Posted on

Cbd oil for behavioral problems of special needs adults

CBD: What Parents Need to Know

Parents are giving it to kids to combat anxiety and other problems. But there are risks, and little research to support it.

What You’ll Learn

  • Is CBD safe for kids?
  • What are the risks of giving kids CBD?
  • Can CBD help kids who have mental health disorders?
  • Quick Read
  • Full Article
  • What do we know about CBD?
  • Concerns about CBD
  • Is CBD safe?
  • CBD oil for anxiety
  • CBD and autism
  • Research boom

Quick Read

These days, you can find CBD everywhere. Some people believe that it can treat everything from chronic pain and cancer to anxiety and ADHD. But is it safe for kids?

CBD is still pretty new, so there’s very little research about its safety or how well it works, especially for children. So far, there’s only one marijuana-derived medication that has been approved by the Food and Drug Administration. It’s called Epidiolex, and it’s used to treat a rare form of epilepsy in patients who are at least two years old.

Because CBD is so new, there also aren’t a lot of rules about what can and cannot be included in CBD products. So, there’s a huge variety in the quality of products. You may even find different amounts of CBD in different packages of the same product.

Since there isn’t a lot of research about CBD, doctors say there are some risks with using CBD for kids. For example, CBD products may contain things other than CBD, and those things could be harmful. Plus, we don’t yet know if CBD works well with other medications or how much you should give your child.

Although a few studies have found that CBD oil might work for anxiety, they only looked at healthy people who were put in situations that made them anxious. There are no studies yet on people with chronic anxiety. Researchers are also exploring CBD for kids with autism spectrum disorder. The results are good so far, but more research needs to be done before we can know if it’s safe and effective.

CBD is everywhere. From corner stores and bars to medical marijuana dispensaries, it’s being offered for its reputed ability to relieve pain and make people feel better.

Though CBD — full name cannabidiol — is extracted from marijuana or hemp, it doesn’t contain THC, the chemical in marijuana that has psychoactive effects, so it doesn’t make you feel high.

Available in the form of vaping, oils, lotions, cocktails, coffee, gummies — you name it — CBD has been touted as a treatment for complaints as far-reaching as chronic pain, cancer, migraines, anxiety and ADHD. You know it’s gone mainstream when even Consumer Reports has issued guides on how to shop for CBD and tips for safe CBD use.

Not only are adults experimenting with CBD for whatever is bothering them, increasingly parents are turning to CBD to help their kids focus, sleep, calm down and more.

But popular use of CBD is blowing up with very little research into its safety or its efficacy, especially in children. The first and only marijuana-derived drug approved by the Food and Drug Administration, Epidiolex, is used to treat a rare, severe form of epilepsy in patients two years of age and older. And since cannabis is in the early stages of legalization and regulation, there is a huge variety in the quality and dosage of products — risks associated with using products that have not been vetted by the FDA.

What do we know about CBD?

For millennia, hemp plants have been used for medicinal purposes around the world. In 1851 marijuana was classified by the United States Pharmocopeia as a viable medical compound used to treat conditions like epilepsy, migraines and pain. But since marijuana and cannabis-related products were made illegal in the US in 1970, there has been a dearth of research about either marijuana or CBD. Its classification as a Schedule 1 drug made it nearly impossible to get federal funding to study cannabis.

“The biggest problem is there’s a lot that we still need to know, especially in kids,” says Paul Mitrani, MD, a clinical psychiatrist at the Child Mind Institute. “In regards to treating mental health disorders in children and adolescents, there’s a lack of evidence to support its use.”

Dr. Mitrani, who is a pediatrician and child and adolescent psychiatrist, says it’s an area worthy of investigation but recommends that parents wait until further research is done before giving a child CBD.

Concerns about CBD

While anecdotal evidence of the benefits of CBD is common, there are risks associated with using these products, especially in children. Some of the concerns:

