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.
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%.
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.
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.
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
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.
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).
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.
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.
Cannabinoids in Pediatrics
Department of Pharmacotherapy and Translational Research (CTC, KM), University of Florida College of Pharmacy, Gainesville, Florida; Department of Pharmacy (CTC, KM), University of Florida Health Shands Children’s Hospital, Gainesville, Florida; Department of Pharmacy (MSP), Augusta University Medical Center, Augusta, Georgia; Department of Clinical and Administrative Pharmacy (MSP), University of Georgia College of Pharmacy, Augusta, Georgia
Despite its controversial nature, the use of medical marijuana and cannabis-derived medicinal products grows more popular with each passing year. As of November 2016, over 40 states have passed legislation regarding the use of either medical marijuana or cannabidiol products. Many providers have started encountering patients experimenting with cannabis products for a wide range of conditions. While the debate continues regarding these agents for both medicinal and recreational use in the general population, special consideration needs to be made for pediatric use. This review will deliver the history of marijuana use and legislation in the United States in addition to the currently available medical literature to equip pediatric health care providers with resources to provide patients and their parents the best recommendation for safe and appropriate use of cannabis-containing compounds.
Over the past several years, medical marijuana use has become a controversial topic not only within the medical community but also at state and national legislative levels. Although marijuana and its derivatives are currently Schedule 1 substances per the federal Controlled Substances Act (CSA), many states have relaxed their legislation to allow use. More recently, the use of cannabidiol (CBD) products in pediatrics has sparked additional debate, and pediatric providers have started encountering patients experimenting with these products in their daily practice, necessitating an understanding of the history and available medical literature on this topic.
Many of the misconceptions regarding medical marijuana in the pediatric population stem from negative connotations associated with the term marijuana owing to its psychoactive effects. Therefore, it is important to define the various terms associated with products that are currently being used by the public as well as by pediatric researchers. Cannabis is a general term that refers to the 3 species of hemp plants (Cannabis sativa, Cannabis indica, Cannabis ruderalis). 1 Marijuana is a term that describes the dried leaves, flowers, stems, and seeds from the hemp plant that are often smoked for recreational and medicinal use. Marijuana contains various different chemicals called cannabinoids. Cannabinoids are the chemicals found within cannabis that interact with specific receptors, namely, cannabinoid (CB) receptors, within the body. The over 60 types of cannabinoids currently identified differ by the degree to which they are psychoactive. 2 While delta-9-tetrahydrocannabinol (THC), the cannabinoid most commonly associated with marijuana as a drug of abuse, is psychoactive, other cannabinoids including CBD are not. THC has been linked to the development of schizophrenia, and a contributor to neurodevelopment deficits in adolescents. 3 , 4 Different marijuana strains will have varying amounts of both THC and CBD, and thus the concentrations and ratios of these different cannabinoids within a product, especially for pediatric use, has been a subject of interest not only for medical professionals but also for state legislators as well.
History and Regulation
Dating back as far as 2000 BC, hemp plants had been used for various medicinal and industrial purposes. In 1851, the United States Pharmacopeia (USP) classified marijuana as a legitimate medical compound and many physicians supported its use for conditions such as epilepsy, chronic migraines, and pain. 5 Reports of Victorian-era neurologists using Indian hemp to treat epilepsy were also promising. 6 However, when phenobarbital and phenytoin came to the market in the early 1900s, the use of marijuana-based products declined.
In the 1930s, political propaganda sought to associate marijuana use, specifically by minority and low-income populations, with psychosis, addiction, and violent crime. Many believe this was influenced by several prominent businessmen in competing synthetic fiber industries in attempts to reduce the size of the growing hemp industry. 5 Marijuana soon became labeled as a drug of abuse and to discourage its use, Congress passed the Marijuana Tax Act of 1937 placing a heavy tax on cannabis and hemp use for both medicinal and industrial purposes. Despite opposition from the American Medical Association (AMA) and physicians who believed in the medical efficacy of marijuana, by 1941, all cannabis preparations were removed from the USP and National Formulary.
