We want to be very careful with this review.
Some of the issues we've investigated are more straightforward forward such as CBD and anxiety.
Even more complicated mental health issues like schizophrenia or ADHD are starting to be unraveled with new research.
Autism is similar in that it's a multi-faceted animal that causes a tremendous amount of suffering.
There are new insights being teased out as well.
Some of which is actionable!
We're going deep and wide into the research to see what we know now.
We'll also look at how CBD affects these pathways as well as other tools that interesting.
These are the topics we'll cover:
- Current views on what causes autism including brain areas affected
- Hormones and autism
- Neurotransmitters and autism
- Inflammation and autism
- The gut microbiome and autism
- Immune response (pruning) and autism
- Rapamycin and autism and other supporters of MTOR
- The endocannabinoid system and autism
- CBD research and autism
- How much CBD for autism
- What's the best CBD for autism
Okay...we've bitten off more than we can chew.
If you're like us, you want to cover all bases so batter up!
Current views on what causes autism
There are two current theories or world views of what drives autism:
- Social Motivation theory
- Overly Intense World theory
There's a great run through these theories here:
We'll begin with the social motivation theory first.
Essentially, this theory starts with a basis that the social reward center of the brain is wired differently.
This network rewards social interaction less than other inputs.
All our "drives" are mediated by chemistry and brain areas and indeed, social interaction also relies on these pathways.
A key player there is called Oxytocin which we'll look at more closely below in the hormone section.
Why does oxytocin matter for a social reward?:
Oxytocin, sometimes call the "love" drug, is the chemical driver of relationship-building, trust, and social seeking behavior.
This is the chemical behind the warm, fuzzy feeling we get from newborn nursing or even hugging and kissing.
The "social seeking" piece there is critical for autism.
It's made in the hypothalamus which is a brain area we'll explore in detail below. Remember that one!
Then there's the Overly Intense World theory:
This theory basically states that stimuli (sounds, touch, visual, smells, textures, etc) from the world are too intense, even overwhelming...a result of not being filtered correctly.
Sound familiar?
Different areas of the brain are in charge of filtering (even reducing) these signals.
For example, the thalamus acts as a "gate" of incoming sensory information before being sent to the cortex where it's analyzed and deciphered.
A great review of that process is here:
The anterior Cingulate Cortex is an important player in this process as well but with an emotional bent.
It works like a relay station between the emotional area and logical areas of the brain.
Speaking of emotional area, the amygdala features strongly.
It's the seat of emotional response and coloring.
This area is one of the oldest parts of our brain and too much activity can result in anxiety overly reactive fear responses.
Essentially, too much (amygdala) or too little (cortex, thalamus, etc) activity at these areas can result in overwhelming sensory information.
Later, we'll look at how neurogenesis (brain repair) and pruning (immune system activity) can affect these pathways.
So, those are the two big theories for what's driving autism but what can do with that?
Let's keep drilling down to the messengers at play in these networks.
We'll start with hormones.
Hormones and autism
Let's begin with oxytocin which is key to social reward, empathy, and pair bonding.
Just look at the effect from a boost of this hormone:
A single intranasal dose of [oxytocin] in healthy humans [has also been seen to enhance] trust, generosity, and empathy."
https://www.medicalnewstoday.com/articles/321967.php
Vasopressin is another player that is interesting to look at.
Researchers are looking at it now specifically:
AVP, especially in its inhaled form, seems to be safe and beneficial in improving social functioning including in children with autism.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6678231/
AVP is arginine vassopressin.
There's an interesting balance between AVP and oxytocin surrounding emotional and social behavior:
For instance, vasopressin is observed to be linked with the feeling of fear and aggression, while OXT seems to reduce these emotions
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6750159/
They appear to shape our response to social stimuli both good and bad.
We finally have studies that looked at differences in both hormones such as the following:
Similar to the findings in monkeys, the concentration of AVP were used to accurately distinguish between children diagnosed with ASD and neurotypical children.
It was too low!
Both of those hormones are made in the hypothalamus (the area we wanted you to remember from above!) and there's a clear association for autism:
We observed diminished grey matter in a region of the hypothalamus, which synthesizes the behaviorally relevant hormones oxytocin and arginine vasopressin.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3134572/
Speaking of hormones, you also have the over-masculinization of the brain during development.
This is especially true for males with autism:
researchers identified key genes that are regulated by testosterone and that contribute to the risk for autism, generating important insight into how male hormones might contribute to the increased male susceptibility to ASD.
https://www.sciencedaily.com/releases/2018/02/180207120622.htm
Of course, there's a big difference in levels of oxytocin based on gender:
Women have much more of it and it actually functions quite differently between the two genders.
There's a fascinating summary of this difference here
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2689929/
Researchers are now getting into the genes and receptors to peel back the onion of what's occurring:
Preliminary results show that the oxytocin receptor gene affects multiple aspects of social functioning relevant to autism.
More importantly, when children with autism are given oxytocin via nasal form, the effects are positive:
Study shows which children with autism respond best to oxytocin treatment
Levels of these hormones vary significantly in the full population and among people with autism.