  • Products are unreliable in delivering a consistent amount of CBD. They could have less, or more, than advertised, and most do not offer independent verification of active contents. Analysis of products for sale show that many do not have the amount of CBD that they advertise. “So you can’t depend on the quality of what you’re getting,” notes Dr. Mitrani.
  • How much is absorbed? Very little is known about how much CBD is actually delivered to the brain in a given product. Various delivery systems — vaping, taking it orally, eating it in baked goods, etc. — have different rates of delivery. Even the oils that the CBD is dissolved in can result in varying effects. “Effects can vary a lot based on the delivery system used and the amount people are exposed to can be inconsistent,” Dr. Mitrani says.
  • Products may contain things other than CBD, and they could be harmful. Lab testing — which provides information about CBD levels, THC levels (if any), and contaminants in the product — isn’t mandatory for CBD products in every state. Without a CoA (Certificate of Analysis) it’s that much harder to verify the safety of the product. Bootleg CBD may be connected to recent lung illnesses and deaths that have been attributed to vaping. The CDC and the American Medical Association recommend avoiding vaping entirely while the cause of these illnesses is determined.
  • CBD may be safe itself, but it may interact with other medications a child is taking, that are also metabolized in the liver.
  • If it’s used for sleep, Dr. Mitrani worries that while it may potentially help with sleep, “your child may become tolerant to it and possibly experience worsening sleep problems if stopped.”
  • Since CBD use — especially for kids — is a still so new, few people are familiar with dosing for children, so determining how much to give your child would be tricky. Clinical doses versus what you might find at a coffeehouse could vary dramatically.
  • The legality of cannabis products and CBD is still murky. CBD derived from hemp is federally legal, while CBD derived from marijuana plants is subject to the legal status in each state — and remains federally illegal. Meanwhile, the FDA issued a statement making clear that products that contain CBD — even if they are derived from legal, commercial hemp — cannot claim to have therapeutic benefits or be sold as dietary supplements unless they have been approved by the FDA for that use.

Is CBD safe?

Last year the World Health Organization, acknowledging the explosion in “unsanctioned” medical uses of CBD, reviewed the evidence for its safety and effectiveness. The WHO report concluded that “CBD is generally well tolerated with a good safety profile.” Any adverse effects could be a result of interactions between CBD and a patient’s existing medications, the WHO noted.

The report found no indication of potential abuse or dependence. “To date there is no evidence of recreational use of CBD or any public health-related problems associated with the use of pure CBD.”

As for effectiveness, the WHO noted that several clinical trials had shown effectiveness for epilepsy, adding: “There is also preliminary evidence that CBD may be a useful treatment for a number of other medical conditions.”

CBD oil for anxiety

In 2015 a group of researchers led by Esther Blessing, PhD, of New York University, investigated the potential of CBD for treating anxiety. In a review of 49 studies, they found promising results and the need for more study.

The “preclinical” evidence (ie from animal studies) “conclusively demonstrates CBD’s efficacy in reducing anxiety behaviors relevant to multiple disorders,” Dr. Blessing wrote. Those include generalized anxiety disorder, PTSD, panic disorder, social anxiety disorder and OCD.

The review notes that the promising preclinical results are also supported by human experimental findings, which also suggest “minimal sedative effects, and an excellent safety profile.” But these findings are based on putting healthy subjects in anxiety-producing situations and measuring the impact of CBD on the anxiety response. Further studies are required to establish treatment with CBD would have similar effects for those who struggle with chronic anxiety, as well as what the impact of extended CBD use may be.

“Overall, current evidence indicates CBD has considerable potential as a treatment for multiple anxiety disorders,” Dr. Blessing concludes, “with need for further study of chronic and therapeutic effects in relevant clinical populations.”

CBD and autism

A group of Israeli researchers have been exploring the use of CBD to reduce problem behaviors in children on the autism spectrum. A feasibility study involving 60 children found substantial improvement in behavioral outbreaks, anxiety and communication problems, as well as stress levels reported by parents.

The researchers, led by Adi Aran, MD, director of the pediatric neurology unit at Shaare Tzedek Medical Center, went on to do a double-blind, randomized, placebo-controlled trial with 150 participants with autism. In this trial, just completed but not yet analyzed, patients were treated CBD for three months.

Research boom

In the US, research has been given a boost by changing guidelines and laws. In 2015 the DEA eased some of the regulatory requirements that have made CBD, as a Schedule 1 substance, difficult to study. “Because CBD contains less than 1 percent THC and has shown some potential medicinal value, there is great interest in studying it for medical applications,” the DEA said in announcing the change.

And in approving the first CBD-based drug, Epidiolex, last year the FDA expressed enthusiasm for the research boom that is sure to come, paired with stern words for the flood of marketers of products claiming unsubstantiated health benefits.

“We’ll continue to support rigorous scientific research on the potential medical uses of marijuana-derived products and work with product developers who are interested in bringing patients safe and effective, high quality products,” the FDA pledged. “But, at the same time, we are prepared to take action when we see the illegal marketing of CBD-containing products with serious, unproven medical claims.”

CBD Oil as a Treatment for Autism

Lisa Jo Rudy, MDiv, is a writer, advocate, author, and consultant specializing in the field of autism.

Verywell Health articles are reviewed by board-certified physicians and healthcare professionals. These medical reviewers confirm the content is thorough and accurate, reflecting the latest evidence-based research. Content is reviewed before publication and upon substantial updates. Learn more.

Stephanie Hartselle, MD, is a board-certified pediatric and adult psychiatrist and Diplomate of the American Board of Psychiatry and Neurology.

