.
- Have difficulty expressing your needs using typical words or movements.
- Repeat actions multiple times.
- Having difficulty adapting to a new routine.
Although ASD has a relatively large number of incidences, it was only in 1993 that the syndrome was added to the World Health Organization's International Classification of Diseases. The delay in including ASD in this ranking reflects the little known about the issue. Even today, the diagnosis is imprecise, and not even a genetic test is able to accurately state the incidence of the syndrome.
As there are a number of degrees of ASD, the intensity of symptoms can vary. “The child at the end of the spectrum is very compromised in behavior, while the mild person can be extremely bright.
Worldwide data on ASD is often difficult to obtain because the condition is not recognized or diagnosed in the same way in all countries.
According to the World Health Organization (WHO), 1 in 160 children worldwide has ASD - but there are still no reliable global numbers for adults.
In the United States, where data have been systematically collected, the Centers for Disease Control and Prevention (CDC), linked to the Department of Health, estimate that 2.21% of the adult population has ASD.
WHO describes ASD as a developmental disorder that affects communication and behavior and can be diagnosed at any age.
ASD is a spectrum, which means that each autistic person experiences different combinations of autistic traits, at different intensities.
Usually, the condition is detected in childhood because symptoms tend to appear in the first two years of life, but many people only realize they have ASD in adulthood or have never been diagnosed.
Memory and learning are inseparable and acquired memory anomalies, whether congenital or early, will affect how an individual learns all things in life, the how and what. In turn, this difficulty will affect the course and outcomes of behavioral and brain development, including the ways in which a person experiences and responds to the external world. It is well established that certain memory impairments are present in all individuals with ASD.
In recent years, pediatric and adult services, both in health and education, have experienced a rapid increase in the number of young people diagnosed with ASD entering their services. A behind time or late diagnosis means that many are very close to leaving school, that is, dropping out of school, hence the competence of pediatric health services.
Several studies highlight the important role of genetics in the etiology of ASD. Data come from studies of families and twins. In fact, the concordance rate among monozygotic twins is high (60% –90%) compared to the concordance rate among dizygotic twins (0% –30%). Technological advances in epidemiological and molecular genetics have recently led to new discoveries in the field of the genetics of neuropsychiatric disorders. These new discoveries also concern the realm of autism genetics and have increased the state of current knowledge about ASD – associated genetic disorders. The identified genetic causes of ASD can be classified as cytogenetically visible chromosomal abnormalities, copy number variants (CNVs), (e.g., variations in the copy number of a DNA segment, including deletions and duplications) and single gene disorders.
CNVs can have different sizes (small to large deletions or duplications) and therefore concern a variable number of genes according to their size. The number of known genetic diseases associated with ASD has increased with the use of matrix comparative genomic hybridization (aCGH), also called chromosomal microarrays (CMAs) or high-resolution molecular karyotyping, which is one of the most commonly used molecular cytogenetic methods by geneticists.
Many susceptibility genes and cytogenetic abnormalities have been reported in ASD and concern almost all chromosomes. How can we explain this genetic diversity associated with cognitive-behavioral phenotypes similar to autism? Given the current state of knowledge, we can hypothesize that most ASD-related genes are involved in brain development and function (such as synapse formation and functioning, brain metabolism, and chromatin remodeling).
ASD is a neurodevelopmental condition characterized by deficiencies in two main domains: (1) social communication, social reciprocity; (2) restricted and repetitive patterns of behavior, interests or activities. In addition to these core symptoms, ASD is often associated with a number of concurrent problems, including emotional and behavioral dysregulation and psychiatric and medical comorbidities (e.g., sleep disturbances). In fact, compared to typically developing children (DT) and other children with developmental disabilities, children with ASD are at a higher risk of having sleep disorders.
The ongoing debate about the possible causes of sleep disorders in ASD is still open, with three possible etiological explanations: (1) sleep problems are a consequence of biological and genetic abnormalities and the disrupted sleep architecture present in individuals with ASD; (2) sleep problems are intrinsic to the clinical phenotype of ASD; (3) sleep problems represent a concomitant condition completely independent of ASD.
Children with ASD often have a variety of behavioral problems, including disruptive behaviors, tantrums, aggression, self-harm, hyperactivity, impulsiveness, and abandonment. These behavioral problems increase parental stress and adversely affect the family's quality of life.
