CBD for Neurologic Conditions in Children

Overview

This resource for primary care providers of children with special health care needs discusses current evidence (as of December 2018) for treatment of pediatric neurologic conditions with FDA-approved and non-FDA approved cannabidiol (CBD), a chemical constituent of the cannabis plant.
In 2018, the FDA approved Epidiolex, a pharmaceutical grade CBD product for 2 rare types of pediatric epilepsy. Medical home clinicians need to understand the safety and side effects of Epidiolex as well as how to address families’ questions and popular beliefs about non-FDA-approved CBD and other marijuana-derived products.
Use of CBD products in children with neurologic conditions other than in specific epilepsy syndromes is not supported by quality evidence. Even when used in epilepsy syndromes, the evidence behind CBD products remains modest. More high-quality, randomized control trials are needed to investigate CBD for treatment of refractory epilepsy and understand the long-term consequences of use of CBD and other cannabis preparations. With the recent FDA approval and re-scheduling of Epidiolex, it is expected that the research results will rapidly flourish.

Other Names

“Medical marijuana” (sometimes spelled marihuana) is not a single drug, but a spectrum of preparations based on the concentrations of cannabinoids. A number of terms describe cannabis preparations, which can be confusing to physicians and families:
  • Cannabidiol
  • Cannabinoids
  • CBD oil
  • Hemp extract
  • Hemp oil
Low-THC (tetrahydrocannabinol) cannabis plants are often referred to as “hemp,” while those containing high-THC concentrations are generally called “marijuana.” Under the 2014 Farm Bill, which allows study of industrial hemp products containing <0.3% THC, pharmaceutical companies have been developing purified and quality-controlled preparations of cannabinoids for medical research and use. Any discussion about medical marijuana must be met with an understanding of the variability (and lack of enforced regulation) that this term entails.

Pearls & Alerts

Only 1 form of CBD approved by the FDA
Epidiolex, a pharmaceutical-grade CBD medication, was approved in 2018 for treatment of refractory epilepsy in children with Dravet syndrome or Lennox-Gaustaut syndrome. [Drug: 2018] CBD medication in FDA-approved formulations was later changed from Schedule I to Schedule V, though Epidiolex is the only one available currently.
Non-regulated CBD products may have harmful or unknown ingredients
Families who give children CBD products other than Epidiolex should be aware that non-pharmaceutical grade products vary in the amount of CBD they contain, if any, and they may not contain the amount of CBD that the label states. They may also contain up to 80 other cannabinoids including THC, unlisted ingredients, and contaminants. [Bonn-Miller: 2017]
Discontinuation anti-epileptic medications can cause death
Increased seizures, status epilepticus, and death have occurred in children taking CBD products after parents have changed or stopped other medications against medical advice or without guidance of a physician. Anti-epileptic medications should not be stopped or titrated after starting Epidiolex or unregulated CBD products unless under the direction of the prescribing physician.
Avoid giving dosing advice to families who use CBD products not approved by the FDA
There is no consensus on recommended dosing for unregulated CBD products in children. In reported studies and case reports, dosing has widely varied, often even within studies, ranging from 1-50 mg/kg/day. [Wong: 2017] Counseling about use of these products is similar to counseling about other unregulated complementary and alternative treatments.

Evidence for Therapeutic Value of CBD

Evidence for Cannabinoids and Childhood Epilepsy
Literature about cannabinoids and childhood epilepsy has shown that pure CBD has the more evidence for efficacy than other preparations and its use significantly improved seizure control for patients in the majority of the few studies that were conducted. [Wong: 2017] [Devinsky: 2014]
Only a few fully randomized, controlled trials of purified CBD products to treat refractory epilepsy in children have been published:
  • Devinsky O, Patel AD, Cross JH, Villanueva V, Wirrell EC, Privitera M, Greenwood SM, Roberts C, Checketts D, VanLandingham KE, Zuberi SM.
    Effect of Cannabidiol on Drop Seizures in the Lennox-Gastaut Syndrome.
    N Engl J Med. 2018;378(20):1888-1897. PubMed abstract