If the hormone levels are working correctly but the pathway (anterior cingulate cortex) is impaired, this could explain the difference.
There's a great introduction to this area's effect and remember that oxytocin and vasopressin do a great deal of work in this area of the brain.
It's the mediator between our emotional and rational brains!
https://medicalxpress.com/news/2017-04-area-brain-affected-autism.html
We'll touch on the gut microbiome below but there's a curious connection with oxytocin production there.
The hormones above primarily fed into the social reward theory of autism.
Let's take a look at the sensory overload side now.
Neurotransmitters and autism
There are many systems in the brain that are comprised of chemicals which oppose each other to hopefully find a balance.
The excitatory and inhibitory system is the most prevalent and powerful example of this balancing act.
It's comprised of two main players:
- Glutamate - our brain's "gas" pedal
- GABA - our brain's "brake" pedal
They're intimately tied in with almost every other pathway in the brain including big hitters like serotonin, dopamine, and the like.
Too much glutamate and you can have anxiety, seizures, and even neuron death.
Given that, we would expect to see more seizures and anxiety with autism, right?
Okay…
ASD and epilepsy co-occur in approximately 30% of individuals with either condition
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6469513/
Bi-directional.
What about anxiety?
It's the highest co-morbidity with autism.
The chart is here:
Check out CBD and autism anxiety or CBD and GABA for anxiety.
The most common up till age 15? Hyperkinetic or too much physical motion.
Again, excitatory.
Check out CBD and glutamate for more info.
This figures directly into the hyperexcitability theory of autism!
There are clues coming to light along this line of thinking:
By fixing a glutamate pathway gene in fragile-x mice, many of the autism-like symptoms went away.
Genetic mapping in families with autism are showing a link to GABA related genes
Oxytocin (mentioned above in the hormone section) affects how Glutamate and GABA are processed in the brain.
A general theory is that too much glutamate resulting from an imbalance of this system is driving not only the short term hyperexcitability but also the long term damage.
We'll look at neurogenesis below which is the process of brain repair and something we can actually boost!
To see if this theory holds water, are there ways to support healthy levels of glutamate?
Hello NAC. N acetylcysteine.
This is a cheap, safe, and readily available amino acid which acts as a glutamate sink while also boosting our native waste removal system (via glutathione).
Check out NAC and mental health here.
Does it have any effects on autism?
The antioxidant, called N-Acetylcysteine, or NAC, lowered irritability in children with autism as well as reduced the children’s repetitive behaviors.
Here's a review of studies on NAC and autism which are very interesting:
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5788395/table/TAB1/
Again, they accredit its support of antioxidants but NAC's ability to absorb excess glutamate may be more powerful.
This runaway excitability in the brain also explains why there is a significant association between autism and seizures.
You can't look at glutamate without touching on GABA since they're two sides of the same coin.
Some research is pointing to the break (GABA) side.
Again, it may not be the level of GABA but the "processing" of it.
It’s not that there’s no GABA in the brain … it’s that there’s some step along that pathway that’s broken.
https://news.harvard.edu/gazette/story/2015/12/a-brain-link-to-autism/
The levels appear fine but it's not processing correctly:
Brain scans further pointed to the GABA break being faulty:
“GABA is not reduced in the autistic brain, but the action of this inhibitory pathway is reduced,”
http://news.mit.edu/2015/altered-brain-chemistry-autism-1217
Check out CBD and GABA for more info.
Let's now go to the topic that seems to be underpinning every mental health issue in new research.
Inflammation and autism
Inflammation (excessive) is a function of our immune system.
This is an exciting new aspect of looking at autism in the brain and nervous system.
We tend to think of immune system as just a response to bacteria and viruses but it's so much more!
It governs the birth/death cycles of neurons.
The main sentinels of this system in the brain are called microglia and they are both architect, gardener, and executioner in our nervous system.
The theory is that the immune system is over-responding in autism and this causes damages.
It's principle weapons in this attack are cytokines and...wait for it...glutamate!
Cytokines are little inflammatory assassins used for fighting infection but also dual purposed for a host of different effects.
When they're too high for too long, damage occurs.
Let's see what research is showing with autism.
It all kicked off with this study:
In a milestone paper, pro-inflammatory cytokines were found to be elevated in plasma of 97 medication-free and healthy children (2 to 5 years old) with ASD
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6027314/
That article then goes through many studies mirroring the same effect for autism.
Something they all had in common:
increased levels of pro-inflammatory IL-1β and TNF-α were found in almost all cases
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6027314/
We'll look at CBD's effect there as well as other supplements.
So...what sets up this inflammatory state to begin with?
An interesting clue looks at one possible cause.
Infection during pregnancy.
This may be a shared pathway for both autism and schizophrenia (with bipolar also linked).
For example:
maternal hospitalization for viral infection in the first trimester was related to a nearly threefold increased risk of autism spectrum disorder and hospitalization for bacterial infection in the second trimester were associated with a significantly increased risk of the disorder
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3435457/?s_campaign=theweek
The theory is that hyperactivation of the immune system is passed down to the baby and as we stated above, the immune system (microglia) don't just handle infection.