In the 1960s and early 1970s, marijuana soon became associated with recreational use by anti-establishment groups further adding to the stigma associated with its usage. By 1970, the CSA labeled cannabis as a Schedule 1 substance. This relatively short era of recreational marijuana use has influenced how the public perceives the drug. Since that time, there have been repeated unsuccessful attempts to reconsider its Schedule 1 status to allow for easier investigation. 5 The AMA and the American Academy of Pediatrics (AAP) have reaffirmed their opposition to the legalization of medical and recreational marijuana use outside of any US Food and Drug Administration (FDA) regulatory process. 7
The AAP also supports further research into the indications and correct dosage for cannabinoids in addition to developing policy around how to verify purity and formulations. 8 In the meantime, the AAP has suggested good practices to follow when considering the use of marijuana, recreationally or medically ( Table 1 ).
Recommendations from the American Academy of Pediatrics 8
To date, however, 8 states and the District of Columbia have passed legislation to legalize recreational marijuana use, with an additional 20 states allowing for some form of medical cannabis. Fourteen nonmedical marijuana states have specific legislation regarding CBD ( Figure ). 9–11 The changing legislative and regulatory landscape has significantly impacted the use of cannabinoid products in this country. Discussion about the safe and efficacious use of these products in a responsible way that protects vulnerable populations, including pediatrics, is necessary.
2017 Legislative status of marijuana in the United States
Similar to endogenous opioids, a human’s central nervous system is impregnated with cannabinoid receptors and endocannabinoids. In the early 1990s, 2 receptors were discovered, cannabinoid type 1 (CB1) and cannabinoid type 2 (CB2). Both CB1 and CB2 are G-coupled protein receptors located presynaptically and control the release of neurotransmitters at both inhibitory and excitatory synapses. CB1 is mostly expressed on presynaptic peripheral and central nerve terminals and is believed to be responsible for psychologic effects on pleasure, memory, thought, concentration, sensory and time perceptions, and coordinated movement. CB2 receptors, concentrated in peripheral tissues and immune cells, may play an anti-inflammatory and immunosuppressive role. In addition to directing the release of various neurotransmitters, this receptor regulates the release of certain cytokines. Innervation of both these receptors results in both physiological (tachycardia, hypertension, dry mouth and throat) as well as psychological (elation, euphoria, heightened perception, irritability, poor coordination and balance) effects. 3 , 5
Additionally, endocannabinoids N-arachidonoylethanolamine (anandamide) and 2-arachidonoylglycerol, both arachidonic acid derivatives, bind with CB1 and CB2. While the function of these endogenous ligands is not fully understood, their action may be attributed as antiemetic, antianalgesic, and anti-inflammatory. Endocannabinoids can also play a role in excitation of the neuronal networks, thus having effect on the quality of a seizure. Previous studies have documented deficiencies in endocannabinoids in temporal lobe epilepsy patients as well as a rise in anandamide concentrations post seizures in mice, suggesting an antiseizure activity profile. 6
The 2 most studied exogenous cannabinoids include THC and CBD. THC is a partial agonist at both CB1 and CB2 receptors and achieves its psychoactive properties likely through modulation of gamma-aminobutyric acid (GABA) and glutamine. THC seems to possess antiseizure activity but may be a proconvulsant in certain species. 12 CBD, however, does not appear to bind to either CB1 or CB2 but does possess neuroprotective and anti-inflammatory effects. 5 Several possible mechanisms of CBD have been proposed: inhibition of cyclooxygenase and lipoxygenase, inverse agonism at CB1/CB2 receptors, and enhancement of anandamide. 3 It is proposed that CBD may be effective in epilepsy through modulation of the endocannabinoid system. CBD halts the degradation of the endocannabinoid anandamide, which may have a role in inhibiting seizures. Additionally, research demonstrates that CBD may play a role with the regulation of T-type calcium channels and nuclear peroxisome proliferator-activated receptor-γ, both of which have been implicated in seizure activity. 12 Because CBD is one of the most abundant cannabinoids within cannabis resin and its mechanism is still unclear, there is peaked interest in the possible clinical indications that it could treat including epilepsy, pain, and inflammatory disorders.