Anxiety has been frequently described in children and adolescents with ASD, and a recent meta-analysis reported that 39.6% of young people with ASD had clinically elevated levels of anxiety or at least one anxiety disorder. Some studies have reported that anxiety is associated with psychological hyperarousal, which in turn can lead to difficulty falling asleep and insomnia. In fact, it is possible that anxiety leads to intrusive thoughts and worries during the pre-sleep period, thus interfering with sleep onset.
Despite a large number of clinical trials, there is no cure for autism. Current treatments for ASD primarily focus on helping children improve their areas of weakness and behavioral problems using treatments such as Applied Behavior Analysis (ABA) and Treatment and Education of Children with Autism and Communication Related Disabilities (TEACCH). Since we currently do not have a clearly identified ASD pathogenesis, there are still no effective pharmacological interventions for the disorder and finding drugs to effectively target the “core symptoms” has been a challenge.
Cannabinoids are lipophilic compounds, so it was initially thought that they exert their effects by interacting with cell membranes. However, several studies have shown that cannabinoid activity is highly stereoselective, leading to the discovery of cannabinoid receptors (CBRs) - CB1 and CB2, which belong to the G protein-coupled family.
After the discovery of CBRs, the existence of endogenous ligands was proposed. N-arachidonoylethanolamine (anandamide, AEA) was the first to be isolated in pig brain in 1992. The second, 2-arachidonoylglycerol (2-AG), was detected in 1995 in the canine intestine and both play important biological roles. These endocannabinoids (eCBs) are synthesized on demand from membrane phospholipids by the enzymes N-acylphosphatidylethanolamine-phospholipase D (NAPE-PLD) and diacylglycerol lipase (DAGL), respectively.
Activation of the CB1 receptor by acute exposure to ∆9-Tetrahydrocannabinol (∆9-THC), or simply THC, is commonly associated with the psychoactive effects of Cannabis and the “tetrad model”: hypolocomotion, hypothermia, catalepsy and analgesia. On the other hand, THC has neuroprotective, antispasmodic and anti-inflammatory actions, which are mediated by the activation of different receptors, such as CB2 and PPAR-γ. In contrast, Cannabidiol (CBD) has no psychotropic effects and several studies have reported anticonvulsant, neuroprotective, antioxidant, anti-inflammatory, analgesic and antiemetic properties.
Although less studied, Cannabidivarin (CBDV), a structural analogue of CBD, has received attention in recent years. CBDV exhibits anticonvulsant properties and clinical trials for the treatment of ASD are currently underway.
Lower serum levels of eCBS, such as AEA, were observed in children with ASD when compared to a control group, suggesting a role for the Endocannabinoid System (ECS) and therefore of cannabinoid signaling in these pathologies. In fact, in a study with rats with ASD-like behavior induced by prenatal exposure to valproic acid, CBDV was able to restore endocannabinoid signaling in the brain, normalizing the levels of FAAH, MAGL and CB1 receptors.
Pathophysiological mechanisms believed to underlie the neurobehavioral deficits present in ASD include aberrant synaptic plasticity, immune dysfunction, and metabolic disturbances. Many of these mechanisms can be modulated by ECS.
ECS exerts its effects through various receptors and channels. These include G protein-coupled cannabinoid receptors CB1 and CB2 (GPCR), transient receptor potential channels (TRP) that modulate calcium flux, α3 and α1 glycine receptors, and nuclear peroxisome proliferator-activated receptors (PPARs). To date, there is no published evidence on the interaction of AEA and 2AG with 5-HT1A receptors.
The signaling of endocannabinoids in the brain is complex. ECS plays an important role in neurodevelopment and is temporarily activated during stressful conditions. In addition, endocannabinoids are key modulators of synaptic function, which is believed to be disrupted in ASD. Many studies have reported a link between ECS and ASD. Disruption of this system can harm social communication, social gaming and reciprocity.
Olivetolic acid and divarinic acid are the two phytocannabinoid precursors that generate cannabigerolic acid (CBGA). CBGA is the central precursor for phytocannabinoid biosynthesis in Cannabis sativa, where tetrahydrocannabinolic acid (THCA), cannabichromenic acid (CBCA) and cannabidiolic acid (CBDA) originate. CBDA forms CBD, the most abundant non-psychotropic phytocannabinoid in Cannabis sativa. CBD has a very low affinity (in the micromolar range) for CB1 and CB2 receptors, yet CBD is able to bind to these receptors.
