Cbd oil for seizures in toddlers

CBD for Neurologic Conditions in Children

This resource for primary care providers of children with special health care needs discusses current evidence 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

  • 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

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]

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.

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.

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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]

  • 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.

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

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.

Patient Education

CBD Use in Children—Miracle, Myth, or Mystery?
A JAMA Pediatrics Patient Page about cannabinoids or cannabis products for children with various health conditions.

Helpful Articles

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

Current Authors and Reviewers:

Authors: Jennifer Goldman-Luthy, MD, MRP, FAAP
Melissa Wright, MD
Contributing Author: Carey A. Wilson, MD
Senior Author: Francis M. Filloux, MD
Reviewer: Lynne M. Kerr, MD, PhD
2019: first version: Francis M. Filloux, MD R

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.

CBD Medication Reduces Seizures in Children on Multiple Anti-Epileptic Drugs, Researchers Find

New study supports possible lower dosing levels of FDA-approved drug derived from cannabis for difficult-to-treat type of epilepsy.

The cannabidiol (CBD) drug Epidiolex — already approved by the U.S. Food and Drug Administration (FDA) to treat seizures in children caused by Dravet syndrome and Lennox-Gastaut syndrome — may now help reduce symptoms in a broader range of doses.

New research published March 2, 2020, in the journal JAMA Neurology confirmed prior study outcomes demonstrating the effectiveness of this oral medication for Dravet syndrome at a dose of 20 milligrams per kilogram (mg/kg) per day. (The drug, which comes in a sesame oil with strawberry flavoring, is given according to a child’s weight.)

Results Show That a Lower Dose Is Safe, Effective

“This is the first study, however, to show efficacy and safety for a 10 mg/kg a day dose in these patients,” says lead investigator Ian Miller, MD, director of the epilepsy and neurophysiology program at Nicklaus Children’s Hospital in Miami. “It will not change the FDA indication, but will inform physicians regarding optimizing the benefit-risk ratio for patients.”

The trial, which included 199 patients ages 2 to 18 with a confirmed diagnosis of Dravet syndrome, showed that the 10-mg dose may be just as effective as the 20-mg dose.

Scientists discovered that those taking 10 mg experienced seizure reductions of 49 percent compared with 46 percent reduction in those taking 20 mg and a 27 percent reduction for those on placebo.

Stephen Schultz, the vice president of investor relations for GW Pharmaceuticals, which makes Epidiolex, indicates that the results should give physicians greater flexibility when it comes to dosing. “For some patients, the 10 [mg] will work well, but others will be more resistant and will need more,” he says.

Notoriously Resistant to Treatment

Dravet syndrome is a rare, catastrophic form of lifelong epilepsy that affects about 1 in every 15,700 individuals in the United States, according to the Dravet Syndrome Foundation.

This severe epilepsy can bring on frequent, prolonged seizures often triggered by high body temperature (hyperthermia), as well as developmental delay, speech impairment, ataxia (a degenerative disease of the nervous system), hypotonia (decreased muscle tone), sleep disturbances, and other health problems.

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So far, the condition has been extremely challenging to treat, with response to medication being inadequate. The participants in this investigation were taking multiple anticonvulsants, such as levetiracetam, divalproex, topiramate, zonisamide, ethosuximide, and clobazam.

“Even with these currently available treatments, only about 10 percent of patients with Dravet syndrome achieve adequate seizure control,” says Dr. Miller.

A report published in September 2019 the journal CNS Drugs, however, highlighted new therapies — including stiripentol, fenfluramine, and cannabidiol — which have produced promising results in reducing convulsive seizure frequency.

Greenlighted by the FDA for Dravet syndrome treatment in June of 2018, Epidiolex is the first prescription pharmaceutical formulation of a highly purified, plant-derived cannabinoid — but without the “high” associated with marijuana.

“This study is not necessarily providing new information but providing further evidence of the usefulness of Epidiolex in Dravet Syndrome,” says Melissa L Bernbaum, MD, director of neurology at Northwell Health’s Huntington Hospital in Huntington, New York.