Several other synthetic forms of cannabinoids have been available for use in some countries, including dronabinol, nabilone, and nabiximols ( Table 2 ). These products are being used to treat nausea and vomiting associated with chemotherapy, anorexia and weight loss in patients with acquired immune deficiency syndrome (AIDS), and relief of spasticity and neuropathic pain associated with multiple sclerosis (MS). 13–16 Epidiolex (GW Pharmaceuticals, Cambridge, United Kingdom) is a CBD product currently in clinical trials. 17
Synthetic Cannabinoid Products
Historically, patients and recreational users have inhaled or vaporized marijuana, resulting in a quick onset and higher peak concentrations. Owing to first-pass metabolism, the enteral route decreases the bioavailability of THC to from 5% to 20% and CBD to from 6% to 19% and increases the time to onset. 3 , 18 , 19 Differences in absorption between various age groups, populations, and individual people make it difficult to recommend a one-size-fits-all dosage strategy. Interpatient variability may affect which blood concentrations will be effective, and tolerance is known to occur owing to downregulation of CB1 receptors. 3 , 18
Both THC and CBD are highly lipophilic with long half-lives, 30 hours versus 9 to 32 hours, respectively. 3 , 18 , 20 CBD is also highly protein bound and is both metabolized by and a potent inhibitor of the CYP450 enzymes (2C19, 3A4), potentially causing significant medication interactions. 3 , 18 , 20 , 21 While CYP inducers such as phenytoin and carbamezapine may decrease CBD concentrations, CBD is known to increase concentrations of clobazam, an antiepileptic drug approved by the FDA in 2011 for the treatment of Lennox-Gastaut syndrome (LGS). CBD inhibits CYP3A4 and CYP2C19, preventing the degradation of clobazam and its active metabolite, N-desmethylclobazam. In an expanded access trial, patients with concomitant clobazam and CBD use had increases in clobazam concentrations of > 60% and N-desmethylclobazam, of 500%. 22 At this time it is not clear what other drug interactions may exist and what dosage manipulations may be necessary.
The debate about the use of cannabinoid products in pediatric patients has persisted owing to the lack of well-developed and published randomized controlled trials. There has been a wide variety of mostly case series and international studies for adult indications, such as chronic pain, MS, headache, and various neuropsychiatric disorders, which are beyond the scope of this review but have been reviewed elsewhere. 20 The pediatric literature lacks the same breadth owing to public stigma and restrictions on investigational use. This has resulted in retrospective and parentally reported data in epilepsy and behavioral conditions. Despite the overall lack of published data on CBD in pediatric patients, most of the literature is devoted to its use in epilepsy. Current large prospective trials are underway for different epilepsy indications, and recent animal studies researching use in perinatal brain injury and neuroblastoma may open new avenues to consider cannabinoids for pediatrics.
Epilepsy. The data in pediatric epilepsy have been surrounding the use of CBD products as well as unregulated THC/CBD products from private dispensaries. A Cochrane review 23 was conducted in 2012 to assess the safety and efficacy of cannabinoid use in patients with epilepsy. The authors included blinded and unblinded randomized controlled trials. Only 4 studies met their criteria, including 1 abstract and 1 letter to the editor ( Table 3 ). All 4 trials were of low quality with small sample sizes and variations in product, dose, frequency, and duration. 24–27 The authors summarized the finding that a CBD dose of 200 mg to 300 mg daily was safely administered over a short period. The only reasonable conclusion made was that the efficacy of CBD use could not be confirmed, but the rate of adverse reactions in each of the studies was low over a short period.
Included Studies in Cochrane Review 23
The American Academy of Neurology conducted a systematic review in 2014 which included 34 studies that used medical marijuana to treat MS, epilepsy, and movement disorders. 28 The authors included 2 studies to assess the role of cannabinoids in decreasing seizure frequency. 25 , 26 Of note, these studies were also evaluated in the Cochrane review. The authors 28 concluded that “data are insufficient to support or refute the efficacy of cannabinoids for reducing seizure frequency” and thus, there is not sufficient evidence to advise patients to use cannabinoid products in epilepsy.
Despite this, parents and patients are making the decision to use these products for 3 reasons according to Cilio et al: 12 1) prominent Internet and nation media attention; 2) reports of cases of children successfully treated with CBD products; and 3) the belief that treatments derived from natural products are safer or more effective. 12 National attention has been on those patients who have moved to states where CBD use is legal and researchers have sought to gather data from parental observations. It is important to note that the following studies are based on parental perceptions and thus we cannot draw definitive conclusions.