They sculpt the developing brain architecture!
What happens if our brain sculpture is all scissors?
Check out CBD and microglia for neuroinflammation to really dig into this area.
The net takeaway is this:
Neuro-inflammation, driven by increased production of pro-inflammatory cytokines, could be the principal mechanism in the pathophysiology of ASD
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6027314/
You really can't talk about inflammation without looking at the gut microbiome.
Let's go south!
The gut microbiome and autism
There's a very curious tie between autism and gastrointestinal issues.
A history of GI symptoms was elicited in 70% of children with ASD compared with 28% of children with typical development
https://pubmed.ncbi.nlm.nih.gov/16685179/
People...we need to start in the gut!
Finally, the microbiome and the so-called gut-brain connection is given the respect it deserves.
The trillions of bacteria down there are intimately involved in modulating this whole system.
They turn genes on and off in the immune cells and gut lining!
They also make neurotransmitters and affect hormones DIRECTLY
Most of your serotonin is made in the gut. You know...the master regulator of all human behavior (see CBD and serotonin).
The vagus nerve is the hub between these two "brains" (the gut is actually called the second brain since its second-largest concentration of actual neurons!).
As we mentioned before:
Children with autism were 6-8 times more likely to have gastrointestinal problems:
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3981895/
Researchers are even looking at specific species of gut bacteria that both harm and help with autism:
For example, one species Lactobacillus Reuteri was added back to the gut of mice with autistic-like behavior and their symptoms improved!
By adding this bacterial species back to the guts of affected mice, the researchers were able to reverse some of the mice’s behavioral deficits, which are reminiscent of symptoms of autism spectrum disorders (ASDs) in humans.
https://www.bcm.edu/news/neuroscience/species-gut-bacteria-autism-related-behavior
Check out CBD and the gut or CBD and probiotics.
Interestingly, guess what that particular species of gut bacteria does?
That species had a direct impact on the amount of oxytocin (mentioned above for social rewards) cells activated.
https://www.ncbi.nlm.nih.gov/pubmed/27793228
There's a wonderful analysis of the powerful interplay between the most powerful neurotransmitters/hormones (including dopamine, GABA, and serotonin) in our bodies and gut bacteria!
https://academic.oup.com/femsre/article/39/4/509/2467625
Some of the bacteria strains even bolster testosterone which is key to the over-masculinization theory.
Then, there are the bad actors:
Stool analysis on 13 patients with regressive autism showed a dramatic increase in titers of the abnormal and potentially toxic Clostridia.
https://www.ageofautism.com/2017/09/hormones-from-the-microbiome-implications-in-autism.html
This may figure into the so-called "regressive" autism, where a child appears to mature and then there's an abrupt change can be affected by antibiotics:
https://www.ncbi.nlm.nih.gov/pubmed/10921511
Here's a good summary of gut bacteria interaction for autism:
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4259177/
So, how does inflammation from the gut get to the brain (aside from the vagus connector)?
Gut permeability!
That's a fancy way to say that the natural barrier of the gut has breaks in it and bacteria can escape into the bloodstream.
The immune system picks up on these wayward stragglers throughout the body and attacks (with cytokines).
This is a basis for autoimmune depending on where they land.
Check out CBD and the gut barrier.
So we see evidence of this gut barrier issue with autism?
A milestone paper detected, by means of lactulose/mannitol test, increased intestinal permeability in 37% of autistic patients and in 21% of their relatives.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6027314/
This brings up the auto-immune connection with autism.
Is there a connection?
an increased risk ratio (IRR), of ASD, was observed in mothers with rheumatoid arthritis (IRR: 1.70) and celiac disease (IRR: 2.97); a familial history of type I diabetes (IRR: 1.78) was also found to increase the risk of having a child with ASD
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5373490/
Remember, this could be tied into "priming" the immune system to overreact.
Lots of new research is looking at diabetes as having an autoimmune pathway (even type 2).
What about cause and effect...what comes first?
They even took antibodies from a mother and injected into mice during birth which resulted in autism-like behavior in the baby mouse.
a single sample from the serum of a mother with a child with ASD was used to demonstrate that antibodies purified and developmental delay reacted to mouse neurons and when injected into a dam during gestation resulted in deficits in the exploratory behaviors in the resulting offspring
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5373490/
They basically took blood from a mother who had a child with autism and when given to baby mice in utero, they developed autistic-like behaviors.
There's a lot of research along these lines at that link above which points to an autoimmune response tied with autism.
The gut barrier is key to autoimmune so check out CBD and the gut barrier for more info.
We'll leave with this from that same link:
A similar study utilizing banked mid-pregnancy (prospective) blood samples also observed maternal autoantibody binding to antigens near 37 and 73 kDa was only found in women whose children later received a diagnosis of ASD
They basically found autoimmune signatures in mothers that would later have children with autism.