CBD also interacts with various G proteins (GPCR). CBD shows a high affinity for TRP channels, in particular for TRPV1 and TRPV2 receptors. Other studies have shown that AEA - one of the main endocannabinoids in the brain, mediated by signaling at CB1 receptors, driven by oxytocin, controls social reward. Modulation of AEA has been reported to alter social behaviors in genetic models of AEA. Deficits present in this signaling mechanism may contribute to social impairment in ASD and may offer a way to treat these conditions.
The therapeutic mechanisms of CBDV in humans with ASD can be deduced from its effects, and from the effects of homologous CBD, in other neuropsychiatric conditions, such as epilepsy, physical dependence, anxiety, depression and schizophrenia, as well as repetitive behaviors analogous to those seen in children with ASD. CBDV has the potential to be a valuable therapeutic agent for individuals with ASD.
Given the significant neurological and immune dysregulation seen in many people with ASD and the clear role that TRP channels play in these systems, it is possible that a TRP channelopathy may be to blame in some people. The presence of such TRP channelopathies has been documented in some individuals with ASD, although their phenotypic effects are not fully understood. The ability of CBD and Cannabigerol (CBG) to activate and desensitize multiple TRP channels suggests a therapeutic potential against neuronal hyperexcitability, inflammation and chronic pain seen in many conditions, including ASD.
At the molecular level, several neurotransmission systems, such as glutamatergic and GABAergic, are altered in ASD. Likewise, ECS (which plays an important role in the modulation of various signaling systems) has also been implicated in the pathophysiology of ASD and has become a target for the development of pharmacological therapies.
In this sense, we will research cannabinoids, terpenes and other components of the Cannabis sativa plant that may present positive results in fighting ASD, starting from in vitro studies, in animal models and, later, with our partners in Portugal and in other countries, carry out clinical studies. We will also carry out studies with monoclonal antibodies, aimed at fighting various diseases, such as neurodegenerative diseases such as ASD.
Piauhy Labs intends to obtain a Certification of Compliance with Good Laboratory Practices, in accordance with the OECD principles, for the pharmaceutical area, so that the results obtained from its research are properly used for the granting of licenses or for the registration of pharmaceutical products, including medicines for human use and similar products.
As a result of the intended research processes, Piauhy Labs wants to create patents and originate intellectual property, with the ultimate goal of producing innovative medicines, medicines that improve the quality of life of patients suffering from various diseases, notably diseases related to the central nervous system.
Elmo Resende, Ph.D
Director of R&D
Piauhy Labs
References
Alves, P.; Amaral, C.; Teixeira, N. and Correia-da-Silva, G. Cannabis sativa: Much more beyond Δ9-tetrahydrocannabinol. Pharmacological Research Jul, 157, 104822, 2020.
Boucher, J.; Mayes, A. and Sally, B. Memory in autistic spectrum disorder. Psychological Bulletin 138 (3), 458–496, 2012.
Cyrille, R.; Pasquier, L.; Cohen, D.; Fradin, M.; Canitano, R.; Damaj, L.; Odent, S. and Tordjman, S. Role of Genetics in the Etiology of Autistic Spectrum Disorder: Towards a Hierarchical Diagnostic Strategy. International Journal of Molecular Sciences 18 (3), 618, 2017.
Fletcher, S.; Pawliuk, C.; Ip, A.; Huh, L.; Rassekh, S. R.; Oberlander, T. F. and Siden, H. Medicinal Cannabis in children and adolescents with autism spectrum disorder: A scoping review. Child: Care, Health and Development, Aug 17, 2021.
Huang, Y.; Huang, X.; Ebstein, R. P. and Yu, R. Intranasal oxytocin in the treatment of autism spectrum disorders: A multilevel meta-analysis. Neuroscience & Biobehavioral Reviews 122, 18–27, 2021.
Hollingdale, J.; Woodhouse, E.; Young, S.; Fridman, A. and Mandy, W. Autistic spectrum disorder symptoms in children and adolescents with attention-deficit/hyperactivity disorder: a meta-analytical review. Psychological Medicine Oct; 50 (13): 2240-2253, 2020.
Keen, Daphne; Ward, Stephanie (2004). Autistic Spectrum Disorder: A Child Population Profile. Autism 8 (1), 39–48, 2004.