She adds that, while there may be a stigma attached to cannabidiol because of the medication’s connection with marijuana, she does not have any patients with such concerns at her practice and in fact, many are interested in “medical marijuana.”

“Parents actually tend to have a positive emotional reaction to the fact that the medication is produced from a plant and then purified, rather than being synthesized in a test tube,” says Miller.

With the benefits of cannabidiol being scientifically proven, GW Pharmaceuticals is seeking the FDA’s thumbs-up for Sativex (naximbols), a spasticity treatment for patients with multiple sclerosis that contains two chemical extracts derived from the cannabis plant. The product is currently approved in 29 countries outside the United States, according to the company.

The company is also exploring cannabinoid-based therapies for autism, spinal cord spasticity, schizophrenia, and post-traumatic stress disorder (PTSD).

Staying Alert to Possible Side Effects

Overall, Epidiolex has a favorable safety profile with notable side effects being the risk of liver enzyme elevations, appetite changes, diarrhea, somnolence (sleepiness), pyrexia (fever), and fatigue.

“It is also important to note potential interactions with other anti-seizure medication,” says Dr. Bernbaum. “Certain combinations may be more likely to cause sedation.”

Schultz stresses that dosing above 25 mg did not significantly improve seizure response, but did increase the number of adverse events. “Given that, it makes sense for the top end of dosing to be around 25 [mg],” he says.

At this time, the sticker cost for the drug is not inexpensive. On average, the price for Epidiolex in the United States for the first year of use was in the $32,000 per year range, according to Schultz, who adds that the out-of-pocket copay may be no more than $25 per patient.

Because dosing depends on patient’s weight, he points out that the product will cost less for young lighter patients and more for older heavier patients.

“Physicians and patients desired a pharmaceutical formulation of a cannabinoid that has gone through proper clinical trials and been tested for safety and efficacy,” says Schultz. “With Epidiolex, they have one that is exactly the same every time that it is taken, and because it is FDA-approved, it will be paid for by insurance.”

Medical Cannabis for Intractable Epilepsy in Childhood: A Review

This is an open-access article. All its content, except where otherwise noted, is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Abstract

In recent years, cannabis has been gaining increasing interest in both the medical research and clinical fields, with regard to its therapeutic effects in various disorders. One of the major fields of interest is its role as an anticonvulsant for refractory epilepsy, especially in the pediatric population. This paper presents and discusses the current accumulated knowledge regarding artisanal cannabis and Epidiolex®, a United States Food and Drug Administration (FDA)-approved pure cannabidiol (CBD), in epilepsy management in pediatrics, by reviewing the literature and raising debate regarding further research directions.

INTRODUCTION

Childhood epilepsy may be coarsely divided into (1) a large group (70%) of benign epileptic syndromes and easily controlled symptomatic epilepsies, and (2) a smaller but significant group of drug-resistant epilepsies which includes idiopathic and genetic epileptic encephalopathies and various symptomatic acquired epilepsies. The burden of intractable epilepsy on infants and children and their families is enormous, and in addition to the risks carried by the actual seizures it significantly affects the children’s development and quality of life. Most of these children are on polytherapy, which has its own consequences. This devastating situation has led to a quest for additional solutions. This quest, with regard to the use of cannabis, has been led by parents and caretakers in parallel to the medical authorities.

