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One of the emerging reasons that so many families and individuals have found relief by using CBD oil for autism is that the endocannabinoid system has been found to be more and more involved in both the pathogenesis of autism, and the overall process of healthy brain development. Variations from typical embryonic conditions, both environmental and genetic, can lead to dysfunctions of the endocannabinoid system (ECS), which then lead to many of the problems associated with autism.
As researchers discover more about the endocannabinoid system, the findings seem to shed light on more and more of the processes of autism. This has lead a portion of the scientific community to believe that the ECS may be a crucial piece in the puzzle of the pathogenesis of autism that was previously overlooked because no one knew of its existence, let alone its many complex and vital roles.
ECS activity is negatively correlated with social anxiety; it’s positively correlated with social comfortability and neurotypical social interactions. Researchers still aren’t entirely sure how it’s involved in this process, but a lack of ECS receptors or of the enzymes that produce their signallers leads to many of the cognitive impairments associated with autism disorders. This means that by targeting the ECS, CBD for autism could be a viable option for many families unsure of where to turn.
What is autism?
Autism, or autism spectrum disorder (ASD), refers to a range of dysfunctions of the central nervous system that result in social apathy and developmental impairments. Emergence of symptoms almost always occurs within the first three years of life, and as of 2015, 1 in every 68 eight-year-olds (1.6%) was somewhere on the autism spectrum. In addition, boys are 4 times more likely than girls to be diagnosed with autism spectrum disorders, and siblings of those with autism are 5-10 times more likely to be diagnosed than the general population.
The various phenotypes (disease presentation, i.e. seizures, non-verbalism, ticks, etc.) of autism represent huge genetic variances between individual cases. There are nonetheless specific genes that are implicated in the pathogenesis (origin of disease) of autism. In addition to genetic factors, environmental aggravants, from gluten found in bread to NSAIDs administered during pregnancy, have been linked in some way to autism, but the vast majority of factors are present in less than 10% of cases, each. Interestingly, 30% of autism cases are comorbid with epilepsy, 50% with anxiety or depression-related mood disorders, and more than 60% with other developmental disorders.
How does autism work?
Researchers have discovered that events leading to autism often begin very early in pregnancy. At the end of the first trimester, the “noodle” part of the brain starts to form: this is where our cognition and personality live. It is believed that the vast number of unique dysfunctions or disruptions of the noodle that are possible during this vital stage of prenatal development can contribute to the vast array of different manifestations of autism, postnatally.
Synaptic dysfunction
Individuals with autism have a high rate of synaptic imbalance. A synapse is the meeting point between the axon of any neuron and the dendrite of another: the axon is presynaptic and the dendrite is postsynaptic. The axon releases signals called neurotransmitters into the synapse, and the dendrite binds with them in order to produce some biological response.
Synapses can either be excitatory or inhibitory. Excitatory synapses release glutamate or dopamine and cause an uptick in the cellular activity of the postsynaptic neuron. Inhibitory neurons release GABA or serotonin, and cause a decrease in the activity of the receiving neuron.
A delicate balance between excitatory and inhibitory synapses is regulated by the endocannabinoid system during pregnancy and throughout early childhood. It is believed that some stimulus, whether it’s infection, or toxicity, or genetics, results in an inordinate number of excitatory synapses, and an insufficient number of inhibitory ones.
Reward system irregularities
fMRI (functional MRI) scans of both autistic and neurotypical individuals perceiving positive social stimuli showed consistently that autism is associated with significantly less activity in the ventral striatum, which is the dopamine reward pathway in the brain. Less activity here produces less reward associated with any given stimulus; less reward associated with social interaction directly leads to less motivation to feel empathy or seek social attention/interaction. If you experience no reward for doing something, then you won’t do it; if you do experience a reward, then you will seek it out to the extent of the reward. This is how dopamine regulates our behavior, simply put.
CBD and autism share a link with neurotransmitter regulation. Medical grade CBD oil has many anecdotal and clinical accounts of both alleviating the severity of autism, and improving other conditions only related to autism by their causal imbalance in neurotransmission.
Brain development and neurogenesis
Extensive abnormalities in the cytoarchitecture of brain tissue are noted in autism disorders across the board. Cytoarchitecture is the architecture of the cell; in the brain this refers to the structure and differentiation of the different neurons that facilitate everything from mood and behavior to muscle function and digestion. Accordingly, deficiencies in the cytoarchitecture of the brain can lead to a myriad of different conditions.
During the first trimester of pregnancy, neurons proliferate at a very high rate. During the first few postnatal months, growth accelerates even more as the “lines” that were drawn prenatally get “colored in” by all of the experiences and stimuli an infant perceives.
In autism, there is an abnormally high rate of prenatal neurogenesis, followed by a remarkable decline in postnatal development. This is generally associated with the strengthening of existing connections rather than the formation of new ones.
Furthermore, areas of brain associated with higher cognition will sometimes “mature” before birth; in a neurotypical person, these same neurons may not mature until well into adulthood. Among the systems involving both reward and new neuron formation is the mirror neuron area. This part of the brain allows us to observe the actions of other people, whether social or physical or ideological, and then to automatically “mirror” them; it’s how baby animals learn to hunt and build nests without language: they just watch their mom. Without this part of the brain, we would not feel the motivation to actively observe social interactions and learn how to replicate them in order to exist appropriately within various social paradigms: a deficiency that is highly congruent with the symptoms of autism.
