Cbd oil use for behaviors dosage

What Is CBD Oil?

This cannabis extract may help treat nerve pain, anxiety, and epilepsy

Cathy Wong is a nutritionist and wellness expert. Her work is regularly featured in media such as First For Women, Woman’s World, and Natural Health.

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.

Meredith Bull, ND, is a licensed naturopathic doctor with a private practice in Los Angeles. She helped co-author the first integrative geriatrics textbook, “Integrative Geriatric Medicine.”

Cannabidiol (CBD) oil is an extract from hemp plants called Cannabis indica and Cannabis sativa . You might be more familiar with cannabis plants because they are grown for marijuana. However, CBD is not the same thing as marijuana.

CBD oil contains CBD that’s mixed with a base (carrier) oil, like coconut oil or hemp seed oil. These are called tinctures. You can get tinctures in different concentrations. The oil can also be put into capsules, gummies, and sprays.

People who support using CBD oil say that it can treat pain and anxiety; can help stimulate appetite and may help manage some types of seizures.

This article goes over what CBD is used for, the possible side effects, and what you should look for if you choose to buy CBD.

CBD vs. Marijuana

CBD is one component (called a cannabinoid ) that’s found in a hemp plant. Marijuana is a separate plant but it’s from the same species that hemp belongs to. Marijuana has CBD and hundreds of other compounds in it.

The main difference between hemp plants and marijuana plants is how much of a compound called tetrahydrocannabinol (THC) is in them. Hemp is grown to have less than 0.3% THC, while marijuana has more.

THC is what’s responsible for the psychoactive effects of cannabis—in other words, it’s what makes you feel “high.”

CBD oil generally does not have THC in it; however, a very small (trace) amount might be in products sold in certain states.

What Is CBD Oil Used For?

We’re not sure exactly how CBD works. Unlike THC, CBD doesn’t have a strong connection with the molecules in the brain that THC binds to create psychoactive effects. These are called cannabinoid receptors.

Instead, CBD works on other receptors, like the opioid receptors that help control pain. It also affects glycine receptors that control a brain chemical called serotonin which helps control your mood.

People that support the use of CBD claim that CBD oil can treat a variety of health problems, including:

  • Acne
  • Anxiety
  • Chronic pain
  • Depression
  • Drug use and withdrawal
  • High blood pressure
  • Muscle spasms
  • Poor appetite

As CBD has gained popularity, researchers have been trying to study it more. Still, there has not been a lot of clinical research to look for evidence in support of these health claims.

CBD is not a safe option for everyone. Talk to your healthcare provider if you want to try it for managing a health condition.

Anxiety

A 2015 review of research that was published in the journal Neurotherapeutics suggested that CBD might help treat anxiety disorders.

The study authors reported that CBD had previously shown powerful anxiety-relieving effects in animal research—and the results were kind of surprising.

In most of the studies, lower doses of CBD (10 milligrams per kilogram, mg/kg, or less) improved some symptoms of anxiety, while higher doses (100 mg/kg or more) had almost no effect.

The way that CBD acts in the brain could explain why this happens. In low doses, CBD might act the same as the surrounding molecules that normally bind to the receptor that “turns up” their signaling.

However, at higher doses, too much activity at this receptor site could produce the opposite effect.

There have not been many trials to look at CBD’s anxiety-relieving effects in humans. However, one was a 2019 study published in the Brazilian Journal of Psychiatry.

For the study, 57 men took either CBD oil or a sugar pill with no CBD in it (placebo) before a public-speaking event.

The researchers assessed the participants’ anxiety levels using measures like blood pressure and heart rate. The researchers also used a reliable test for mood states called the Visual Analog Mood Scale (VAMS).

The men who took 300 mg of CBD oil reported less anxiety than the men who were given a placebo; however, the men who took 100 mg or 600 mg of CBD oil did not experience the same effects.

Addiction

CBD oil might help people with substance use disorder, according to a 2015 review published in the journal Substance Abuse.

The review looked at the findings from 14 published studies. Nine of the studies looked at the effects of CBD on animals, and five studies looked at the effects on humans.

The researchers reported that CBD showed promise for treating people with opioid, cocaine, or psychostimulant use disorders.