Loss, C. M.; Teodoro, L.; Rodrigues, G. D.; Moreira, L. R., et al. Is Cannabidiol During Neurodevelopment a Promising Therapy for Schizophrenia and Autism Spectrum Disorders? Frontiers in Pharmacology, 11, 2021.
Mazzone, L.; Postorino, V.; Siracusano, M.; Riccioni, A. and Curatolo, P. The Relationship between Sleep Problems, Neurobiological Alterations, Core Symptoms of Autism Spectrum Disorder, and Psychiatric Comorbidities. Journal of Clinical Medicine, May 3; 7 (5): 102, 2018.
Mostafavi, M. and Gaitanis, J. Autism Spectrum Disorder and Medical Cannabis: Review & Clinical Experience. Seminars in Pediatric Neurology 35, October, 100833, 2020.
Nezgovorova, V.; Ferretti, C. J.; Taylor, B. P.; Shanahan, E.; Uzunova, G., et al. Potential of cannabinoids as treatments for autism spectrum disorders. Journal of Psychiatric Research 137, 194–201, 2021.
Silva Junior, E. A.; Medeiros, W. M. B.; Torro, N.; Souza, J. M. M.; Almeida, I. B. C. M.; Costa, F. B., et al. Cannabis and cannabinoid use in autism spectrum disorder: a systematic review. Trends Psychiatry Psychother, 2021.
Zamberletti, E.; Rubino, T. and Parolaro, D. Therapeutic potential of cannabidivarin for epilepsy and autism spectrum disorder. Pharmacology & Therapeutics, 226, October, 107878, 202
Cannabis sativa and its use in the treatment of Autistic Spectrum Disorder
Autism is a psychiatric problem that is usually identified in childhood, between 1 year and a half and 3 years, although the initial signs sometimes appear in the first months of life. The disorder affects the child's communication and the ability to learn and adapt.
It is a developmental disorder that causes problems in people's language, communication, social interaction and behavior.
Autism — or Autism Spectrum Disorder (ASD), as it is technically called — is a health condition characterized by impairments in three important areas of human development: socio-emotional skills, shared attention, and language. Currently, science speaks not only of one type of ASD, but of many different types, which manifest themselves in a unique way in each person.
ASD is a multifactorial disorder for which the causative mechanism is not completely known. A study showed that 97% to 99% of ASD cases have a genetic cause, with 81% hereditary. Scientific work, with 2 million individuals from five different countries, also suggests that 18% to 20% of cases have a somatic (non-hereditary) genetic cause. And the remainder, approximately 1% to 3%, must have environmental causes, due to exposure to intrauterine agents — such as drugs, infections and/or trauma during pregnancy.
The term “Autism Spectrum Disorder” started to be used as of 2013, in the new version of the Diagnostic and Statistical Manual of Mental Disorders, official publication of the American Psychiatric Association, the DSM-5, when four diagnoses were merged under code 299.00 for ASD: Autism, Childhood Disintegrative Disorder, Pervasive Developmental Disorder Not Otherwise Specified, and Asperger's Syndrome. Science and experts can better assess and study the degrees of autism from this consideration of spectra.
In other words, this means that it is a condition that changes from person to person. So, depending on the spectrum, autism can be milder or more dysfunctional. This is variable.
ASD is a complex developmental disorder that manifests itself at the behavioral and social level.
Signs usually appear during early childhood and affect a person's ability to communicate and interact with other people. Most children with ASD are similar to others, but exhibit different behavior, performing strange and incomprehensible activities.
- Do not point at objects to show interest.
- Do not look at objects when another person points at them.
- Not being interested in the people around you.
- Avoid eye contact and want to be alone.
- Having difficulty understanding other people's feelings or talking about your own feelings.
- Seem not to know when people talk to them, but respond to other sounds.
- Being very interested in people, but not knowing how to talk, play with or relate to them.
- Repeat or echo words or phrases that are said to them.
- Have difficulty expressing your needs using typical words or movements.
- Have difficulty expressing your needs using typical words or movements.
- Repeat actions multiple times.
- Having difficulty adapting to a new routine.
Although ASD has a relatively large number of incidences, it was only in 1993 that the syndrome was added to the World Health Organization's International Classification of Diseases. The delay in including ASD in this ranking reflects the little known about the issue. Even today, the diagnosis is imprecise, and not even a genetic test is able to accurately state the incidence of the syndrome.