Various ancient cultures have mentioned cannabis as a useful tool to treat epileptic convulsions. There are historical records from ancient China dating back to 2700 BC 1 and tablets written by the Sumerian and Akkadian peoples in 1800 BC, 2 as well as other ancient historical records. In the nineteenth century several leading physicians published papers on its use as an anticonvulsant, presenting both case reports 3 and their general impression on its effectiveness when added to bromides. 4

Despite the Marijuana Tax Act of 1937, which led to the removal of cannabis from the US pharmacopeia in 1941, and its classification as a schedule 1 substance, several researchers and physicians renewed investigation on the biological effects and medicinal use of its various components in the 1970s. Several animal studies and small-scale clinical trials examined its use. Studies focusing mainly on purified cannabidiol (CBD) in epilepsy management in drug-resistant patients were published. 5 – 10 The above clinical studies were assessed in a 2012 Cochrane review stating that the trials were based on small samples with inconsistent products, dosages, dose frequencies, and treatment durations. These deficiencies led the Cochrane reviewers to conclude that CBD efficacy in the treatment of epilepsy could not be confirmed, but that a dosage within the range 200–300 mg daily was safe enough to be given over a short time period. 11

In the last decade social media, patient and family advocacy groups, and Internet activity have led to significant public interest in cannabis as an alternative treatment for those living with epilepsy. This public demand revived both basic and clinical research into cannabis and CBD use for epilepsy treatment particularly in the pediatric population. This review provides an overview and discussion of the current data relating to artisanal cannabis and pure CBD use in epilepsy.

CANNABIS AND CANNABIDIOL ANTIEPILEPTIC MECHANISM OF ACTION AND PHARMACOKINETICS

The marijuana plant, Cannabis sativa, and Cannabis indica contain up to 500 chemical species, with more than 100 different phytocannabinoid compounds. 12 The two main components of cannabis—Δ-9-tetrahydrocannabiniol (THC) and CBD—have generated the most interest in terms of their putative effectiveness as anti-seizure agents: THC is a psychoactive agent, with equivocal value for seizure control and a potential to trigger seizure activity; CBD is a non-psychoactive agent with both anecdotal and scientific evidence suggesting its usefulness as an antiepileptic medication. 13 , 14

Biologically, THC’s mechanism of action is primarily related to its effect on endogenous cannabinoid receptors in the brain, mainly cannabinoid receptor type 1 (CB1), and to the extra central nervous system (CNS) receptor, CB2. 15 Cannabidiol, on the other hand, has a relatively small direct affinity to the CB1 and CB2 receptors but has an inhibitory effect on THC binding to the CB1 receptors. 16 This inhibitory effect may lead to positive modulation (“fine tuning”) of CB1 activation by THC which may reduce anxiety and paranoia caused by its non-modulated activation. 17

The CBD anticonvulsant activity is most probably multifactorial and relates to: gamma-aminobutyric acid (GABA)-mediated inhibition of glutaminergic forebrain neurons 18 ; intracellular calcium current modulation through an effect on several transient receptor potential channels of the vanilloid subtype; its direct effect on the G-protein-coupled receptor GPR55; and the inhibition of adenosine reuptake and modulation of tumor necrosis factor (TNF)-alpha release, affecting the inflammatory related components of epileptiform activity. 19 The affinity of CBD for the 5-HT1A and 5-HT2A receptors is also considered a novel target for refractory epilepsy treatment. 20 In addition to its indirect antagonism on CB1, CBD may affect the seizure threshold as shown in several animal studies. 21

CANNABIDIOL ANTICONVULSANT EFFECTS IN ANIMAL MODELS

Cannabidiol has been tested in several animal epileptic models, including maximal electroshock, pentylenetetrazol, pilocarpine, penicillin, audiogenic seizures, 6-Hz, subcutaneous metrazol threshold test, and cobalt implantation, 22 – 26 and was found to have an anticonvulsant effect in all models. Its anticonvulsant profile was re-evaluated using the focused screening protocol developed by the National Institute of Neurological Disorders and Stroke (NINDS)-funded Epilepsy Therapy Screening Program. Intraperitoneal introduction of CBD produced a dose-dependent protection against maximal electroshock-induced seizures in mice and rats and was found to be effective in the 6 Hz, 44 mA seizure model and the corneal kindling model in mice. 27