Only women with autism.
Since we're talking about autoimmune, let's dive deeper into the immune system to one of its other functions.
This is where it gets interesting (and groundbreaking).
Immune response (pruning) and autism
What's the connection between our immune system and autism?
First, remember how antibodies from mother's infection while pregnant can be passed down to the baby?
Then there are the increased cytokines (the infantry of the immune system).
What about the connection with glutamate, the "gas" pedal tied to hyperactivity?
Thought you would never ask.
Let's introduce microglia, our immune generals in the brain.
They guide activity and in this case, overactivity.
Excess glutamate can be a result of this hyperactivation:
Our data suggest the new hypothesis that activated microglia collude with astrocytes to cause the elevation of extracellular L-Glu in the early stages of neuroinflammation.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3575281/
Again, why does this matter for autism?
Evidence indicates that children with autism spectrum disorder (ASD) suffer from an ongoing neuroinflammatory process in different regions of the brain involving microglial activation.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3523548/
It's the collateral damage of our immune response triggered by early infection or anything that sets the immune system on a rampage.
The net effect matches what brain scans show with autism:
Microglial activation can then result in a loss of connections or underconnectivity.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3523548/
This is also the missing link with schizophrenia and bipolar, both of which show immune system priming for at least part of the risk.
This ties up many clues neatly.
The positive effects of antibiotics (minocycline). The anti-inflammatories (curcumin, NAC, etc).
Check out CBD and microglia to really get into it. This is the future of mental health for many issues.
So...what do we mean by brain "pruning"?
The microglia guide the process of cutting back connections during critical periods of brain development (a big one at age 2-3). Puberty is yet another big one.
This "pruning" leads to a more efficient brain function.
What if the microglia are revved up and excessive with the scissors (glutamate)?
One interesting study found a genetic clue to this effect in microglia specifically:
Xu and his colleagues found that in the male ASD-like mice with elevated microglial eIF4E, there were more synapses than normal, suggesting a pruning deficit–a pattern also thought to be widely present in people with autism.
https://neurosciencenews.com/asd-males-microglia-16168/
The fascinating piece? The effect only occurred in males.
Remember that there's a 4:1 ratio with autism for males to females.
We're not going to get into the whole vaccine and autism question but a percentage of people may have an immune response to the active agents or preservatives/chemicals in the vaccine.
This would only apply if a person has a genetic susceptibility (such as immune response gene above).
Let's drill down even further into this pruning process to see if there are ways we can actually support this pathway.
Rapamycin and autism and other supporters of MTOR
mTOR. It sounds ominous but sticks with us. There's a payoff.
mTOR is short for the mechanistic target of rapamycin.
Thank goodness for the abbreviation.
Rapamycin gained popularity a few years back for its effects on longevity.
Basically, mTOR is the system in control of proper cellular growth and removal.
Sounds important considering that autism is marked by abundance in certain pathways and reductions in others.
You could almost argue that autism is a disease of mTOR (with the immune system kicker added on).
There's a good review of the science here but the researcher's net take away:
finally, we suggest that mTOR signaling pathway will be revolutionary in the field of translation research as a promising strategy to discover remedies for idiopathic autism.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6675248/
Let's cut to the chase...is there research on substances that support mTOR and autism symptoms?
Yes!
A recent study by Sato et al reported that rapamycin reverses impaired social interactions associated with an autism spectrum disorder in a mouse model of TSC.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3972801/
Interestingly, they used valproic acid during pregnancy which speeds brain growth (again, mTOR signaling is off).
Remember that mTOR is the regulator of brain growth/removal. It's about a finely tuned balance.
Let's put it all together now.
What happens when microglia (our immune generals) come in contact with infection in terms of mTOR??
Lipopolysaccharide induces neuroinflammation in microglia by activating the mTOR pathway
https://jneuroinflammation.biomedcentral.com/articles/10.1186/s12974-019-1644-8
Lipopolysaccharide is the signature of bacterial infection to our immune system.
Essentially, microglia can jack up mTOR in response to infection.
And the tie to autism?
It is a common feature of idiopathic autism patient where there is an increase of cell growth that could be an outcome of increased protein synthesis due to mTOR hyperactivation (19).
If your head is spinning, let's simplify down:
- Early infection or genetics cause a hyperactivation of our immune system
- Our immune system also controls brain architecture and leads too much or too little connectivity
As we saw above, rapamycin helped with social symptoms of autism.
What else affects this pathway?
Luteolin, Fisetin, and Quercetin are huge supporters of the mTOR pathway
Berberine affects an upstream pathway called AMPK and it's a powerful gut remodeler!
We'll look at these below in our Tools section.
Of course, CBD comes into play which we'll discuss below.
One last stop before CBD but it's important.
The endocannabinoid system and autism
It's a fascinating system that we all have. By all, we mean every living animal.
Scientists put it at about 600 million years old on the evolutionary scale so it's clearly been useful.
Think of this system as the interchange between the outside world and inner workings of the body and brain.
It's tasked with balancing other key systems after any type of "stress".