As there are a number of degrees of ASD, the intensity of symptoms can vary. “The child at the end of the spectrum is very compromised in behavior, while the mild person can be extremely bright.
Worldwide data on ASD is often difficult to obtain because the condition is not recognized or diagnosed in the same way in all countries.
According to the World Health Organization (WHO), 1 in 160 children worldwide has ASD - but there are still no reliable global numbers for adults.
In the United States, where data have been systematically collected, the Centers for Disease Control and Prevention (CDC), linked to the Department of Health, estimate that 2.21% of the adult population has ASD.
WHO describes ASD as a developmental disorder that affects communication and behavior and can be diagnosed at any age.
ASD is a spectrum, which means that each autistic person experiences different combinations of autistic traits, at different intensities.
Usually, the condition is detected in childhood because symptoms tend to appear in the first two years of life, but many people only realize they have ASD in adulthood or have never been diagnosed.
Memory and learning are inseparable and acquired memory anomalies, whether congenital or early, will affect how an individual learns all things in life, the how and what. In turn, this difficulty will affect the course and outcomes of behavioral and brain development, including the ways in which a person experiences and responds to the external world. It is well established that certain memory impairments are present in all individuals with ASD.
In recent years, pediatric and adult services, both in health and education, have experienced a rapid increase in the number of young people diagnosed with ASD entering their services. A behind time or late diagnosis means that many are very close to leaving school, that is, dropping out of school, hence the competence of pediatric health services.
Several studies highlight the important role of genetics in the etiology of ASD. Data come from studies of families and twins. In fact, the concordance rate among monozygotic twins is high (60% –90%) compared to the concordance rate among dizygotic twins (0% –30%). Technological advances in epidemiological and molecular genetics have recently led to new discoveries in the field of the genetics of neuropsychiatric disorders. These new discoveries also concern the realm of autism genetics and have increased the state of current knowledge about ASD – associated genetic disorders. The identified genetic causes of ASD can be classified as cytogenetically visible chromosomal abnormalities, copy number variants (CNVs), (e.g., variations in the copy number of a DNA segment, including deletions and duplications) and single gene disorders.
CNVs can have different sizes (small to large deletions or duplications) and therefore concern a variable number of genes according to their size. The number of known genetic diseases associated with ASD has increased with the use of matrix comparative genomic hybridization (aCGH), also called chromosomal microarrays (CMAs) or high-resolution molecular karyotyping, which is one of the most commonly used molecular cytogenetic methods by geneticists.
Many susceptibility genes and cytogenetic abnormalities have been reported in ASD and concern almost all chromosomes. How can we explain this genetic diversity associated with cognitive-behavioral phenotypes similar to autism? Given the current state of knowledge, we can hypothesize that most ASD-related genes are involved in brain development and function (such as synapse formation and functioning, brain metabolism, and chromatin remodeling).
ASD is a neurodevelopmental condition characterized by deficiencies in two main domains: (1) social communication, social reciprocity; (2) restricted and repetitive patterns of behavior, interests or activities. In addition to these core symptoms, ASD is often associated with a number of concurrent problems, including emotional and behavioral dysregulation and psychiatric and medical comorbidities (e.g., sleep disturbances). In fact, compared to typically developing children (DT) and other children with developmental disabilities, children with ASD are at a higher risk of having sleep disorders.
The ongoing debate about the possible causes of sleep disorders in ASD is still open, with three possible etiological explanations: (1) sleep problems are a consequence of biological and genetic abnormalities and the disrupted sleep architecture present in individuals with ASD; (2) sleep problems are intrinsic to the clinical phenotype of ASD; (3) sleep problems represent a concomitant condition completely independent of ASD.
Children with ASD often have a variety of behavioral problems, including disruptive behaviors, tantrums, aggression, self-harm, hyperactivity, impulsiveness, and abandonment. These behavioral problems increase parental stress and adversely affect the family's quality of life.
Anxiety has been frequently described in children and adolescents with ASD, and a recent meta-analysis reported that 39.6% of young people with ASD had clinically elevated levels of anxiety or at least one anxiety disorder. Some studies have reported that anxiety is associated with psychological hyperarousal, which in turn can lead to difficulty falling asleep and insomnia. In fact, it is possible that anxiety leads to intrusive thoughts and worries during the pre-sleep period, thus interfering with sleep onset.