The most famous case was presented on a CNN special, “Weed.” 29 Charlotte is a little girl from Colorado who was diagnosed with Dravet syndrome at the age of 3 months. She suffered from frequent status epilepticus. Charlotte failed multiple medications, and at 5 years of age, she had significant cognitive delay and required help with all of her activities of daily living. 30 Her parents sought out a group in Colorado that created an oral, liquid, high-concentration CBD-to-THC strain of cannabis. Once her parents started giving her this strain, dubbed “Charlotte’s Web”, within 3 months Charlotte had a > 90% reduction in her seizure frequency and by month 20, Charlotte was able to perform most of her daily activities independently with only 2 to 3 nocturnal tonic-clonic seizures per month. Stories like Charlotte’s have prompted parents across the country in similar situations to move their families across the country to gain access to these products.
In a retrospective chart review of 75 children and adolescents younger than 18 years who were given oral cannabis extracts for treatment of their epilepsy, 57% of parents reported some improvement in seizure frequency with 33% reporting a >50% reduction in seizures. 31 Dosage information was not reported and parents used various formulations and concentrations of CBD and THC. Parents also described improvements in behavior and alertness (33%), language (11%), and motor skills (11%). Major adverse effects noted were somnolence (12%) and gastrointestinal symptoms (11%).
Investigators at Stanford University administered a survey to 150 parents on Facebook to identify parentally reported effects of CBD on their child’s seizures. 32 Of 19 respondents aged 2 to 16 years, 18 had treatment-resistant epilepsy for more than 3 years before CBD use. Based on parental response, 84% reported a reduction in child’s seizure frequency with 50% having a greater than 80% reduction in seizure frequency. Twelve of these 19 patients were also able to be weaned from another antiepileptic drug. In addition, parents reported overall better mood, increased alertness, and better sleep. Parents reported oral CBD dosages of 0.5 mg/kg/day to 28.6 mg/kg/day and THC of 0 to 0.8 mg/kg/day.
In a similar Facebook survey administered by researchers at the University of California, Los Angeles, the authors 33 similarly reported an 85% reduction in seizure frequency among 117 respondents, with an average age of 6 years. Most patients (86%) conveyed that changes in frequency occurred within 14 days. As with previous surveys, dosage and formulations were varied but based on parental report of formulation used. Overall, most parents (83.5%) reported using an oral CBD product with at least a 15:1 ratio of CBD to THC. Of the 40% of respondents who provided dosages, the median weight-based dose of CBD was 4.3 mg/kg/day given in 2 to 3 oral doses. As mentioned above, these surveys should be evaluated carefully given the inability to verify dose, formulation, and response. The conclusion that can be made is that there is a rather strong positive parental perception regarding the efficacy of cannabinoids, specifically CBD.
Most orphan drug designations for CBD are for pediatric seizure disorders ( Table 4 ). 34 A search of ClinicalTrials.gov in November 2016 identified 4 completed Phase 2 and Phase 3 protocols for pediatric seizure disorders, as well as 14 ongoing treatment trials, including intermediate-size expanded access protocols (up to 50 patients each). Published findings from open-label use of CBD for treatment-resistant epilepsy under an expanded-access program at 11 epilepsy centers in the United States suggest that CBD might reduce seizure frequency and might have an adequate safety profile in children and young adults with this condition. 35 Congressional testimony in June 2015 indicated that 20 intermediate-size expanded access Investigational New Drug Applications had been authorized to treat approximately 420 children with 1 CBD product; most of these are not listed on ClinicalTrials.gov. 36
Orphan Drug Designations for Cannabidiol in the Treatment of Pediatric Conditions 34 *
After announcing positive results from 2 pivotal randomized, double-blind, Phase 3 trials for the treatment of seizures related to LGS, and a third for seizures associated with Dravet syndrome in 2016, GW Pharmaceuticals expects to submit a single New Drug Application for both indications to the FDA in the first half of 2017 for its proprietary pharmaceutical-grade CBD product Epidiolex. 37 In the second LGS study, patients randomized to the investigational product 20 mg/kg/day (n = 76) or 10 mg/kg/day (n = 73) added to their current antiepileptic treatment, experienced a median reduction in monthly drop seizures of 42% and 37%, compared to 17% in the placebo group (n = 73); a difference that was statistically and clinically significant (p = 0.0047 and p = 0.0016, respectively). 37 These data confirmed the results of the first LGS trial in which 86 patients receiving Epidiolex 20 mg/kg/day achieved a 44% mean reduction in monthly drop seizures as compared to 22% for 85 patients in the placebo group (p = 0.0135). 38 Patients with Dravet syndrome receiving the GW Pharmaceuticals’ CBD in addition to their baseline antiepileptic regimen (n = 61) achieved the primary endpoint of a significant reduction in convulsive seizures (p = 0.01, median reduction of 39%) assessed over the 14-week treatment period as compared with the addition of placebo (n = 59). 39 Insys Therapeutics (Phoenix, AZ) has reported that their synthetic pharmaceutical CBD in a nonalcoholic, medium-chain triglyceride-based formulation was generally well tolerated in a completed Phase 1/Phase 2 safety and pharmacokinetic study in 61 pediatric patients with treatment-resistant epilepsy at total daily doses up to 40 mg/kg. 40