  • Devinsky O, Marsh E, Friedman D, Thiele E, Laux L, Sullivan J, Miller I, Flamini R, Wilfong A, Filloux F, Wong M, Tilton N, Bruno P, Bluvstein J, Hedlund J, Kamens R, Maclean J, Nangia S, Singhal NS, Wilson CA, Patel A, Cilio MR.
    Cannabidiol in patients with treatment-resistant epilepsy: an open-label interventional trial.
    Lancet Neurol. 2016;15(3):270-8. PubMed abstract

  • Thiele EA, Marsh ED, French JA, Mazurkiewicz-Beldzinska M, Benbadis SR, Joshi C, Lyons PD, Taylor A, Roberts C, Sommerville K.
    Cannabidiol in patients with seizures associated with Lennox-Gastaut syndrome (GWPCARE4): a randomised, double-blind, placebo-controlled phase 3 trial.
    Lancet. 2018;391(10125):1085-1096. PubMed abstract

  • Devinsky O, Cross JH, Laux L, Marsh E, Miller I, Nabbout R, Scheffer IE, Thiele EA, Wright S.
    Trial of Cannabidiol for Drug-Resistant Seizures in the Dravet Syndrome.
    N Engl J Med. 2017;376(21):2011-2020. PubMed abstract

These studies contributed to the FDA’s decision to approve Epidiolex (pharmaceutical grade pure CBD) as an evidence-based treatment for treatment-resistant epilepsy due to Dravet or Lennox-Gastaut syndrome. Ongoing clinical trials can be found at ClinicalTrials.gov.
Remaining studies have lacked appropriate controls and large sample sizes, and they are subject to significant bias, especially given that many rely on parental reports of improved seizure control and quality of life. For example, parents who relocate to Colorado to obtain legal cannabis products for their child report a greater perceived benefit of oral cannabis extracts compared to parents already living in the state. [Treat: 2017] Some studies have also demonstrated high termination of CBD use during studies; up to 71% suggest minimal efficacy, high side-effect profile, or other complicating factors including cost, access, and administration. [Treat: 2017] The use of “artisanal” non-purified and non-pharmaceutical grade preparations of CBD or other marijuana products has even more mixed evidence regarding the treatment of epilepsy. The overwhelming consensus in the literature is that more high-quality, randomized control trials are needed to investigate CBD products for treatment of refractory epilepsy, ideally with regulated, pharmaceutical grade products.
Cannabinoids and Other Neurologic Disorders
It has been suggested that cannabis derivatives could be of potential therapeutic use for other neurologic conditions including spasticity, movement disorders, multiple sclerosis, chronic pain syndromes, autism, and psychiatric disorders. The evidence for treatment of these disorders with cannabis products is even more sparse than the evidence for the treatment of epilepsy with cannabis products. There is only low-quality evidence (retrospective reviews and case reports) supportive of efficacy for treatment of spasticity in children. [Koppel: 2014] [Wong: 2017] Although new research is still emerging, current literature does not support the use of cannabis products in the treatment of other neurologic conditions in children. The American Academy of Pediatrics (AAP) opposes the use of medical cannabis outside of FDA-approved pharmaceutical products given the paucity of literature on the topic. [Ammerman: 2015] They do, however, recommend higher-quality research in the field.

Epidiolex

Epidiolex, which consists of purified cannabidiol, was approved by the FDA in 2018 for treatment of refractory seizures in children ≥2 years old with Dravet syndrome or Lennox-Gastaut syndrome. It is the first cannabis-derived medication to gain approval from the FDA. (See FDA Approval for Epidiolex (FDA) for press release.)

Prescribing

Like other controlled substances, a physician with a current DEA license may prescribe Epidiolex for children with Dravet or Lennox-Gastaut syndrome. It is unknown whether off-label use of Epidiolex to treat other types of refractory epilepsy or neurologic conditions will be covered by insurance or be considered on a case-by-case basis.

Dosing

Dosing guidelines are available on the manufacturer's website at Epidiolex: Recommended Dosage (Greenwich Biosciences); however, primary care clinicians are strongly advised to consult with a pediatric neurologist, particularly an epileptologist, rather than starting this medication independently.