CBD for autism: how the ECS (endocannabinoid system) is involved
Genetic variations associated with CBD and autism
One of the genetic variations that is most common among those on the autism spectrum has to do with silencing of the FMR-1 gene; it’s still there, it just doesn’t get “turned on”. It codes for an enzyme that breaks down endocannabinoids (eCBs) for the purpose of preventing the kind of signalling that causes a synapse to be strengthened. This is important because neurons are supposed to form prenatally, but not become reinforced or strengthened until information from the world can start to stimulate them and direct their development so they can best function in the world. Scientists say CBD could help in several ways. First, it inhibits the CB1 receptor that endocannabinoids (eCBs) bind with, so even if there’s too many eCBs, they won’t be able to have as much of an effect on reinforcement. Secondly, CBD binds to several proteins that could be thought of as the circuit breaker of our genetic code: they control what gets turned on and what doesn’t. The exact process of this activity is not yet well understood, but administration of CBD in rats demonstrated elevated expression of this gene in cells that previously weren’t expressing it at all.
Another gene associated with both the endocannabinoid system and autism is the CNR1 gene, which codes for CB1 endocannabinoid receptors. These are the most numerous receptors in the brain; there are more CB1 receptors than all of the other receptors combined. In autism, there are several polymorphic variants of this gene, which means unlike FMR-1, it still gets expressed, but incorrectly, and there are several different incorrect ways that it gets expressed.
In most cases, the change causes less CB1 receptors to be produced. Whether there’s a lack of eCBs or a lack of the receptors, the result is the same: impaired social/cognitive development. Interestingly, lack of this receptor may result in an increase of eCB synthesis to compensate for the lack of receptors, which would further impair development, and could explain the lack of change in 2-AG numbers in some cases of CNR-1 deficiency.
Research suggests CBD’s activity as a negative allosteric modulator at CB1 receptors could make up for the decreased number of receptors by further increasing the number of eCBs produced.
The most recent genetic discover related to autism, and perhaps the most important, is the notable deficiency of the neuroligin-3 gene in the brains of those with autism. Neuroligin and neurexin are two recently-discovered proteins which are essential for the formation of synapses in the young mammalian brain. Neuroligin attaches to the postsynaptic dendrite, and neurexin attaches to the presynaptic axon. They then bind with one another and physically hold the two connecting neurons in place. Without neuroligin, not only is the synapse physically less stable, but nearly all retrograde endocannabinoid signalling is blocked. Researchers still aren’t clear with how this takes place, but it’s yet another discovery that supports the general rule that an impaired ECS is associated with autism. The discovery gets much juicier, however.
In autism, neuroligin is significantly impaired in inhibitory synapses only. This leads to no “inhibition” of activities and signalling, only more and more excitation. While this could be related to the epilepsy comorbidity, researchers think that it leads to reinforcement of activities that would be inhibited under normal circumstances.
Specifically, a failure to inhibit a circuit in the nucleus accumbens which normally produces a “reward” feeling when an action is carried out, followed by a quick inhibition in order to delay reinforcement of synapses and therefore of behavior. Without neuroligin, this immediate inhibition isn’t possible, so any and all activity gets reinforced, leading to the highly-repetitive behavior that many individuals with autism and general developmental impairments exhibit. This concept is one of the first discoveries of the link between a particular behavioral impairment (stacking objects, hand-flapping, rocking back and forth, etc) and the neurological impairment that produces it.
Other factors associated with autism
Postnatal neuroinflammation is overwhelmingly common among those on the autism spectrum. Inflammatory processes in the brain produce an increase in AEA in the fear center of the brain, which causes decreased social behavior across the board, probably due to a compensatory decrease of CB1 receptors due to the increase in AEA, resulting in something similar to “tolerance” experienced with certain drugs. FAAH inhibitors, like CBD, reduce the atypical social behavior exhibited by mice which had neuroinflammation induced just after birth.
FAAH, fatty acid amide hydrolase, is the enzyme that degrades both endocannabinoids and some plant cannabinoids, so its inhibition results in increased levels of both eCBs and pCBs in the brain. While most associations between autism and the ECS have to do with a general decrease in endocannabinoid activity, CBD’s activity as an FAAH inhibitor helps to correct problems that arise from too much ECS activity.
AM-404, a metabolite of tylenol, is a selective endocannabinoid reuptake inhibitor: it causes the same kind of problem as an increase in FAAH. This is the scientific reason behind the “myth” that a pregnant woman taking tylenol is risking her baby’s mental health. While it certainly can’t cause autism by itself, there is strong reasoning behind the idea that in the presence of some of the other genetic or environmental factors, tylenol could push an embryonic brain over the ASD tipping point. AM-404 causes AEA and 2-AG, to stay active in the brain for much longer than they normally would. While this is majorly important after birth when the brain has to learn new things and form new connections, prenatal spikes in eCBs are strongly correlated with ASD-related symptoms.
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