Cannabidiol , sometimes called CBD, is a chemical compound found in the cannabis plant. The American Academy of Child and Adolescent Psychiatry does not support the use of any cannabinoids in children or teens for the diagnosis of autism.

In fact, CBD oil has been studied as a potential treatment for autism, but the results do not support its use in treating children or adults who have this disorder. And, according to Harvard Health Publishing, “because CBD currently is typically available as an unregulated supplement, it’s hard to know exactly what you are getting.”

Currently, there are some treatments that may alleviate some symptoms of autism, but there is no cure.

About CBD

CBD can be derived from hemp or cannabis (the marijuana plant) and is now legal in many states in the United States and in many countries around the world. It can be purchased without a prescription as an oil, tincture, pill, or chewable pill online and is also an ingredient in edibles ranging from coffee to pastries. It comes in many dosages and at many price points.

Claims for CBD range from the realistic to the absurd. Some websites and companies claim, for example, that CBD can cure cancer (it can’t). On the other hand, CBD does seem to alleviate some symptoms of disorders such as epilepsy, nausea, and muscle spasticity—all issues that can affect some people with autism. According to Harvard Health Publishing, “the strongest scientific evidence is for its effectiveness is in treating epilepsy disorders of Dravet syndrome and Lennox-Gastaut syndrome (LGS), which typically don’t respond to anti-seizure medications.”

The FDA has approved a cannabis-derived medicine for the treatment of certain types of epilepsy, Epidiolex, which contains CBD.

It’s important for parents to know that CBD is not helpful for everyone who uses it, and it can cause side effects, such as sleepiness or nausea.

CBD and Autism

Neither CBD nor any other drug can remove or cure core symptoms of autism, which include social communication challenges, sensory dysfunction, and restricted, repetitive behaviors.

CBD can, however, help to alleviate epilepsy in some children and adults with autism. Fewer seizures can lessen stress and make it easier to interact socially.

Research Findings

A few full-scale studies have explored the impact of CBD on children with autism—none, however, have explored its impact on adults on the spectrum. One of the largest such studies took place in Israel. The report includes the following finding:

“In 2014, The Ministry of Health began providing licenses for the treatment of children with epilepsy. After seeing the results of cannabis treatment on symptoms like anxiety, aggression, panic, tantrums and self-injurious behavior, in children with epilepsy, parents of severely autistic children turned to medical cannabis for relief.”

Studies are ongoing in clinics and research centers around the world.

Before Trying CBD

Before considering CBD oil, it’s important to follow these steps:

  • Check with your child’s (or your) doctor to be sure that no allergies or sensitivities exist that could cause a reaction to CBD.
  • Check with your child’s doctor to see if the medical benefits of CBD oil are relevant to your child’s symptoms.
  • Check to be sure that CBD is legal in your state, province, or country.
  • Research sources of CBD to be sure the brand you’re using is well-regarded and properly licensed.
  • Take careful notes about your child’s (or your own) behaviors and symptoms so that you can make a useful comparison before and after using CBD.

Using CBD

CBD comes in many forms and at many dosage levels, including candy forms. It’s important to keep candy-like drugs and supplements out of the reach of children.

Lower doses are more easily tolerated than higher doses.

When you start using any new supplement, drug, or treatment, it’s important to be sure your child’s doctor is aware of the new treatment and has no concerns about it relative to your child’s health. Let everyone working with your child know that you’ve started something new and ask them to look for and report any changes in behaviors or skills.

Take careful notes of any changes you see so you can easily review your records to determine how helpful the new treatment really is. Keep an eye open for any troubling side effects. Be sure to communicate any side effects to a doctor or healthcare professional immediately.

A Word From Verywell

Children with autism grow and learn every day, simply because they are maturing. As a result, there is no simple way to determine whether a change in behavior or an increase in skills is due to a particular treatment or to ordinary maturation. This reality makes it very easy to see a change in behaviors and inaccurately attribute them to the newest treatment you’ve tried. By far, the best way to know whether a particular treatment is truly effective is to be rigorous about evaluating your child before and after its use.

CBD-enriched cannabis for autism spectrum disorder: an experience of a single center in Turkey and reviews of the literature

Autism spectrum disorder is a neurodevelopmental disorder characterized by deficits in communication, social interaction, restricted interest, and repetitive behaviors. Although more cases are being diagnosed, no drugs are approved to treat the core symptoms or cognitive and behavioral problems associated with autism. Therefore, there is an urgent need to develop an effective and safe treatment.

Objective

In this study, we aim to share our 2-year experience with CBD-enriched cannabis treatment in autism and review the latest studies.