We put stress in quotations since we're using a broader meaning which is anything that pushes one system one way or another.
The endocannabinoid system is tasked with balancing other key systems:
- Endocrine system - hormones such as oxytocin and vasopressin.
- Nervous system - neurotransmitters like GABA, glutamate, and dopamine
- Immune system - inflammatory response including cytokines and microglia
Goodness...did we just list out all the key players for autism above?
Based on this, you would expect to see alterations in this system with autism.
What do we find?
We found lower serum levels of AEA, PEA, and OEA in children with ASD.
https://molecularautism.biomedcentral.com/articles/10.1186/s13229-019-0256-6
AEA is a big one. It's short for anandamide which is named after the Hindu goddess of bliss, Anand.
It's one of the two big ones in the brain and generally slows down activity.
Let's take one powerful example with direct implications to what we discussed above.
Glutamate...the "gas" pedal.
Look at anandamide's effect (we'll walk you through it):
In this biological context, endocannabinoids are released to retain NMDAR activity within physiological limits.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5342457/
What is NDMA? It just happens to be the primary receptor for glutamate.
The endocannabinoids help to keep these other pathways within a certain range.
That's critical! Excessive glutamate is a critical facet of autism (hence the seizure and anxiety comorbidities).
Newer research is actually pointing to GABA (the opposing force to glutamate) as a key player.
The same thing applies though with endocannabinoids.
Check out CBD and glutamate or CBD and GABA to learn more.
Essentially, anandamide acts as a stress response buffer in the nervous system.
There are plenty of clues such as this one:
Consistent with this, reduced CB1 receptor expression was found in postmortem brains of individuals with autism
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5618565/
A gene variant tied to autism is found on the CB1 receptor, our primary site of brain activity for endocannabinoids.
This system is very important for social reward circuits and in fact:
In some of these models, activating the ECS rescued the social deficits.
https://molecularautism.biomedcentral.com/articles/10.1186/s13229-019-0256-6
Where does CBD (a cannabinoid) fit into this puzzle?
Let's finally go there...thank you for your patience!
CBD research and autism
We've looked at multiple pathways above.
Let's zero in on how CBD affects these pathways followed by research on CBD and autism specifically.
Here are the topics:
- CBD and hyperexcitability for autism
- CBD and oxytocin for autism
- CBD and gut health for autism
- CBD and neuroinflammation for autism
- CBD and mTOR (the rapamycin connection)
- CBD and autism research
- Other tools with autism
Let's get started. Lots to cover.
Before we get into those sections, we need to understand how CBD works in the endocannabinoid system.
There are three common actions that a substance can have on a given pathway:
- Agonist - boosts activity
- Antagonist - reduces activity
- Inhibitor - blocks activity
Let's take benzos for example. They directly boost levels of GABA.
The problem is that the brain sees this and pushes back the other way with long term use.
This is the basis for tolerance, withdrawal symptoms, and (partially) even addiction.
Check out CBD versus benzos or CBD and tolerance to understand more.
CBD is technically called a negative allosteric modulator.
Goodness...that's a mouthful.
Basically, it means that it sends a message backwards...say from a receiving neuron.
It works like a feedback mechanism!
This leads to some interesting effects.
We don't see overdoses or significant side effects as a result of this.
A quick look at cancerous cells explains why.
CBD can have three completely different effects depending on the state of the cell or neuron:
- Healthy cell or neuron with low inflammation - CBD has no effect
- Healthy cell or neuron with high inflammation - CBD decreases inflammation
- Cancerous or virally infected cell or neuron - CBD INCREASES inflammation
Read that back over. What's going on in the third one?
It doesn't make sense till you realize that ramping up inflammation (technically, oxidative stress) is how our immune system naturally kills off wayward cells.
This feedback mechanism is key to balancing systems such as glutamate and GABA. LEt's go there now.
CBD and hyperexcitability for autism
We'll start with the most important piece...at least according to the most recent research and brain scanning advances.
The delicate balance between glutamate (gas pedal) and GABA (brake pedal).
Newer studies are pointing to a mismatch here as a key driver and we saw above how hyperactivation of the immune system can also feed this loop.
Does CBD have any impact there?
Yes!
We've written on this in-depth at our CBD and glutamate or CBD and GABA reviews but some quick takeaways.
In fact, this is right in the wheelhouse of CBD and maybe it's a greatest asset (outside of serotonin and immune effects).
The clues abound.
Remember that CBD was originally discovered for seizures (#1 comorbidity for autism) and there's an FDA approved drug based on CBD for this very use.
The second most prolific source of research is on anxiety which also has a component of reduced GABA function (See CBD and GABA for anxiety).
Let's dig deeper into this pathway.
We'll try not to get lost in the weeds but there's interesting new research to share.
Let's start with GPR55. It's an android from Star Wars.
Actually, it's one of 1000's weird little pathways that make our brain work (or not).
There's a specific tie connecting autism and CBD however along this particular path.