Safety and Side Effects

Although previous research suggested that CBD is relatively safe with no significant side effects or adverse events associated with use [Devinsky: 2014], more recent pharmaceutical research has demonstrated side effects and safety considerations that may interfere with some patients’ tolerance or use of this medication.
The most common side effects of Epidiolex in clinical trials have been elevated liver enzymes, decreased appetite, diarrhea, sleepiness, fatigue, malaise, asthenia, insomnia or poor sleep quality, infections, and rashes. In trials of Epidiolex in children, the most reported side effects, including somnolence, diarrhea, fatigue, and appetite suppression [Filloux: 2015], were not significant enough to stop administration for most families. As is true for essentially all drugs that treat epilepsy, there is increased risk for suicidal thoughts and behavior.
Monitoring of transaminase and bilirubin levels should be obtained prior to starting treatment, at 1, 3, and 6 months after initiation of treatment, and periodically after that particularly if the patient also takes valproate, clobazam, or other medications that affect the liver. Other medications metabolized through the cytochrome P450 system may have altered concentrations when taken with CBD. [Filloux: 2015] This is illustrated by a study showing that families of children taking clobazam concurrently with CBD products all reported sedation as the main side effect. [Porcari: 2018] The potential changes in metabolism of other anti-epileptic medications are concerning and require close monitoring by a clinician aware of potential interactions. Counsel families to avoid abrupt discontinuation because of the risk of increased seizure frequency and status epilepticus. Epidiolex: Important Considerations (Greenwich Biosciences) lists further efficacy and safety information from the drug manufacturer's website.

Other Cannabis-Derived Pharmaceutical Medications

Sativex, which contains a 50:50 ratio of THC:CBD, was developed in the early 2000s for treatment of spasms related to multiple sclerosis in adult patients. It has also been used as adjunctive analgesia in advanced stage cancer. The drug is marketed in many countries, but it is not available in the United States. [Wong: 2017]
Synthetic cannabinoids, including dronabinol (Marinol, Syndros), are legally prescribed in the US. Dronabinol is a synthetic delta-9-THC that has received FDA approval for treatment of anorexia in AIDS patients and chemotherapy-induced nausea and vomiting in both adults and children. It is a schedule III drug.
Nabilone (Casamet) has a similar structure to THC and is also used for treatment of refractory nausea and vomiting in children and adults receiving chemotherapy. [Wong: 2017] Physicians are able to prescribe this medication because it is a Schedule II drug.

Unregulated CBD and “Medical Marijuana” Products

Legality

The 1970 US Comprehensive Drug Abuse Prevention and Control Act categorized cannabis as a Schedule I drug, which makes possession and use of the drug and its derivatives illegal. [Mead: 2017] Schedule I drugs are defined as those with high abuse potential and no accepted medical use per the federal government. Only Epidiolex has been rescheduled to Schedule V; other forms of CBD are still illegal to prescribe. Legislation has been introduced to the US Congress to change marijuana from a Schedule I to a Schedule II drug; however, under federal law, it remains illegal for physicians to prescribe marijuana to their patients.
Some states have legalized marijuana for medical and/or personal use. A list of current state laws can be found here: Currently, marijuana and its derivatives remain illegal substances at the federal level, despite legalization in certain states.