However, the effects of CBD were quite different depending on the substance. For example, CBD without THC did not decrease withdrawal symptoms related to opioid use.

On the other hand, it did reduce drug-seeking behaviors in people using cocaine, methamphetamine, and other similar drugs.

Some experts suggest that CBD could help treat cannabis and nicotine dependence, but more research is needed to provide this theory.

High Blood Pressure

A 2017 study found that CBD oil may reduce the risk of heart disease because it can lower high blood pressure in some people.

For the study, nine healthy men took either 600 mg of CBD or the same dose of a placebo. The men who took CBD had lower blood pressure before and after experiencing stressors like exercise or extreme cold.

The study also looked at the amount of blood remaining in the heart after a heartbeat (stroke volume).

The stroke volume in the men who took CBD was lower than in was in the placebo group, meaning their hearts were pumping more efficiently.

The study suggested that CBD oil could be a complementary therapy for people with high blood pressure that is affected by stress and anxiety.

However, there is no evidence that CBD oil can treat high blood pressure on its own or prevent it in people at risk. While stress can complicate high blood pressure, it does not cause it.

Seizures

In June 2018, the U.S. Food and Drug Administration (FDA) approved a CBD oral solution called Epidiolex.

Epidiolex is used to treat two rare forms of epilepsy in children under the age of 2: Dravet syndrome and Lennox-Gastaut syndrome. These are very rare genetic disorders that cause lifelong seizures starting in the first year of life.

Other than for these two disorders, CBD’s effectiveness for treating seizures is not known. Even with Epidiolex, it’s not clear if the anti-seizure effects are from CBD or another factor.

However, there is some evidence that CBD interacts with seizure medicines like Onfi (clobazam) and raises their concentration in the blood. That said, more research is needed to understand the link.

Possible Side Effects

Clinical research has shown that CBD oil can cause side effects. The specific side effects a person has and how bad they are varies from one person to the next and from one type of CBD to another.

Some common side effects people report from using CBD include:

  • Anxiety
  • Changes in appetite
  • Changes in mood
  • Diarrhea
  • Dizziness
  • Dry mouth
  • Nausea
  • Vomiting

CBD oil may also increase liver enzymes, which is a marker of liver inflammation.

People with liver disease should talk to their healthcare provider before taking CBD oil. They may need to have their liver enzymes checked regularly if they are using CBD.

Can You Use CBD If You’re Pregnant?

You should not use CBD oil if you’re pregnant or breastfeeding. Even though the effects of CBD are not fully understood, it does pass through the placenta.

The American Academy of Pediatrics (AAP) further states that pregnant people should not use marijuana because of the potential risks to a developing fetus.

Do not drive or use heavy machinery when taking CBD oil—especially when you first start using it or switch to a new brand. Remember that some products do contain THC, even in small amounts.

Interactions

CBD oil can interact with medications, including many that are used to treat epilepsy. One of the reasons for this has to do with how your body breaks down (metabolizes) drugs.

Cytochrome P450 (CYP450) is an enzyme your body uses to break down some drugs. CBD oil can block CYP450. That means that taking CBD oil with these drugs could make them have a stronger effect than you need or make them not work at all.

Drugs that could potentially interact with CBD include:

  • Anti-arrhythmia drugs like quinidine
  • Anticonvulsants like Tegretol (carbamazepine) and Trileptal (oxcarbazepine)
  • Antifungal drugs like Nizoral (ketoconazole) and Vfend (voriconazole)
  • Antipsychotic drugs like Orap (pimozide)
  • Atypical antidepressants like Remeron (mirtazapine)
  • Benzodiazepine sedatives like Klonopin (clonazepam) and Halcion (triazolam)
  • Immune-suppressive drugs like Sandimmune (cyclosporine)
  • Macrolide antibiotics like clarithromycin and telithromycin
  • Migraine medicine like Ergomar (ergotamine)
  • Opioid painkillers like Duragesic (fentanyl) and alfentanil
  • Rifampin-based drugs used to treat tuberculosis

Always tell your healthcare provider and pharmacist about all the medicines you take, including prescription, over-the-counter (OTC), herbal, or recreational drugs.