Materials and methods

The study included 33 (27 males, six females) children diagnosed with autism spectrum disorder who were followed up between January 2018 and August 2020. The mean age was 7.7 ± 5.5 years. The average daily dosage of cannabidiol (CBD) was 0.7 mg/kg/day (0.3–2 mg/kg/day). The median duration of treatment was 6.5 months (3–28 months). The preparations used in this study contained full-spectrum CBD and trace elements tetrahydrocannabinol (THC) of less than 3%.

Results

The outcomes were evaluated before and after treatment based on clinical interviews. At each follow-up visit, parents were asked to evaluate the effectiveness of the CBD-enriched cannabis treatment. According to the parents’ reports, no change in daily life activity was reported in 6 (19.35%) patients. The main improvements of the treatment were as follows: a decrease in behavioral problems was reported in 10 patients (32.2%), an increase in expressive language was reported in 7 patients (22.5%), improved cognition was reported in 4 patients (12,9%), an increase in social interaction was reported in 3 patients (9.6%), and a decrease in stereotypes was reported in 1 patient (3.2%). The parents reported improvement in cognition among patients who adhered to CBD-enriched cannabis treatment for over two years. The antipsychotic drug could be stopped only in one patient who showed mild ASD symptoms. No change could be made in other drug use and doses. Additionally, this study includes an extensive review of the literature regarding CBD treatment in autism spectrum disorder. According to recent studies, the average dose of CBD was 3.8±2.6 mg/kg/day. The ratio of CBD to THC in the used preparations was 20:1. The most significant improvements were seen in the behavioral problems reported in 20–70% of the patients.

Conclusion

Using lower doses of CBD and trace THC seems to be promising in managing behavioral problems associated with autism. In addition, this treatment could be effective in managing the core symptoms and cognitive functions. No significant side effects were seen at the low doses of CBD-enriched cannabis when compared to other studies.

Background

Autism spectrum disorder (ASD) is a neurodevelopmental disorder that varies in severity and is characterized by deficits in communication, social interaction, restricted interest, and repetitive behaviors (Fusar-Poli et al. 2020). During the last three decades, there has been a threefold increase in the number of children diagnosed with ASD (Lihi Bar-Lev Schleider et al. 2019). Currently, it affects up to 1 in 54 individuals (Maenner et al. 2020). Cooccurring medical conditions such as epilepsy, intellectual disability, and behavior problems occur in these individuals (Pretzsch et al. 2019a; Pretzsch et al. 2019b).

The etiopathogenesis of ASD remains largely unknown. Several genetic, perinatal, and environmental factors seem to be involved. Some researchers have evidenced an imbalance in the endogenous neurotransmission system, such as the serotoninergic, γ aminobutyric acid (GABA), and endocannabinoid system (ECS), which regulate functions such as emotional responses and social interactions typically impaired in ASD (Fusar-Poli et al. 2020).

Endocannabinoids (eCBs) and their receptors are present in the nervous system, connective tissue of internal organs, glands, and immune system. Cannabinoid receptor 1 (CB1) is a G protein-coupled receptor (GPR) that is found mainly in the central nervous system (Mc Partlan et al. 2014). In mammals, high concentrations of CB1 are found in the brain area that regulates appetite, memory, fear extinction, motor responses, and postures such as the hippocampus, basal ganglia, basolateral amygdala, hypothalamus, and cerebellum (Aran et al. 2019; Mc Partlan et al. 2014). CB1 can also be found in nonneuronal cells. Data indicate that cannabinoid receptor type 2 (CB2) is linked to a variety of immune functional events. However, it may play a functionally relevant role in the central nervous system (Aran et al. 2019; Bridgemanan and Abazia 2017).

There are two endogenous cannabinoids, N-arachidonoylethanolamine (anandamide) and two arachidonoylglycerols (2-AG). The ECS has been broadened by discovering new secondary receptors, ligands, and ligand metabolic enzymes, including transient receptor potential cation channel subfamily V member 1 (TRPV1) (Mc Partlan et al. 2014).

Anandamide and 2-AG can act via CB1 and CB2 receptors and exert a range of biological effects in central and peripheral cells. Anandamide is broken down by fatty acid amide hydrolase (FAAH); inhibitors of FAAH lead to an increase in anandamide. CBD act as an inhibitor of FAAH (Bridgemanan and Abazia 2017). Endocannabinoid signaling occurs in a retrograde direction; that is, signaling is initiated in postsynaptic neurons and acts upon presynaptic terminals. In contrast to classical neurotransmitters, eCBs are not stored. They are produced on demand upon stimulation of postsynaptic cells (Aran et al. 2019; Zamberletti et al. 2017).