Safety

Increase in Seizures
Seizures have been noted in children with accidental cannabis overdoses, which brings up the concerning possibility that cannabis products could worsen symptoms in some children with epilepsy. [Wong: 2017] Studies of “hemp oil” preparations obtained in Colorado have noted significant adverse effects of seizure increase, status epilepticus, and even death. [Filloux: 2015] If families perceive CBD products to be effective, they might decrease or stop other anti-epileptics without consulting a physician, which could potentially be life-threatening.
Emotional and Cognitive Function
With the evidence behind medicinal cannabis products lacking, it is helpful to evaluate safety considerations in states that have legalized marijuana for recreational use. In Colorado, legalization has led to a significant increase in hospital admissions and emergency room visits for acute THC intoxication. [Monte: 2015] Recreational marijuana use in adolescents has been associated with lower than expected IQs, decreased cognitive function, depression, suicidality, symptoms of psychosis, and poor school performance. [Rosenberg: 2015] Currently, THC is thought to be responsible for more significant and neurotoxic side effects than CBC; CBD may actually protect from some of these. Some research supports the “entourage effect,” which suggests that phytocannabinoids work synergistically with each other and purifying may inhibit the full effect. [Rosenberg: 2015] Because unregulated products may contain THC or other psychoactive cannabinoids or chemicals, it is difficult to predict the effect or safety for pediatric use.
Synaptic Plasticity
Significant development of the brain and endocannabinoid system occurs during childhood and adolescence. Because of the known neuromodulatory effects of cannabinoids, use of cannabis products may negatively alter synaptic plasticity when used during critical times of development. This especially raises concerns for developmentally vulnerable populations, such as children with epilepsy and other neurologic conditions. Long-term effects of cannabis products in children and adolescents are unknown.
Inability to Monitor for Safety
Evaluation and safety monitoring of cannabis use are difficult because the content of the formulations that parents give their children is often unknown. For example, some preparations may have much higher amounts of THC and/or pesticides than pharmaceutical-grade medications. Concentrations of CBD may vary from batch to batch. One recent study found that less than 1/3 of various commercially available CBD products were labeled with correct concentrations. [Bonn-Miller: 2017] Reliable sources for acquisition of non-pharmaceutical grade CBD products are difficult to identify.
Access During Hospitalization
Even if a CBD product appears to be an effective adjunct treatment for a child’s seizures at home, some hospital and institutional policies prohibit its use to avoid exposing their staff and credentialing to undue risk. [Filloux: 2015] In turn, this puts children currently using CBD products at risk of potential worsening of seizures while hospitalized. As long as marijuana is a Schedule I substance, families and physicians will face complex decisions about the ethical and legal issues surrounding the use of non-FDA approved CBD products in children with refractory epilepsy.

Discussing CBD with Families

As far back as 2900 BC, cannabis has been used to treat seizures and other neurologic conditions. In recent years, however, popularized reports of dramatic effects and anecdotal evidence of efficacy have caught the attention of media outlets, pharmaceutical companies, entrepreneurs, patients, physicians, and policymakers alike. In particular, there has been much media coverage of children with Dravet syndrome, a devastating epilepsy syndrome, who have had remarkable decreases in seizure frequency and improvements in cognitive function after taking CBD. [Maa: 2014]
When asked about CBD and its efficacy, the following points should be discussed with families:
  • Cannabis contains many chemicals, including CBD and THC. CBD is the substance felt to be helpful in epilepsy. THC is thought of as psychoactive and responsible for the “high” people experience with marijuana.
  • Preparations of CBD or “hemp” vary widely in the amounts of THC and CBD that they contain.
  • Even when products have CBD and THC concentrations on the label, they are often inaccurate.
  • There is no consensus on dosing of CBD for the treatment of epilepsy.
  • Depending on how much THC or CBD a child is actually receiving, common side effects can include diarrhea, somnolence, irritability, and changes in appetite.
  • CBD may affect the concentrations of other anti-epileptic medications in their child’s body. This could lead to possible toxicities and over-sedation.
  • Increased seizures, status epilepticus, and death have occurred in children taking CBD after families have chosen to stop their child’s other epilepsy medications without the guidance of a doctor. It is essential that families discuss any changes to anti-epileptic drugs (AEDs) with the prescribing physician.
Aside from Epidiolex, CBD is a Schedule I drug and it is illegal to prescribe. Because of this, physicians should avoid making specific recommendations about use, dosing, and places to purchase non-pharmaceutical grade products.

Resources

Information & Support

Neurophysiology of Cannabinoids
A brief description of the complex nature of cannabinoids and the difficulties in targeting the correct receptors and desired effects; Medical Home Portal.

For Professionals

Medical Marijuana (AES)
Position statements, press releases, journal articles, clinical trials, and other resources; American Epilepsy Society.

FDA and Marijuana: Questions and Answers (FDA)
Answers to frequently asked questions about the FDA stance on cannabis-derived therapeutics and their role in ongoing research; US Food and Drug Administration.