Despite a large number of clinical trials, there is no cure for autism. Current treatments for ASD primarily focus on helping children improve their areas of weakness and behavioral problems using treatments such as Applied Behavior Analysis (ABA) and Treatment and Education of Children with Autism and Communication Related Disabilities (TEACCH). Since we currently do not have a clearly identified ASD pathogenesis, there are still no effective pharmacological interventions for the disorder and finding drugs to effectively target the “core symptoms” has been a challenge.
Cannabinoids are lipophilic compounds, so it was initially thought that they exert their effects by interacting with cell membranes. However, several studies have shown that cannabinoid activity is highly stereoselective, leading to the discovery of cannabinoid receptors (CBRs) - CB1 and CB2, which belong to the G protein-coupled family.
After the discovery of CBRs, the existence of endogenous ligands was proposed. N-arachidonoylethanolamine (anandamide, AEA) was the first to be isolated in pig brain in 1992. The second, 2-arachidonoylglycerol (2-AG), was detected in 1995 in the canine intestine and both play important biological roles. These endocannabinoids (eCBs) are synthesized on demand from membrane phospholipids by the enzymes N-acylphosphatidylethanolamine-phospholipase D (NAPE-PLD) and diacylglycerol lipase (DAGL), respectively.
Activation of the CB1 receptor by acute exposure to ∆9-Tetrahydrocannabinol (∆9-THC), or simply THC, is commonly associated with the psychoactive effects of Cannabis and the “tetrad model”: hypolocomotion, hypothermia, catalepsy and analgesia. On the other hand, THC has neuroprotective, antispasmodic and anti-inflammatory actions, which are mediated by the activation of different receptors, such as CB2 and PPAR-γ. In contrast, Cannabidiol (CBD) has no psychotropic effects and several studies have reported anticonvulsant, neuroprotective, antioxidant, anti-inflammatory, analgesic and antiemetic properties.
Although less studied, Cannabidivarin (CBDV), a structural analogue of CBD, has received attention in recent years. CBDV exhibits anticonvulsant properties and clinical trials for the treatment of ASD are currently underway.
Lower serum levels of eCBS, such as AEA, were observed in children with ASD when compared to a control group, suggesting a role for the Endocannabinoid System (ECS) and therefore of cannabinoid signaling in these pathologies. In fact, in a study with rats with ASD-like behavior induced by prenatal exposure to valproic acid, CBDV was able to restore endocannabinoid signaling in the brain, normalizing the levels of FAAH, MAGL and CB1 receptors.
Pathophysiological mechanisms believed to underlie the neurobehavioral deficits present in ASD include aberrant synaptic plasticity, immune dysfunction, and metabolic disturbances. Many of these mechanisms can be modulated by ECS.
ECS exerts its effects through various receptors and channels. These include G protein-coupled cannabinoid receptors CB1 and CB2 (GPCR), transient receptor potential channels (TRP) that modulate calcium flux, α3 and α1 glycine receptors, and nuclear peroxisome proliferator-activated receptors (PPARs). To date, there is no published evidence on the interaction of AEA and 2AG with 5-HT1A receptors.
The signaling of endocannabinoids in the brain is complex. ECS plays an important role in neurodevelopment and is temporarily activated during stressful conditions. In addition, endocannabinoids are key modulators of synaptic function, which is believed to be disrupted in ASD. Many studies have reported a link between ECS and ASD. Disruption of this system can harm social communication, social gaming and reciprocity.
Olivetolic acid and divarinic acid are the two phytocannabinoid precursors that generate cannabigerolic acid (CBGA). CBGA is the central precursor for phytocannabinoid biosynthesis in Cannabis sativa, where tetrahydrocannabinolic acid (THCA), cannabichromenic acid (CBCA) and cannabidiolic acid (CBDA) originate. CBDA forms CBD, the most abundant non-psychotropic phytocannabinoid in Cannabis sativa. CBD has a very low affinity (in the micromolar range) for CB1 and CB2 receptors, yet CBD is able to bind to these receptors.
CBD also interacts with various G proteins (GPCR). CBD shows a high affinity for TRP channels, in particular for TRPV1 and TRPV2 receptors. Other studies have shown that AEA - one of the main endocannabinoids in the brain, mediated by signaling at CB1 receptors, driven by oxytocin, controls social reward. Modulation of AEA has been reported to alter social behaviors in genetic models of AEA. Deficits present in this signaling mechanism may contribute to social impairment in ASD and may offer a way to treat these conditions.