Interestingly, CBD displays a low affinity for CB1 and CB2 receptors. CBD facilitates excitatory glutamate and inhibitory GABA neurotransmission across the brain through agonism at the TRPV1 receptor (Pretzsch et al. 2019a; Mc Partlan et al. 2014). Additionally, CBD can increase GABAergic transmission by antagonizing G protein-coupled receptor 55 (GPR55), especially in the basal ganglia. CBD is thought to be an agonist at prefrontal serotonin 5-HT1A receptors (Castillo et al. 2012) (Fig. 1).

CBD and mechanism of action. CBD, cannabidiol; FAAH, fatty acid amide hydrolase CB, cannabinoid receptor; TRPV1, transient receptor potential cation channel subfamily V member 1; PPAR-γ, peroxisome proliferator-activated receptor-gamma; GPR, G protein-coupled receptor; GPR55, G protein-coupled receptor 55; 5-HT1A, serotonin 5HT receptor; MC4R, melanocortin 4 receptor; ROS, reactive oxygen species

Another mechanism of action can be via vasopressin and oxytocin. The presence of oxytocin in the CSF seems to originate from neuronal oxytocinergic extensions to the limbic system, brain stem, and spinal cord. Oxytocin receptors are distributed in different parts of the central nervous system, such as the basal ganglia, limbic system, thalamus and hypothalamus, and brain stem. Oxytocin modulates social behavior, motor function, pain control, memory and learning, eating behavior, stress and anxiety, and emotional processing. Oxytocin administration reduces stress and anxiety and depression in animal models. This effect seems to be modulated at least partly by the effects of oxytocin on the hypothalamic-pituitary-adrenal (HPA) axis and the opioidergic and dopaminergic systems in limbic brain structures. Several animal model studies support the role of oxytocin in improving social behavior, an effect that appears to involve the melatoninergic and endocannabinoid systems, specifically an increase in social interactions produced by agonism at the melanocortin four receptor (MC4R (Russo et al. 2005; Dos Santos et al. 2019). CBD leads to enhancement in the release of vasopressin and oxytocin; thus, it could positively affect ASD core symptoms. Studies have shown that oxytocin administration to patients with ASD improves social interactions, reduces classic repetitive behavior, and increases eye contact (Weia et al. 2015). Another mechanism of action of CBD is to act as a dopamine receptor antagonist, which can facilitate its use as an antipsychotic (Dos Santos et al. 2019; Weia et al. 2015).

CBD may act as a neuroprotectant against mitochondrially acting toxins (Davies and Bhattacharyya 2019; Bartova and Birmingham 1976). The highly lipophilic aspect of CBD gives them access to intracellular sites of action. Many studies have suggested mitochondria as targets for CBD, and many theories are based on this idea; one of these theories is that the outer mitochondrial membrane has CB1 receptors. This theory reveals that CBD affects the function of the cells by establishing homeostasis and influencing mitochondria and energy production (Bartova and Birmingham 1976; Ryan et al. 2009).

THC is known to be a major psychoactive component of Cannabis. THC is a partial agonist at CB1 and CB2 (Ryan et al. 2009). Signals through transducing G-proteins and activation of these G-proteins by THC cause inhibition of adenyl cyclase activity, the closing of voltage-gated calcium channels, and the opening of inward rectifying potassium channels. The psychoactive nature of THC limits its use due to side effects. However, a varied mixture of THC with other phytocannabinoids with very weak or no psychoactivity quality has started to be used as a therapeutic drug in humans (Bloomfield et al. 1982; Rodríguez De Fonseca et al. 1992). In this study, we aim to share our 2-year experiences with CBD-enriched cannabis treatment in autism and review the latest studies.

Methods and materials

Patients

This research was conducted in accordance with the Declaration of Helsinki at the Pediatric Clinics of Neurology in Istanbul. CBD-enriched cannabis treatment was started in 54 patients who were diagnosed with ASD. The study included 33 (27 males, six females) children diagnosed with autism spectrum disorder who were followed up between January 2018 and August 2020. The diagnosis of ASD was based on DSM V criteria (American Psychiatric Association 2013). Twenty-one participants refused to participate in this study. The most common reasons for not participating in the study were fear of adverse effects, cost of CBD-enriched cannabis, bitter taste, and behavioral problems. The mean age of the non-participating 21 children was 7.2 ± 4.2. Ten patients had mild, while 11 had severe autism according to the DSM V. Four patients were female, and 17 were male. Three children had abnormal EEG, and one was diagnosed with epilepsy, and he was on valproic acid treatment. Three patients attended mainstream schools and received their education there, while eighteen patients had intellectual disabilities. All non-participating 21 ASD patients used antipsychotic drugs. Sixteen patients used risperidone, and five patients used aripiprazole. The median duration of antipsychotic drug administration was 8.2 ± 2.6 months. The median duration of follow-up was 4.4 1 ± 1 years.