State Medical Marijuana Laws (NCSL)
State and federal laws about medical marijuana; National Conference of State Legislatures.

Practice Guidelines

Ryan SA, Ammerman SD.
Counseling Parents and Teens About Marijuana Use in the Era of Legalization of Marijuana.
Pediatrics. 2017;139(3). PubMed abstract / Full Text
This clinical report offers guidance to the practicing pediatrician based on existing evidence and expert opinion/consensus of the American Academy of Pediatrics regarding anticipatory guidance and counseling to teenagers and their parents about marijuana and its use.

Helpful Articles

PubMed search for therapeutic cannabidiol use in children, last 3 years.

Gaston TE, Bebin EM, Cutter GR, Liu Y, Szaflarski JP.
Interactions between cannabidiol and commonly used antiepileptic drugs.
Epilepsia. 2017;58(9):1586-1592. PubMed abstract

Wong SS, Wilens TE.
Medical Cannabinoids in Children and Adolescents: A Systematic Review.
Pediatrics. 2017;140(5). PubMed abstract
Systematic review to identify the evidence base of cannabinoids as a medical treatment in children and adolescents.

Koppel BS, Brust JC, Fife T, Bronstein J, Youssof S, Gronseth G, Gloss D.
Systematic review: efficacy and safety of medical marijuana in selected neurologic disorders: report of the Guideline Development Subcommittee of the American Academy of Neurology.
Neurology. 2014;82(17):1556-63. PubMed abstract / Full Text
A systematic review of medical marijuana (1948-November 2013) to address treatment of symptoms of multiple sclerosis (MS), epilepsy, and movement disorders.

Gloss D, Vickrey B.
Cannabinoids for epilepsy.
Cochrane Database Syst Rev. 2014(3):CD009270. PubMed abstract
Cochrane systematic review to assess the efficacy and safety of cannabinoids when used as monotherapy or add-on treatment for people with epilepsy

Ammerman S, Ryan S, Adelman WP.
The impact of marijuana policies on youth: clinical, research, and legal update.
Pediatrics. 2015;135(3):e769-85. PubMed abstract
AAP Technical Report on the epidemiology of marijuana use, definitions and biology of marijuana compounds, side effects, and effects of use on adolescent brain development. Legal and safety issues concerning medical marijuana specifically are also addressed, including effects on youth of criminal penalties for marijuana use and possession.

Authors & Reviewers

Initial Publication: September 2018; Last Update: December 2018
Current Authors and Reviewers (click on name for bio):
Authors: Jennifer Goldman-Luthy, MD, MRP, FAAP
Melissa Wright, MD
Contributing Author: Carey A. Wilson, MD
Senior Author: Francis Filloux, MD

Page Bibliography

Ammerman S, Ryan S, Adelman WP.
The impact of marijuana policies on youth: clinical, research, and legal update.
Pediatrics. 2015;135(3):e769-85. PubMed abstract
AAP Technical Report on the epidemiology of marijuana use, definitions and biology of marijuana compounds, side effects, and effects of use on adolescent brain development. Legal and safety issues concerning medical marijuana specifically are also addressed, including effects on youth of criminal penalties for marijuana use and possession.

Bonn-Miller MO, Loflin MJE, Thomas BF, Marcu JP, Hyke T, Vandrey R.
Labeling Accuracy of Cannabidiol Extracts Sold Online.
JAMA. 2017;318(17):1708-1709. PubMed abstract / Full Text

Devinsky O, Cilio MR, Cross H, Fernandez-Ruiz J, French J, Hill C, Katz R, Di Marzo V, Jutras-Aswad D, Notcutt WG, Martinez-Orgado J, Robson PJ, Rohrback BG, Thiele E, Whalley B, Friedman D.
Cannabidiol: pharmacology and potential therapeutic role in epilepsy and other neuropsychiatric disorders.
Epilepsia. 2014;55(6):791-802. PubMed abstract / Full Text

Devinsky O, Cross JH, Laux L, Marsh E, Miller I, Nabbout R, Scheffer IE, Thiele EA, Wright S.
Trial of Cannabidiol for Drug-Resistant Seizures in the Dravet Syndrome.
N Engl J Med. 2017;376(21):2011-2020. PubMed abstract