The interactions between these medications and CBD are often mild and you might not have to change your treatment.

However, in some cases, you might have to change medications or space out your doses to avoid a reaction. That said, never change or stop medication without talking to your provider.

Dosage and Preparation

There are no guidelines for using CBD oil. Each product works a bit differently, depending on the form.

For example, putting the oil under your tongue can produce effects more quickly than swallowing a capsule that needs to be digested.

Here are a few ways that you can take CBD oil:

  • Placing one or more drops under your tongue and holding it there for 30 to 60 seconds without swallowing. You can also use a spray that is spritz in your mouth/under your tongue.
  • Taking a capsule or chewing a gummy

There’s no “correct” dose of CBD oil. How much you take and the form you choose will depend on your needs and what you hope to get for effects. The average dose range is from 5 mg to 25 mg.

Most oils come in 30-milliliter (mL) bottles and include a dropper cap to help you measure.

That said, it’s hard to figure out the exact amount of CBD per milliliter of oil. Some tinctures have concentrations of 1,500 mg per 30 mL, while others have 3,000 mg per mL or more.

How to Calculate CBD Dose

To determine an exact dose of CBD, remember that each drop of oil equals 0.05 mL of fluid. This means that a 30-mL bottle of CBD oil will have about 600 drops in it.

If the concentration of the tincture is 1,500 mg per mL, one drop would have 2.5 mg of CBD in it. The math to figure that out looks like this: 1,500 mg ÷ 600 drops = 2.5 mg

What to Look For

CBD oil comes in different forms: isolates, broad-spectrum, and full-spectrum.

  • Isolates contain only CBD
  • Broad-spectrum oils nearly all of the components of the plan (e.g., proteins, flavonoids, terpenes, and chlorophyll), but does not have THC oils have all the compounds including THC (up to 0.3%)

Alternative medicine practitioners believe that the compounds provide more health benefits, but the is a lack of evidence to support these claims.

Remember that CBD oils are unregulated. There’s no guarantee that a product is what it claims to be on its packaging. You also can’t know for sure that it’s safe and effective.

A 2017 study reported that only 31% of CBD products sold online were correctly labeled. Most had less CBD in them than was advertised, and 21% had significant amounts of THC.

If you are interested in buying CBD products, here are a few tips to keep in mind:

  • Buy American: Domestically produced CBD oil might be a safer option than those that have been imported.
  • Go organic: Brands certified organic by the U.S. Department of Agriculture (USDA) are less likely to expose you to pesticides and other harmful chemicals.
  • Read the product label: Even if you choose a full-spectrum oil, don’t assume that every ingredient on the product label is natural. CBD products can also have preservatives, flavorings, or thinning agents in them. If you don’t recognize an ingredient, ask the dispenser what it is or check online.

Summary

Hemp plants can be grown for different purposes. Some species are made for marijuana but others are used to make CBD products.

Unlike marijuana, CBD oil does not “get you high.” Instead, it may help relieve stress, anxiety, drug withdrawals, and nerve pain.

While there are many claims about the health benefits of using CBD oil, the evidence is lacking. A lot of studies were done with animals, not humans.

If you want to try CBD oil, you should learn about the different dosages and preparations first.

You should also know that the products are not regulated, which means you can’t know for sure that a product will work and be safe.

Before you use CBD oil, talk to your provider. If you take certain medications or have a health condition, you may not be able to use these products.

Frequently Asked Questions

It would be hard to overdose on CBD oil. Research has shown that human tolerance for CBD is very high. One study reported the toxic dose would be about 20,000 mg taken at one time.

It depends on where you live, the type of product, how it was sourced (e.g., is it from hemp or marijuana), and its intended purpose (medical or recreational). In many states, you must be 18 or 21 to buy CBD oil. Check your state’s laws.

Not necessarily. While the names are sometimes used interchangeably, hemp oil can also refer to hemp seed oil, which is used for cooking, food production, and skincare products.

CBD oil is made from the leaves, stems, buds, and flowers of the Cannabis indica or Cannabis sativa plant. It should contain less than 0.3% THC.

Hemp oil is made from the seeds of Cannabis sativa and does not have TCH in it.

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.