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Cannabinoids and autism spectrum disorder (ASD)

By Mariano Garcia de Palau

Born in Barcelona, 17 February 1956. Graduated in medicine and surgery from the University of Barcelona in 1979. For 38 years has worked as an emergency physician in the area of occupational medicine. He became interested in cannabis by chance, and for the last 15 years has studied its therapeutic uses. He currently works at Kalapa Clinic, where he advises on treatments with cannabinoids, performs clinical work with patients and collaborates with different organisations and associations such as Catfac. He is a member of the Spanish Observatory for Medicinal Cannabis. He is a regular member of IACM.

Autism can be described as a disorder of neurodevelopment, causing alterations in social interaction and with the subject’s surroundings. It also causes problems with verbal and non-verbal communication, and sometimes very restricted and usually repetitive behaviour.

Parents usually start to become aware of these features during the first two years of life. However, this may depend on the degree of autism, which can vary from very mild in some cases to extreme in others.

This variability —as well as other features discussed below— has led to the development of the concept of Autism Spectrum Disorder (ASD). This category encompasses three types of disorder with separate and distinguishable characteristics, namely autistic disorder, Asperger’s syndrome, and PDD-NOS (Pervasive Developmental Disorder-Not Otherwise Specified). Diagnosis can sometimes prove very difficult and be complicated by the degree of autism and a correlation with other pathologies, such as refractory epilepsy.

Autism per se (autistic disorder) involves retardation in cognitive development; this is not the case, however, with Asperger’s syndrome, where numerous cases have been reported of patients with above-average cognitive performance; some individuals are even exceptionally gifted at performing certain mental tasks.

The causes of this disorder are not known with any certainty. Although there are different theories, we do know that there is a proven genetic predisposition. ASD has been related to the so-called fragile X syndrome. However, it is not known whether other chromosomal changes might also be causes or contributors.

Other causes that have been reported include the MMR vaccine, use of paracetamol, food and environmental factors and celiac disease.

Neurotransmitters such as dopamine, serotonin, tryptophan and oxytocin might also be involved.

We know that the endocannabinoid system (ECS) is involved in regulating the processes that are altered in these disorders. One might therefore consider that phytocannabinoids (plant-extracted cannabinoids) might help treat the symptoms of ASD.

We can give some idea of what everyday life for autistic children and the people around them by describing their behavioural and empathic characteristics.

They reject physical contact; there is either no or only very brief eye contact; they do not respond to their parents’ facial gestures; they do not point to objects or actions to draw attention to them or look at objects that their parents point to; they do not properly use facial expressions to show feelings; they show no kind of concern for others; they normally do not have friends and show no interest in making them.

At 16 months, they are normally still unable to say isolated words. They do not point at objects they need or share with others. They tend to repeat what others say without understanding the meaning; they do not usually answer to their names, though they sometimes respond to other sounds. They appear to be uninterested in communicating.

In many cases, they make repetitive movements with their head, arms or hands and suck their fingers.

These children suffer great frustration because they cannot convey and express their emotions. In many cases they have no verbal language, but probably do want to communicate. Imagine living like that.

In cases of severe autism, many children and adolescents display unstable and aggressive behaviour, often including self-harming. This causes major problems for keeping them under control, often necessitating the use of neuroleptic drugs or benzodiazepines to solve behavioural issues.

Prospects for use of phytocannabinoids

As we have said, the ECS is involved in controlling these processes; as early as the foetal period it regulates the essential processes related to neuron differentiation and synapse positioning.

Some studies have shown that ECS CB1 receptors —the most common in the central nervous system— show functional alterations in the cerebral regions involved in autism, such as the hippocampus and basal ganglia.

If this is one of the causes (or a decisive factor) in ASD, the most appropriate cannabinoid might be thought to be THC, since there are also studies that implicate the CB2 receptor in ASD.

THC is the cannabinoid that acts by way of these two receptors, CB1 and CB2.

However, cannabidiol or CBD has been shown to be of great interest for intervention in ASD. Its mechanisms of action differ from those of THC, although they both act on GPR55 receptors and also on transient receptor potential vanilloid (TRPV). All of these receptors are also found in the central nervous system.

The effect of CBD is very unusual. As we have said, many children with ASD display aggressive behaviour and often self-harm. The “conduct normalising” effect is of great interest, since there are no signs of sedation; patients remain properly alert and have no difficulty remaining so. However, in many cases their behaviour is stabilised (though I must reiterate that it is always necessary to assess the severity of the patient’s condition).

Some patients acquire skills they had either lost or never had, such as getting dressed on their own, interacting with the tablet, listening to music and paying attention to their surroundings when out walking. They are less inclined to reject physical contact and may even give hugs, possibly for the first time in years. Their facial expressions improve and they can hold eye contact.