Informed consent was obtained from the parents of all children participating in the study. The mean age of the participating 33 children was 7.7 ± 5.5. Fifteen patients had mild autism, while 18 had severe autism according to the DSM V. Three patients were diagnosed with epilepsy before starting CBD-enriched cannabis; two of them used oxcarbazepine, while one used valproic acid. Seven patients had abnormal electroencephalography (EEG) results without any episodes of previous seizures. Five patients attended mainstream schools and received their education there, while twenty-eight patients had intellectual disabilities and attended schools that catered to special educational needs. Two patients were using CBD-enriched cannabis for over two years. There was no predefined duration of this treatment in our patients. All ASD patients used antipsychotic drugs. Twenty-six patients used risperidone, and seven patients used aripiprazole. The median duration of antipsychotic drug administration was 8.5 ± 2.3 months. All the patients were provided with psychosocial treatment. The median duration of follow-up was 4.6 ± 1.3 years. There were no significant differences between the 2 group profiles (participating and non-participating) regarding sex ratio, median age, and autism severity.

Treatment

The legal basis for using cannabis-related drugs is not fully apparent in Turkey, and a maximum of 0.3% THC is allowed to be used in these preparations. Due to the lack of availability and difficulty of access to these therapeutic preparations, various cannabis strains of CBD-enriched cannabis extracts have been used. The two CBD-enriched cannabis brands used were CBDistillery and CBDodgamax. Both had similar available forms of drops of 500, 1000, and 2500 mg/30 ml and contained full-spectrum CBD and trace THC. These drops were started with dosages that were calculated according to the patient’s body weight, with one sublingual drop twice a day and one drop every three days. The average daily CBD-enriched cannabis dose was 0.7 mg/kg (0.3–2 mg/kg). No patient was given a daily maintenance dose of CBD higher than 40 mg/day. The average duration of treatment was 6.5 months (3–28 months).

Results and outcomes

The outcomes were evaluated before and after treatment based on clinical interviews. At each follow-up visit, parents were asked to assess the overall effectiveness of CBD-enriched cannabis treatment. According to the parents’ reports, no change in daily life activity was reported in 6 (19.35%) patients. The main improvements of the treatment were as follows: a decrease in behavioral problems was reported in 10 patients (32.2%), an increase in expressive language was reported in 7 patients (22.5%), improved cognition was reported in 4 patients (12.9%), an increase in social interaction was reported in 3 patients (9.6%), and a decrease in stereotypes was reported in 1 patient (3.2%). The parents reported improvement in cognition in patients who adhered to CBD-enriched cannabis treatment for over two years. The antipsychotic drug could be stopped only in one patient who showed mild ASD symptoms. No change could be made in other drug use and doses.

Discontinuation and side effects

A 13-year-old male patient with severe autism had generalized seizures after using 5 mg sublingual CBD, and the drug was discontinued because of this side effect. The epileptic seizures persisted despite the discontinuation of the treatment. Interictal sleep EEG showed symmetrical bilateral frontotemporal sharp-slow wave complexes. The patient was regularly treated with valproic acid and remained seizure-free after starting this antiepileptic drug. CBD-enriched cannabis was also discontinued in a nine-year-old male patient with severe autism after two weeks because of a significant increase in stereotypes. No change in laboratory values related to CBD-enriched cannabis was found in any patient.

Restlessness was the only reported side effect in 7 (22%) out of 31 patients who continued treatment for at least three months, and the CBD-enriched cannabis dose was reduced in these patients. As the amount was reduced, restlessness decreased.

A review of other studies

The popularity of CBD-enriched cannabis for the treatment of autism is increasing. Scoping reviews were done to achieve a broad and thorough examination of the literature in this area. Aran et al. (2019) were the first to retrospectively assess CBD-enriched cannabis effects on 60 children with ASD and severe behavioral problems using an open-label cohort study. The mean age was 11.8 ± 3.5 years; 82% of patients used psychiatric medications; 77% of patients had low cognitive function; and 23.3% of patients had epilepsy. All the children received CBD and THC in a 20:1 ratio. The mean total daily dose was 3.8 ± 2.6 mg/kg/day CBD and 0.29 ± 0.22 mg/kg/day THC for children who received three daily doses (n=44) and 1.8 ± 1.6 mg/kg/day CBD and 0.22 ± 0.14 mg/kg/day THC for children who received two daily doses (n=16). The doses were titrated over 2–4 weeks. The mean follow-up period was 10.9 ± 2.3 months. Efficacy was assessed using the Caregiver Global Impression of Change (CaGI) scale. Considerable improvement in behavioral problems was noticed in 61% of patients. Improvement in anxiety and communication problems was seen in 39 and 47%, respectively. Based on these promising results, Aren et al. launched a new placebo-controlled crossover trial. This study is ongoing, and new outcomes will be addressed in future publications (Aran et al. 2019).