Devinsky O, Marsh E, Friedman D, Thiele E, Laux L, Sullivan J, Miller I, Flamini R, Wilfong A, Filloux F, Wong M, Tilton N, Bruno P, Bluvstein J, Hedlund J, Kamens R, Maclean J, Nangia S, Singhal NS, Wilson CA, Patel A, Cilio MR.
Cannabidiol in patients with treatment-resistant epilepsy: an open-label interventional trial.
Lancet Neurol. 2016;15(3):270-8. PubMed abstract

Devinsky O, Patel AD, Cross JH, Villanueva V, Wirrell EC, Privitera M, Greenwood SM, Roberts C, Checketts D, VanLandingham KE, Zuberi SM.
Effect of Cannabidiol on Drop Seizures in the Lennox-Gastaut Syndrome.
N Engl J Med. 2018;378(20):1888-1897. PubMed abstract

Drug Enforcement Administration.
Epidiolex placed in schedule V of Controlled Substance Act.
US Department of Justice; (2018) https://www.dea.gov/press-releases/2018/09/27/fda-approved-drug-epidio.... September 27, 2018 Press Release. Accessed on 12/20/2018.

Filloux FM.
Cannabinoids for pediatric epilepsy? Up in smoke or real science?.
Transl Pediatr. 2015;4(4):271-82. PubMed abstract / Full Text

Koppel BS, Brust JC, Fife T, Bronstein J, Youssof S, Gronseth G, Gloss D.
Systematic review: efficacy and safety of medical marijuana in selected neurologic disorders: report of the Guideline Development Subcommittee of the American Academy of Neurology.
Neurology. 2014;82(17):1556-63. PubMed abstract / Full Text
A systematic review of medical marijuana (1948-November 2013) to address treatment of symptoms of multiple sclerosis (MS), epilepsy, and movement disorders.

Maa E, Figi P.
The case for medical marijuana in epilepsy.
Epilepsia. 2014;55(6):783-6. PubMed abstract

Mead A.
The legal status of cannabis (marijuana) and cannabidiol (CBD) under U.S. law.
Epilepsy Behav. 2017;70(Pt B):288-291. PubMed abstract

Monte AA, Zane RD, Heard KJ.
The implications of marijuana legalization in Colorado.
JAMA. 2015;313(3):241-2. PubMed abstract / Full Text

Porcari GS, Fu C, Doll ED, Carter EG, Carson RP.
Efficacy of artisanal preparations of cannabidiol for the treatment of epilepsy: Practical experiences in a tertiary medical center.
Epilepsy Behav. 2018;80:240-246. PubMed abstract

Rosenberg EC, Tsien RW, Whalley BJ, Devinsky O.
Cannabinoids and Epilepsy.
Neurotherapeutics. 2015;12(4):747-68. PubMed abstract / Full Text
This provides a review of current understanding of the endocannabinoid system, the pro- and anticonvulsive effects of cannabinoids [e.g., Δ9-tetrahydrocannabinol and cannabidiol (CBD)], and evidence from pre-clinical and clinical trials of cannabinoids in epilepsy.

Thiele EA, Marsh ED, French JA, Mazurkiewicz-Beldzinska M, Benbadis SR, Joshi C, Lyons PD, Taylor A, Roberts C, Sommerville K.
Cannabidiol in patients with seizures associated with Lennox-Gastaut syndrome (GWPCARE4): a randomised, double-blind, placebo-controlled phase 3 trial.
Lancet. 2018;391(10125):1085-1096. PubMed abstract

Treat L, Chapman KE, Colborn KL, Knupp KG.
Duration of use of oral cannabis extract in a cohort of pediatric epilepsy patients.
Epilepsia. 2017;58(1):123-127. PubMed abstract

Wong SS, Wilens TE.
Medical Cannabinoids in Children and Adolescents: A Systematic Review.
Pediatrics. 2017;140(5). PubMed abstract
Systematic review to identify the evidence base of cannabinoids as a medical treatment in children and adolescents.