Many children with ASD seem to be unhappy and to be in constant pain or suffering. However, once they start treatment this situation appears to change — or at least improve. Some smile or even laugh!

These changes might seem trivial, but for the children’s parents, they are a major breakthrough and offer some glimmer of hope where none had previously existed.

No clinical trials are yet available to provide the necessary statistics on the effectiveness of cannabinoid use in ASD. Nor have any studies been conducted on prolonged medium and long term use of CBD or on potential unwanted consequences. However, for the moment CBD has shown to be safe and very untoxic. Indeed, no maximum dose has yet been identified.

We know, then, that both of these cannabinoids can be effective in cases of ASD. I think we now have to determine the most effective treatments, in terms of the ratio or proportion of THC to CBD which should be used.

Patients must not display any form of psychoactive effect from THC. Initially, CBD should be used. Only subsequently should we assess the need to add differing proportions of THC, until an improvement is achieved in different areas, depending in all cases on the patient’s evolution. Evidently, it is essential to assess the effectiveness of treatment and be vigilant for the possible appearance of any side effects.

Each case must be appraised on its own merits; no two patients are the same. It is also extremely important that clinical trials be conducted, to allow us to work with scientifically proven data. Although there is plenty of information available on cannabinoids, it is mostly based on preclinical data, essentially from animal experiments.

Autism can be described as a disorder of neurodevelopment, causing alterations in social interaction and with the subject's surroundings. It also causes problems with verbal and non-verbal communication, and sometimes very restricted and usually repetitive behaviour. Parents usually start to become aware of these features during the first two years of life. However, this may

Cannabis and autism, explained

by Peter Hess / 7 September 2020
This article is part of:
Autism 101
Topics:
Science & Society, Treatments
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Over the past decade, autistic people and their families have increasingly experimented with medical marijuana and products derived from it. Many hope these compounds will alleviate a range of autism-related traits and problems. But scientists are still in the early stages of rigorous research into marijuana’s safety and effectiveness, which means that people who pursue it as treatment must rely mostly on anecdotal information from friends and message boards for guidance.

Here we explain what researchers know about the safety and effectiveness of cannabis for autism and related conditions.

What is medical marijuana?
Medical marijuana generally refers to any product derived from cannabis plants — including dried flowers, resins and oils — that has been recommended by a doctor. It may be consumed directly or infused into an array of foods, lozenges and candies. These products have become popular among autistic people and their families for treating a broad swath of conditions, including insomnia, epilepsy and chronic pain.

Depending on the strain of the plant and the processing methods used, these products contain varying levels of active ingredients, including tetrahydrocannabinol (THC) — responsible for the ‘high’ associated with marijuana — and cannabidiol (CBD), which is minimally psychoactive. Much of the research on medical applications focuses on CBD. There are also more than 500 other compounds in marijuana that may affect people’s behavior and cognition 1 .

Is medical marijuana legal?
Yes and no. Federal law in the United States classifies marijuana and its derivatives as ‘Schedule 1’ drugs, meaning that they have no accepted medical use and a high potential for abuse. Schedule 1 drugs are illegal, and research on them requires labs to follow strict security protocols and adhere to regular facility inspections.

In 33 states, along with the District of Columbia and Puerto Rico, however, people can legally buy and use medical cannabis for certain approved conditions, such as seizures and sleep problems, although the list of qualifying conditions varies by state. These same states, plus 13 others, also allow CBD oil. Fourteen states plus Puerto Rico have approved medical marijuana for autism, and some additional states may allow it for autistic people at a doctor’s discretion.

Under U.S. federal law, CBD products manufactured from industrial hemp are legal as long as they contain no more than 0.3 percent THC. And in some states, CBD oil is permitted to contain up to 5 percent THC.

In many states where medical marijuana is legal, licensed dispensaries sell products that have been tested by accredited laboratories to verify the presence of active ingredients and the absence of contaminants. Some states permit individuals or their licensed caregivers to grow their own cannabis plants for personal use. Most states in the U.S. require people who use medical marijuana to register and get a special identification card.

In many European countries, as well as in Australia, Canada, Israel and Jamaica, medical cannabis is legal, with specific laws varying from country to country.

Are there any cannabis-derived drugs approved to treat autism or related conditions?
To date, the U.S. Food and Drug Administration has approved only one cannabis-derived drug: Epidiolex. It is a liquid cannabis extract containing purified CBD that can decrease seizures in people with Dravet syndrome or Lennox-Gastaut syndrome — severe forms of epilepsy that are sometimes accompanied by autism — and in those with tuberous sclerosis complex. It is available only by prescription, and only for these three conditions.