First autism:
Moreover, the same study documented a downregulation of GPR55 and PPAR gene expression, supporting a role for these receptors in the cognitive mechanisms involved in autism
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4604173/
It's also tied to anxiety which similarly displays an inadequate GABA function.
CBD's effect?
CBD is a GPR55 antagonist and can modulate neuronal Ca2+ levels depending on the excitability of cells [95]. CBD antagonism is manifested as an anticonvulsant effect
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7023045/
There are two keys in that sentence.
"Depending on the excitability of the cells". Again, a feedback mechanism!
"Anticonvulsant". The biggest comorbidity with autism...seizures.
The ability to adjust depending on the excitability state (which is ultimately governed by GABA and glutamate) is the key.
As researchers said:
Both phytocannabinoids and endogenous cannabinoids function as retrograde messengers that provide feedback inhibition of both excitatory and inhibitory transmission in brain through the activation of presynaptic CB1 receptors.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5938896/
This just means that CBD sends a message backwards to help find balance and they do it via the CB1 receptor (where anandamide functions to slow down activity).
Speaking of anandamide since it generally brings down activity (hence the "bliss" nickname), what about CBD there.
Remember how anandamide partially controls glutamate activity?
What about CBD there:
Cannabidiol enhances anandamide signaling and alleviates psychotic symptoms of schizophrenia
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3316151/
Check out CBD and schizophrenia here.
Remember that autism and schizophrenia share the early infection driver and immune response hyperactivity.
The newest brain scans are showing that GABA doesn't seem to be functioning correctly in autism.
What about CBD there?
This is fascinating because one study looked at autism specifically.
They compared GABA effects from CBD in scans of brains for people with autism versus a control group.
The results:
Across regions, CBD increased GABA+ in controls, but decreased GABA+ in ASD; the group difference in change in GABA + in the DMPFC was significant.
https://pubmed.ncbi.nlm.nih.gov/30758329/
Okay...this is very interesting. First, they concluded that it was indeed GABA pathways that were different versus glutamate. This is also bearing out in other research.
It also shows different effects between neurotypical and autistic brains...not one size fits all.
There's an interesting study where certain parts of the brain including the DMPFC have resting periods during downtime (between task-oriented work).
People with autism do not appear to have these "deactivations".
Applying this approach to autism, we found that the autism group failed to demonstrate this deactivation effect.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1472462/
Imagine an area of the brain which is directly involved in thinking, planning, etc that never gets to turn off? (glutamate is on on on).
It would be exhausting and indeed, it would exhaust.
As the researchers went on to say:
We speculate that the lack of deactivation in the autism group is indicative of abnormal internally directed processes at rest, which may be an important contribution to the social and emotional deficits of autism.
It's similar to how newer research is showing that sleep problems may drive many mental health issues such as schizophrenia. There's no recovery and repair period.
Sleep is also implicated with autism (to be expected where glutamate and GABA are involved...the leading sleep aids all focus on GABA boosting but with tolerance).
Check out CBD and sleep or CBD and GABA for more info.
We'll look at the actual results of CBD on symptoms of autism below but clearly, GABA/glutamate balancing is a key concern.
What about the social reward side of things?
CBD and oxytocin for autism
Let's focus on this one player of many in the hormone suite since there's a strong connection with autism.
Remember that oxytocin is our social reward hormone...the driver of social interactions essentially.
There's a fascinating study that looked at anandamide (the "bliss" molecule) and oxytocin.
Here's the net net of that study:
The results indicate that anandamide-mediated signaling at CB1 receptors, driven by oxytocin, controls social reward.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4653148/
Essentially, social interaction increases (while isolation decreases) anandamide which is required for oxytocin function and social reward.
Too little anandamide. Why does this matter?
Plasma anandamide concentrations are lower in children with autism spectrum disorder
https://molecularautism.biomedcentral.com/articles/10.1186/s13229-018-0203-y
Goodness. This points to an underlying issue in the endocannabinoid system since it's tasked with balancing everything else.
Are there ways to boost anandamide function outside of THC which builds tolerance and has other issues (see CBD versus THC)?
Yes. CBD.
CBD increases anandamide levels by inhibiting its transporter-mediated reuptake and degradation by FAA
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6486906/
Check out the review of the woman who can't feel pain, anxiety, or depression due to a gene variant of this pathway.
Interestingly, CBD doesn't keep jacking up anandamide activity (really CB1 activity) like THC to the point of side effects.
We'll see specific studies of CBD and autism below which focus on this pathway.
Next up, gut health!.
CBD and gut health for autism
We mentioned how there's a clear inflammatory aspect to autism and all immune response leads us to the gut and the microbiome (the trillions of bacteria and other living organisms that do a lot of heavy lifting for our brain and body).
We've written extensively on this at our CBD and the gut barrier or CBD and probiotics but some quick takeaways.
First, the gut barrier...the key to preventing autoimmune issues.
What does CBD do there?
Cannabidiol improved Clostridium difficile toxin A-induced damage in Caco-2 cells, by inhibiting the apoptotic process and restoring the intestinal barrier integrity, through the involvement of the CB1 receptor.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5721977/
Let's translate that, please!