The therapeutic mechanisms of CBDV in humans with ASD can be deduced from its effects, and from the effects of homologous CBD, in other neuropsychiatric conditions, such as epilepsy, physical dependence, anxiety, depression and schizophrenia, as well as repetitive behaviors analogous to those seen in children with ASD. CBDV has the potential to be a valuable therapeutic agent for individuals with ASD.
Given the significant neurological and immune dysregulation seen in many people with ASD and the clear role that TRP channels play in these systems, it is possible that a TRP channelopathy may be to blame in some people. The presence of such TRP channelopathies has been documented in some individuals with ASD, although their phenotypic effects are not fully understood. The ability of CBD and Cannabigerol (CBG) to activate and desensitize multiple TRP channels suggests a therapeutic potential against neuronal hyperexcitability, inflammation and chronic pain seen in many conditions, including ASD.
At the molecular level, several neurotransmission systems, such as glutamatergic and GABAergic, are altered in ASD. Likewise, ECS (which plays an important role in the modulation of various signaling systems) has also been implicated in the pathophysiology of ASD and has become a target for the development of pharmacological therapies.
In this sense, we will research cannabinoids, terpenes and other components of the Cannabis sativa plant that may present positive results in fighting ASD, starting from in vitro studies, in animal models and, later, with our partners in Portugal and in other countries, carry out clinical studies. We will also carry out studies with monoclonal antibodies, aimed at fighting various diseases, such as neurodegenerative diseases such as ASD.
Piauhy Labs intends to obtain a Certification of Compliance with Good Laboratory Practices, in accordance with the OECD principles, for the pharmaceutical area, so that the results obtained from its research are properly used for the granting of licenses or for the registration of pharmaceutical products, including medicines for human use and similar products.
As a result of the intended research processes, Piauhy Labs wants to create patents and originate intellectual property, with the ultimate goal of producing innovative medicines, medicines that improve the quality of life of patients suffering from various diseases, notably diseases related to the central nervous system.
Elmo Resende, Ph.D
Director of R&D
Piauhy Labs
References
Alves, P.; Amaral, C.; Teixeira, N. and Correia-da-Silva, G. Cannabis sativa: Much more beyond Δ9-tetrahydrocannabinol. Pharmacological Research Jul, 157, 104822, 2020.
Boucher, J.; Mayes, A. and Sally, B. Memory in autistic spectrum disorder. Psychological Bulletin 138 (3), 458–496, 2012.
Cyrille, R.; Pasquier, L.; Cohen, D.; Fradin, M.; Canitano, R.; Damaj, L.; Odent, S. and Tordjman, S. Role of Genetics in the Etiology of Autistic Spectrum Disorder: Towards a Hierarchical Diagnostic Strategy. International Journal of Molecular Sciences 18 (3), 618, 2017.
Fletcher, S.; Pawliuk, C.; Ip, A.; Huh, L.; Rassekh, S. R.; Oberlander, T. F. and Siden, H. Medicinal Cannabis in children and adolescents with autism spectrum disorder: A scoping review. Child: Care, Health and Development, Aug 17, 2021.
Huang, Y.; Huang, X.; Ebstein, R. P. and Yu, R. Intranasal oxytocin in the treatment of autism spectrum disorders: A multilevel meta-analysis. Neuroscience & Biobehavioral Reviews 122, 18–27, 2021.
Hollingdale, J.; Woodhouse, E.; Young, S.; Fridman, A. and Mandy, W. Autistic spectrum disorder symptoms in children and adolescents with attention-deficit/hyperactivity disorder: a meta-analytical review. Psychological Medicine Oct; 50 (13): 2240-2253, 2020.
Keen, Daphne; Ward, Stephanie (2004). Autistic Spectrum Disorder: A Child Population Profile. Autism 8 (1), 39–48, 2004.
Loss, C. M.; Teodoro, L.; Rodrigues, G. D.; Moreira, L. R., et al. Is Cannabidiol During Neurodevelopment a Promising Therapy for Schizophrenia and Autism Spectrum Disorders? Frontiers in Pharmacology, 11, 2021.
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Autism is a psychiatric problem that is usually identified in childhood, between 1 year and a half and 3 years, although the initial signs sometimes appear in the first months of life. The disorder affects the child’s communication and the ability to learn and adapt.