Another study was conducted to evaluate the efficacy and safety of CBD-enriched cannabis effects on autism. This prospective, open-label study was carried out by Lihi Bar-Lev Schleider et al. and included 188 patients. The mean age was 12.9 ± 7 years. A total of 14.4% of patients had epilepsy. Most patients used preparations with 30% CBD and 1.5% THC, and the average concentrations of CBD and THC were 79.5 ± 61.5 mg and 4.0 ± 3.0 mg, respectively. After one month of treatment, 179 patients adhered to the treatment, and only 119 patients could be evaluated. Significant improvement was reported in 48.7% of patients, moderate improvement was reported in 31.1% of patients, and no change was reported in 14.3% of patients. Side effects were reported in 5.9% of patients. After 6 months of treatment, 155 patients continued treatment with CBD. Of the latter group, 93 patients responded to the questionnaire, 30.1% reported significant improvement, 53.7% reported moderate improvement, 6.4% reported slight amelioration, and 8.6% of the patients reported no change. Quality of life, mood, and ability to perform daily living activities were evaluated before the treatment and at 6 months. A total of 31.3% of the patients reported good quality of life before treatment. After 6 months, this percentage increased up to 66.8% (Lihi Bar-Lev Schleider et al. 2019).

Paulo Fleury et al. (2019) conducted a prospective, observational, and open-label study with a cohort of 18 autistic patients who received CBD-enriched cannabis (with a CBD-to-THC ratio of 75/1). The average dose of CBD was 4.55 mg/kg/day (a minimum of 3.75 mg and a maximum of 6.45 mg/kg/day). The average THC dose was 0.06 mg/kg/day (a minimum of 0.05 and a maximum of 0.09 mg/kg/day). The mean age was ten years. Fifteen patients adhered to the treatment (10 nonepileptic and five epileptic), and only one patient showed a lack of improvement in autistic behaviors. The most significant improvements were reported for seizures, attention-deficit/hyperactivity disorder, sleep disorders, communication, and social interaction (Paulo Fleury et al. 2019). Barchel et al. (2019) performed an open-label study on 53 autistic children. The median age was 11 (4–22) years; these patients received CBD at a concentration of 30% and a 1:20 ratio of CBD to THC. The median THC interquartile range (IQR) daily dose was 7 (4–11) mg, and the median CBD (IQR) daily dose was 90 (45–143) mg. The median duration of treatment was 66 days (30–588). Self-injury and rage attacks improved by 67.6% and worsened by 8.8%, respectively. Improvement in hyperactivity symptoms was reported in 68.4% of patients, 28.9% reported no change, and 2.6% reported worsening symptoms. Sleep problems improved by 71.4% and worsened by 4.7%. There was an improvement in anxiety in 47.1% and worsening in 23.5% of patients (Barchel et al. 2019). Mojdeh Mostafavi et al. (2020) reported positive effects of cannabis in ASD, especially in aggressive and self-injurious behaviors (Mostafavi and Gaitanis 2020). McVige et al. (2020) carried out an important retrospective and open-label study on 20 patients with ASD (6 with epilepsy and 14 with pain). These patients were on cannabis treatment. The study reported very significant positive outcomes. The Autism/Caregiver Global Impression of Change (ACGIC) scale revealed improvements in sleep, mood, and aggression toward the self or others; there were also improvements in patient communication abilities and attention/concentration (McVige et al. 2020).

According to Aren et al.’s study, adverse events such as hypervigilance aggravated sleep disturbances in 14% of patients. This side effect was resolved by omitting or adjusting the evening doses. Irritability in 9% and loss of appetite in 9% were seen. A thirteen-year-old girl received 6.5 mg/kg/day CBD and no other medications; when she gradually increased the THC dose up to 0.72 mg/kg/day, she developed sudden behavioral changes such as unusual vocalization and refusal to sleep and eat for two days. The symptoms resolved when she stopped CBD and THC and received antipsychotic treatment (ziprasidone). After cannabis treatment, psychiatric medications were regulated in most patients; 33% received fewer or lower doses, 24% stopped taking medications, and 8% received more medication or higher doses (Aran et al. 2019). Lihi Bar-Lev Schleider et al. reported mild side effects such as restlessness, sleepiness, dry mouth, and digestion problems (Lihi Bar-Lev Schleider et al. 2019). Paulo Fleury et al. reported that three patients stopped using CBD-enriched cannabis in a period shorter than one month due to side effects (autistic behaviors had worsened in two patients, which might happen due to the unsupervised and sudden cessation of the antipsychotics; one patient had insomnia, irritability, increased heart rate, and worsening of psych-behavioral crises that might be due to the interaction of cannabis with previous prescribed antipsychotic drugs). Mild and transient adverse effects such as sleepiness, moderate irritability, diarrhea, increased appetite, conjunctival hyperemia, and increased body temperature were also reported (Paulo Fleury et al. 2019).