Essentially, the introduced a very nasty bacteria called c difficile which is known to destroy the gut barrier.
We picked this particular nasty bacteria for a reason with autism:
The number of Clostridium spp. (Clostridium paraputri, Clostridium bolteae, and Clostridium perfringens) found in the stools of ASD children was greater than neurotypical children.
https://link.springer.com/article/10.1007/s12031-020-01482-2
Remember that GI issues are a very common comorbidity with autism.
Looked what happened after a fecal transplant, essentially a reboot to the gut bacteria world:
A professional evaluator found a 45% reduction in core ASD symptoms (language, social interaction, and behavior) at two years post-treatment compared to before treatment began.
https://www.sciencedaily.com/releases/2019/04/190409093725.htm
Inflammation is bi-directional between the gut and the brain so let's go there now.
CBD and neuroinflammation for autism
Let's look at two different aspects of the brain for inflammation.
- Microglia activation - the sentinels of brain immune response AND brain remodeling
- Cytokines - the inflammatory markers
First, microglia which can become hyperactivated by early exposure to infection.
What does CBD do there?
One study looked at the effect of CBD on inflammation due to viral infection which can lead to MS:
Moreover, CBD administration at the time of viral infection exerts long-lasting effects, ameliorating motor deficits in the chronic phase of the disease in conjunction with reduced microglial activation and pro-inflammatory cytokine production.
https://www.sciencedirect.com/science/article/pii/S0969996113001939
We kind of showed all our cards there. Both microglia activation and cytokines were calmed down to offset the damage and improved symptoms.
What about the king of brain inflammation (after the stroke of course), Alzheimer's?:
In summary, CBD is able to modulate microglial cell function in vitro and induce beneficial effects in an in vivo model of AD.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3102548/
Check out CBD and microglia or neuroinflammation for more detail.
This immune function is the key to mental health including autism.
One last stop before we get to the studies.
CBD and MTOR (the rapamycin connection)
Remember how we discussed the main pathway that governs the birth/death of cells and brain pathways...which is critical to autism?
mTOR.
What does CBD do there?
A study looked at the effects of CBD after encephalitis, essentially a very serious brain infection.
mTOR is tasked with getting rid of virally or cancer infected cells (the death side). It can be overrun by infection or cancer in this capacity.
Look at CBD's effect:
Our results showed a clear downregulation of the PI3K/Akt/mTOR pathway following EAE induction. CBD treatment was able to restore it, increasing significantly the phosphorylation of PI3K, Akt and mTOR.
https://pubmed.ncbi.nlm.nih.gov/27890794/
Let's walk through that because it's too interesting.
EAE is the autoimmune encephalitis. It exhausts the pathway (mTOR) tasked with removing faulty cells (since there are so many from the infection).
CBD restored this function! Significantly!
That's not the fascinating piece.
In another situation where mTOR is running too hot, CBD can actually slow it down!
In cancer cells, CBD shrunk the size of leukemia cells by reducing the mTOR (cancer feeds on the birth side of the equation):
Cannabidiol reduced phosphorylation of mTOR, PKB and S6 pathways related to survival and cell size.
https://www.frontiersin.org/articles/10.3389/fphar.2017.00144/full
Remember, the key to CBD's function is that it acts as a feedback mechanism. It doesn't just push in one direction.
Remember how too much glutamate (the "gas" pedal) was an issue with autism?
Look at this effect after cocaine use:
Cocaine increases, whereas cannabidiol reduced glutamate release. mTOR inhibition prevents cannabidiol effects
https://www.sciencedirect.com/science/article/abs/pii/S0161813X15001229
Goodness...three very different responses depending on what was needed for balance.
We'll look at other powerful supporters of mTOR below in the tools section.
Finally, what about actual research on CBD and autism.
Let's go there now...this is all relatively new (last few years).
CBD and autism research
First, a study of 18 people with autism with CBD-rich cannabis:
Among the 15 patients who adhered to the treatment (10 non-epileptic and five epileptics), only one patient showed a lack of improvement in autistic symptoms.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6834767/
Although there may be shared basis for both epilepsy and autism (remember the glutamate/GABA imbalance??), look at this result:
This was especially true for the 10 non-epileptic patients, nine of which presented improvement equal to or above 30% in at least one of the eight categories, six presented improvement of 30% or more in at least two categories and four presented improvement equal to or above 30% in at least four symptom categories
Another study looked at 56 children with the following results:
Self-injury and rage attacks (n = 34) improved in 67.6% and worsened in 8.8%. Hyperactivity symptoms (n = 38) improved in 68.4%, did not change in 28.9% and worsened in 2.6%. Sleep problems (n = 21) improved in 71.4% and worsened in 4.7%. Anxiety (n = 17) improved in 47.1% and worsened in 23.5%.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6333745/
Another study found similar effects:
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.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6336869/
Speaking to the ability to have different results depending on the state of the system, studies are starting to tease out brain area response to CBD and how it's different between autism and neurotypical:
Our results suggest that, especially in ASD, CBD alters regional fALFF and FC in/between regions consistently implicated in ASD.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6732821/
There are many new studies directly testing CBD for autism finally underway. Unfortunately (but expected), the US is slow to the party.