GW Pharmaceuticals, the company that makes Epidiolex, is conducting a trial of the drug for Rett syndrome, a neurodevelopmental condition related to autism. The Rett syndrome trial is not focused on alleviating seizures, but on improving cognitive and behavioral problems. The company is also recruiting autistic children and teenagers for a phase 2 trial of cannabidivarin, another component of cannabis. That trial will examine cannabidivarin’s effect on a range of traits in autistic children, including repetitive behaviors, and on quality of life.

How might cannabis help autistic people?
Epidiolex’s success has spurred many parents to try marijuana and cannabis extracts for seizures, behavioral issues and other autism-related traits in their children, but experts warn that these drugs remain largely untested for such purposes. Some studies on cannabinoids have shown promising results in animal models and in early-stage clinical trials, but this research does not yet support their widespread use.

Cannabis’ active ingredients are thought to exert their effects by binding to proteins called cannabinoid receptors in the brain: THC activates the CB1 and CB2 receptors, whereas CBD seems to block them 2 .

Both types of cannabinoid receptors are located in neurons in the brain and throughout the body. The brain contains more CB1 than CB2 receptors, and the activation of each receptor type affects a range of ion channels and proteins involved in cell signaling 3 . The ultimate effects of cannabinoid receptor activation depend on which body system they belong to. For instance, the activation of CB1 receptors in the brain can either increase or decrease neuron excitability, depending on which kind of neuron a cannabinoid binds to; activation of CB2 receptors in the digestive system can decrease inflammation 4,5 .

Blocking the CB1 receptor can relieve seizures and memory issues in a mouse model of fragile X syndrome, a condition related to autism, according to a 2013 study in Nature Medicine 6 . A 2018 clinical trial of a synthetic CBD drug by the drug maker Zynerba showed significant improvements in anxiety and other behavioral traits in people with fragile X. Cannabinoid receptor activation has also been shown to lead to memory improvements in fragile X mice 7 .

Research has also demonstrated that CBD alleviates seizures in children with CDKL5 deficiency disorder, an autism-linked condition that is characterized by seizures and developmental delay. CBD also lessens seizures and improves learning and sociability in a mouse model of CDKL5 deficiency disorder.

Complicating the picture, CBD alone may not be sufficient for cannabis’ therapeutic effects. A 20-to-1 ratio of CBD to THC relieves aggressive outbursts in autistic children, a 2018 study suggests 8 . This same ratio of compounds significantly improved quality of life for some children and teenagers with autism in a 2019 study 9 . Specifically, researchers observed significantly fewer seizures, tics, depression, restlessness and outbursts. Most participants reported improvements, and about 25 percent of participants experienced side effects such as restlessness.

Cannabis may have effects that go beyond the cannabinoid receptors, too. Mice that ingested CBD over extended periods of time displayed changes to DNA methylation in sections of the genome associated with autism, a 2020 study showed 10 . The researchers suggested that epigenetic changes may be at least partly responsible for CBD’s behavioral effects, though they did not directly examine the mice’s behavior.

Is cannabis safe?
It’s unclear. Large doses are usually not fatal, but taking it regularly may have long-term effects.

Based on the clinical trials of Epidiolex, the FDA warns that the drug could cause elevated liver enzymes, which can be a sign of liver damage. This is especially likely in people who take Epidiolex and the epilepsy drug valproate at the same time.

CBD is considered minimally psychoactive, but many preparations of it contain undisclosed amounts of THC, which may lead to inadvertent intoxication and impairment.

Many studies have shown that cannabis treatment carries only minor side effects such as sedation or restlessness, but these studies have not looked at long-term side effects. Researchers still don’t have a solid grasp on how the active ingredients in marijuana actually affect the brain, nor do they know how these compounds might impact a child or teenager’s developing brain or interact with other medications.

Some research has shown that recreational marijuana use beginning in one’s teenage years can have negative long-term effects on cognition 11 . But experts note that the dosages used for medical purposes are often quite lower than those used in a recreational context.

Are some cannabis products safer or more effective than others?
Many people who self-administer cannabinoids for epilepsy or other conditions cultivate it at home. Others purchase it directly from companies rather than buying it at state-licensed dispensaries, and research has shown that these products are not created equal.

The actual potency of CBD products varies widely from their advertised concentrations, according to a 2017 study in JAMA, and some products contain more than the legal limit of THC — potentially enough to cause intoxication, especially in children 12 . Less than one-third of the products tested contained within 10 percent of the advertised CBD concentration, and THC was detected in about 21 percent of samples.

In a presentation at the 2020 meeting of the American Academy of Neurology, researchers concluded that ‘artisanal’ CBD products available for purchase online and in health-food stores are not as effective at controlling seizures as pharmaceutical-grade CBD.

Autistic people and their families are increasingly experimenting with marijuana to try to ease problems such as insomnia, epilepsy and chronic pain — and traits of autism. But there is little evidence for its safety or effectiveness. ]]>