Discussion

In the updated review, preliminary evidence announcing that cannabinoids (compounds with different ratios of CBD and THC) could exert beneficial effects on some ASD-associated symptoms, such as behavioral problems, hyperactivity, and sleep disorders, with a lower number of metabolic and neurological side effects than approved medications. Importantly, treatment with cannabinoids permits a reduction in the number of prescribed drugs and significantly reduces the frequency of seizures in participants with comorbid epilepsy. In this paper, we aimed to make some critical points related to the main findings and mechanisms of action of cannabinoids, such as a decrease in behavioral problems, an increase in the expressive language, an improvement in cognition, and an increase in social interaction when patients used CBD-enriched cannabis at a dose of 0.7 mg/kg (0.3–2 mg/kg), which is lower than the doses reported in other studies. Furthermore, these results are consistent with other studies that suggest that supplementing ASD patients with CBD-enriched cannabis could improve behavioral problems. A dose of 3.8 ± 2.6 mg/kg/day CBD was used in Aren et al.’s study and yielded improvements in anxiety and communication problems. According to Paulo Fleury et al., the average dose of CBD was 4,55 mg/kg/day, and the results showed that only one patient reported no improvement in autistic behaviors. The most significant improvements were reported for seizures, attention-deficit/hyperactivity disorder, sleep disorders, communication, and social interaction. In addition, improvements in expressive language were seen. CBD-enriched cannabis might help children with ASD via several possible mechanisms, including its anxiolytic and antipsychotic properties and its impact on the endocannabinoid system (ECS) and oxytocin (Dos Santos et al. 2019; McVige et al. 2020; Premolia et al. 2019). According to our results, we recommend using lower doses of CBD-enriched cannabis.

CBD use is not devoid of health risks; known risks include liver damage, adverse effects on the male reproductive system, potential drug interactions that may be associated with adverse events or diminished efficacy of approved therapies, and additional unknown health risks. However, the pharmacology of CBD has not been well studied; thus, little is known about both the potential therapeutic benefits and the hazards of short- or long-term use (Leas et al. 2020). According to our study, restlessness was the only mild side effect seen in some patients which was resolved on making some doses adjustments. In addition, generalized seizures after starting CBD-enriched cannabis. And these seizures re-occurred even several months after cessation of CBD treatment, and abnormal EEG results were seen. Therefore, this study cannot make causal inferences on the relation between CBD-enriched cannabis and seizures. Not all patients benefit equally from the use of CBD. The reason why some patients experienced benefits while others experienced side effects could be due to candidate genes that may influence the acute effects of cannabis. Genes posited to have specific influences on cannabis include CNR1, CB2, FAAH, MGL, TRPV1, and GRP55. When some patients have a mutation in these receptors, different results could be seen when cannabis was used (Agrawal and Lynskey 2009). Other studies also reported reversible and some mild side effects, none of which were life-threatening. Most of the side effects were overcome by adjusting the doses. Furthermore, the use of recreational cannabis in adolescents is associated with several risks, including decreased motivation, addiction, mild cognitive decline, and schizophrenia. However, these complications are all attributed to THC. Our study drug was full-spectrum CBD and trace THC. Nevertheless, systematic evaluation of safety data of CBD use in children is still lacking. Future research is recommended that examines the clinical impact of CBD-enriched cannabis. Additionally, rarer side effects were seen in our patients compared to other studies, which could be due to using lower doses of CBD and trace THC (a brief overview of all these studies is given in Tables 1 and 2).

These preclinical data and the current study results render further exploration of this treatment avenue in controlled studies. Until such evidence is available, physicians should be cautious when using medical cannabis to treat children with ASD since initial reports of promising treatment in children with ASD are often found.

Limitations of the study

The absence of the control study group, the use of various strains of CBD-enriched cannabis extracts, different durations of treatment and dosages, and depending on the reports of the parents instead of standard assessment scales are considered to be the main limitations of the study. The clinical assessments were done with knowledge of the patients’ treatment (it was an open-label case series, not a blinded clinical trial.

Conclusion

Using lower doses of CBD and trace THC seems to be promising in the management of behavioral problems associated with autism. In addition, this treatment could be effective in managing core symptoms and cognitive functions. No significant side effects were seen at the low doses of CBD-enriched cannabis when compared to other studies.

Availability of data and materials

The datasets used and analyzed in this review article are available from the corresponding author upon reasonable request.