Behavioral Conditions. Cannabinoids and CBD use in this patient population is a growing interest on social media sites. While the data for these indications are limited to case reports using dronabinol, some of the benefits of CBD on behavior and motor skills reported in the aforementioned retrospective studies in epilepsy may be transferable to this population as well. A 6-year-old patient with early infant autism received enteral dronabinol drops titrated up to 3.62 mg/day. He had improvements in hyperactivity, irritability, lethargy, stereotype, and speech. 41 In a published abstract, Kruger et al 42 report on the effect of dronabinol use in treating self-injurious behavior in 10 mentally retarded adolescents. The dronabinol dose ranged from 2.5 mg twice daily to 5 mg 4 times a day. Seven of the 10 patients had significant improvement in their self-injurious behavior that lasted through the follow-up at 6 months. Two of the 10 patients experienced agitation and the drug was discontinued. An Israeli single-center, double-blind, placebo-controlled cross-over trial of CBD and THC in a 20:1 mixture for behavioral problems in children with autistic spectrum disorder is scheduled to start in January 2017. 43
Perinatal Brain Injury. Perinatal brain injury can be induced by neonatal asphyxia, stroke-induced focal ischemia, and neonatal hypoxia-ischemic encephalopathy, among other things. These conditions lead to long-lasting functional impairment due to neuroinflammation, apoptotic-necrotic cell death, and brain lesions. 44 Several adjunctive medication therapies in addition to hypothermia, include magnesium sulfate and minocycline which may play a role in modulating neuroinflammation and apoptosis. The endocannabinoid system responds early to neuronal damage, working to prevent glutamate excitotoxicity and regulate the inflammatory response. While there are no current human studies, results from mice and pig models demonstrate that CBD can reduce the density of necrotic neurons and modulate cytokine release. 45 , 46
Neuroblastoma. Most recently, researchers have reported on the use of CBD in both in vitro and in vivo animal studies of neuroblastoma (NBL), a common childhood cancer. 47 Investigators are proposing that antitumor activity is achieved by action at vanilloid and peroxisome proliferator-activated receptors. In vitro, they found that both CBD and THC reduced the viability of NBL cells in a dose- and time-dependent manner. When comparing the two, CBD had a significantly better response in reducing viability of NBL cells than THC. They next treated mice with daily intraperitoneal injections of THC, CBD, or ethanol, or gave no treatment. Tumor growth in both the THC and CBD groups was significantly reduced.
What’s The Harm?
Worldwide, marijuana is the most commonly abused illegal substance and adolescent daily use is on the rise. 18 Adolescents perceive that marijuana use is not as much of a risk owing to legalization and decriminalization, leading to its use both recreationally and to self-treat anxiety and other psychiatric conditions. Unfortunately, the neurocognitive and behavioral effects of marijuana use in pediatric patients, including its effects on psychological dysfunction, amotivation syndrome, and carcinogenic risk, have been widely reported. 4 , 21
Evolving legislation and the increased use of cannabinoid products outside of investigational studies have also impacted our health care delivery and emergency resources. The state of Colorado has been on the forefront of the medicinal and recreational use of cannabis debate. Wang et al 48 reported the occurrences of pediatric emergency department visits associated with marijuana exposure before and after changes in drug enforcement in 2009. A total of 1378 patients younger than 12 years were evaluated for unintentional ingestions from January 1, 2005, to December 31, 2011. Before 2009, no patients (0/790; 0%) sought care at this emergency department for accidental marijuana ingestions as compared with 14 patients (14/588; 2.4%) after 2009 (p < 0.001). Patients ranged in age from 8 months to 12 years and presented with symptoms of lethargy, ataxia, and respiratory insufficiency. While the dosages were not reported, 7 patients ingested a marijuana edible. Eight of the 14 patients were admitted to the hospital with 2 admissions to the pediatric intensive care unit. Prior to diagnosis, these 14 patients received routine testing such as urinalyses, complete blood counts, and complete metabolic panels. Some of these patients also received more invasive testing including computed tomography, activated charcoal, lumbar punctures, and intravenous antibiotics. All of these contribute to higher hospital and emergency room costs, increased lengths of stay, and potential harm to the patients.