We'll add those as they come on but we expect more of the same...just with better study design!
Let's also mention powerful tools on the pathways above.
Other tools with autism
Here are the honorable mentions:
NAC - N acetylcysteine is a powerful supporter of our anti-oxidation system (see CBD and glutathione or CBD and oxidative stress). More importantly (for us, anyway), it acts like a sink for excess glutamate! Check out the review!
Berberine - a powerful remodeler of the gut barrier and microbiome. Mimics effects of metformin but available to everyone. A powerful supporter of AMPK pathway (longevity) which drives mTOR activity. Also remodels the insulin response which is a key component for autism (again, one more clue for the gut's responsibility).
Quercetin or Fisetin - Speaking of mTOR, both are strong supporters and great for oxidative stress and inflammation. Fisetin is actually shown to be stronger there.
Curcumin - this popular herb is an all-around agent with profound effects on inflammation pathways such as this animal study:
The major finding of the study is that curcumin restored the core and associated symptoms of autistic phenotype by suppressing oxidative-nitrosative stress, mitochondrial dysfunction, TNF-α and MMP-9 in PPA-induced autism in rats.
We didn't really get into mitochondria but there's clearly a connection (see CBD and mitochondria).
Fish oil - The brain literally runs on fat. It's mainly fat! Look at the studies of omega 3's and autism such as this summary one:
Our meta-analysis showed significant positive treatment effects of supplementation of omega 3 fatty acids relative to placebo not only on core symptoms of autism such as lethargy (social withdrawal) and stereotypy but also on other related secondary behavioral problems such as hyperactivity.
Of course, Vitamin Bs, D, and C (reduces the stress hormone, cortisol) are critical. D levels need to be checked.
Finally, there's CDP Choline to support the acetylcholine pathway. This is a critical player in the "rest and digest" pathway as well as cognitive function and it's all oversleep.
There are interesting studies on its effect for pathways with autism-like this one:
Acetylcholine Elevation Relieves Cognitive Rigidity and Social Deficiency in a Mouse Model of Autism
https://www.nature.com/articles/npp2013274
This almost requires a whole separate article since the research is newer.
CBD, NAC, and Fisetin all have very safe profiles and low side effects.
Berberine usually has a transition period as the gut is remodeled. Curcumin is similar.
Let's look at practical questions on CBD.
How much CBD for autism
In one of the studies above, the dose of CBD was between 80 and 140 mg.
In the second study, the dose was between 100-300 mg per day.
The third study was at 600 mg per day.
The median point of these numbers actually points to other research we've seen on a powerful effect of CBD called neurogenesis.
Studies show that neurogenesis, the process of brain repair and remodeling, actually peaks at 300 mg.
From 300 mg to 600 mg, it would continue but at a lower amount as other pathways are triggered.
For this reason, 300 mg would likely be the peak mg level per day until we have more definitive research.
Check out CBD and brain repair or CBD and BDNF.
Remember that the entire suite of cellular brain/death appears to be off with autism.
It's generally accepted to start low and work up. A lower test dose is around 30-40 mgs.
Let's look at the type of CBD to match the research.
What's the best CBD for autism
First, the basic requirements.
- Organically grown in the US at an FDA registered farm
- 3rd party tested
- CO2 processed
- No THC
- No Solvents
- No Heavy Metals
- No Pesticides
- No Bacteria
- No Mold
We actually test ours twice since our whole family uses it.
Then, there's the question of full-spectrum versus CBD isolate.
All the research referenced throughout this site is for CBD isolate.
The bigger issue is the histamine response.
Histamine, which is responsible for both allergic reactions and the wake cycle, is altered in people with autism:
A high level of histamine in the brain is associated with neuroinflammation, which is also observed in ASD and is predicted to be involved in the pathogenesis of many neurological diseases, including ASD.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5534955/
The last thing we want with autism is to introduce a bunch of plant material and other components which might set off the immune response or histamine activity.
In fact, many people who try full-spectrum have stomach issues that go away with CBD isolate.
Check out CBD isolate versus full spectrum for histamine.
Finally, there's the cost.
If 300 mg is the peak level for neurogenesis which is key to repair and remodeling brain pathways, that can get expensive.
The key is the cost per mg of CBD.
That's why we price our 6000 mg bottles at about 2-3 cents per mg and that's before various discounts up to 30% (subscription, referral, review, etc).
It's the lowest price on the market by far for high-quality CBD isolate.
We discovered CBD due to traumatic perimenopause (our story is here) so we've been there.
Our goal is to bring the research and accessibility to as many people suffering as possible.
Be well and take care of each other.
Always work with a doctor or naturopath with any supplement!
The information provided here is not intended to treat an illness or substitute for professional medical advice, diagnosis, or treatment from a qualified healthcare provider.