In addition to increased emergency room visits, from 2005 to 2011, the call volume at Poison Control Centers for pediatric marijuana exposures had increased by 30.3% in states where marijuana has been decriminalized as compared to a steady rate in states that have not adopted marijuana decriminalization legislation. 49 While marijuana and CBD products are becoming more available, these products remain in DEA (Drug Enforcement Administration) Schedule 1 status and are therefore not regulated in manufacturing, packaging, and labeling outside of clinical trials. As seen in the Colorado case study, 50% of the unintentional ingestions were secondary to an edible, which children can easily mistake for food if not supervised by parents. None of these products are required to have safety packaging to prevent accidental ingestion by children. In addition, no warning labels or verification of product ingredients is required, leaving the medical community caught between providing safe medical care and allowing patient autonomy. As mentioned previously, the AAP has published recommendations to limit the access of marijuana to children.
In 2007, amidst medical marijuana legalization in several states, Seamon et al 21 identified that pharmacists needed to be attentive to the legislative changes going on at the state and federal levels. Pharmacists are uniquely poised to understand the medicinal chemistry as well as the practical implications associated with decriminalization and legalization. Pharmacists can continue to educate both medical professionals and lay people about the differences among cannabinoids, and help to remove the stigma around appropriate and legal use of CBD products. At the same time, medical professionals need to remember the documented deleterious effects of acute marijuana intoxication on neurocognitive development and psychiatric issues.
Many health care facilities are working through processes that address patient use of these medications. Because use of cannabis products outside of approved clinical trials is not legal under federal law, thus not permitted under Centers for Medicare & Medicaid Services (CMS) Conditions of Participation, there are significant challenges in managing hospitalized patients. Whatever the state and situation, pharmacists need to be aware of the external factors associated with allowing a patient to use CBD in an inpatient setting.
Pharmacists are also poised to participate in the design and evaluation of current and future research in this area. The importance of drug interactions between CBD and other antiepileptics remains uncertain both for the efficacy and safety of CBD products. The difference in concentrations, dosages, and formulations of various products sold at private dispensaries is not standardized or regulated. Differences in state legislation on allowable concentrations and amounts can be confusing for patients and their families, and pharmacists can help to provide that information. Various organizations have been helpful in updating and summarizing this information. 9
Cannabis and its ingredients have had a fascinating history over the past 4000 years, but lack of published data precludes fully recommending its use for medicinal purposes in pediatrics. Further study is underway and will add to our knowledge of the efficacy and safety of CBD in pediatrics. Long-term studies to assess neurocognitive development with CBD will need to be assessed as well. As pharmacists, it is our duty to provide our patients and their parents with the most accurate, safe, and legally appropriate advice.
|AAP||American Academy of Pediatrics|
|AIDS||acquired immune deficiency syndrome|
|AMA||American Medical Association|
|CB1||cannabinoid type 1 receptor|
|CB2||cannabinoid type 2 receptor|
|CMS||Centers for Medicare & Medicaid Services|
|CNN||Cable News Network|
|CSA||Controlled Substances Act|
|DEA||Drug Enforcement Administration|
|FDA||US Food and Drug Administration|
|USP||United States Pharmacopeia|
Disclosures The authors declare no conflicts or financial interest in any product or service mentioned in the manuscript, including grants, equipment, medications, employment, gifts, and honoraria. Of note, both Augusta University (ClinicalTrials.gov Identifier: > NCT02397863) and the University of Florida (ClinicalTrials.gov Identifier: > NCT02461706) are sponsors of expanded access clinical trials of cannabidiol and drug-resistant epilepsy in children.
Copyright Published by the Pediatric Pharmacy Advocacy Group. All rights reserved. For permissions, email: [email protected]
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Articles from The Journal of Pediatric Pharmacology and Therapeutics : JPPT are provided here courtesy of Pediatric Pharmacology Advocacy Group