Because of the specific interest given to the positive effect of CBD in Dravet syndrome patients, this compound was studied in an SCN1A knockout mouse model showing decreased spontaneous seizure frequency and duration, as well as decreased severity of heat-induced seizures. Autistic-like social interaction deficits improved with low-dose CBD but failed to improve with the higher dosages required for seizure control. 28

Studying the effect of THC on seizures in various animal models showed conflicting results—including anticonvulsant, no effect, and proconvulsant responses—making it less attractive for clinical epilepsy treatment. 29

PHARMACOKINETICS

Cannabidiol has poor oral bioavailability of around 6%, which is related to its lipophilic structure, variable absorption rate, and extensive hepatic first-pass metabolism by isozymes CYP2C19 and CYP3A4. Its bioavailability can be increased or decreased by exposure to a strong enzyme inhibitor or inducer, respectively. 30 It is highly protein-bound and because of its lipophilic structure may accumulate in adipose tissues. The CBD peak plasma concentrations after oral administration in oily formula is about 2.5 hours, 31 with its biphasic elimination (initial half-life of 6 hours and terminal half-life of 18–32 hours) reflecting distributive processes into tissues. 32

CURRENT CLINICAL EXPERIENCE

Over the last six years, medical publications regarding epilepsy treatment with cannabis oil extracts and pure CBD can be divided into several groups: retrospective surveys and chart reviews of patients independently treated with artisanal cannabis by their caretakers which was reported to physicians; retrospective chart reviews of CBD-enriched cannabis oil use, as directed by physicians; and open-label followed by placebo-controlled prospective studies of US Food and Drug Administration (FDA)-approved pure CBD oil (Epidiolex®); in addition to anecdotal reports of other “pure CBD” compounds used. 33

Porter et al. surveyed parents who belong to a Facebook group that used CBD extracts to treat their children’s seizures. Nineteen out of 150 participants in the group responded: 84% reported a reduction in seizure frequency; of these, 11% (2/16) experienced a positive effect and became seizure-free. 34 Another online survey on CBD extract effect published by Hussain et al. included responses from 117 parents of children with epilepsy (more than 40% with intractable epileptic encephalopathies); the parents reported 85% responders, with 14% of the children achieving seizure freedom. 35 A third internet survey was reported from Mexico, 36 describing 53 patients, age range 9 months–18 years, using various cannabis extract compounds, mostly of unknown composition: 83% of patients experienced improved seizure control, and 16% became seizure-free, with only a 5% rate of seizure aggravation. However, for all these publications there is selection bias of the reports, and additionally the extract used, reported dosages, and lengths of treatment were inconsistent.

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A retrospective medical chart review was performed on 75 children and adolescents who received various types and dosages of oral cannabis extracts to treat their epilepsy. Based on parental reports, within the subgroup of responders (33%), more than a 50% reduction of seizures was noted in children with Lennox–Gastaut syndrome (LGS) and Dravet syndrome. Interestingly there was a significantly higher response rate from families who had moved to Colorado in order access artisanal cannabis treatment for their child as compared to the families who were already Colorado residents (47% versus 22%), suggesting a higher placebo effect in those with higher treatment expectations. 37

A retrospective multicenter study was performed with data from three epilepsy clinics in Israel treating 74 children for intractable epilepsy with one of two well-controlled cannabis oil extracts (CBD:THC ratio, 20:1; dosage range 1–20 mg/kg/d for 3–12 months). The authors found that 52% of patients experienced more than 50% reduction in seizure frequency; only 7% of patients experienced seizure aggravation. 38 This study differs from the previous ones in that the cannabis oil treatment was directed by the pediatric neurologists responsible for all patient treatment decisions during the follow-up period. The largest chart review published so far on the effect of artisanal cannabis in pediatric epilepsy is by Sulak et al., reviewing information on 272 pediatric patients from Washington and California states who were followed for 3–30 months. They noted a more than 50% reduction in seizure frequency in 45% of patients, with 10% becoming seizure-free. 39

While the use of artisanal cannabis preparations can be criticized as being inaccurate and not as precise as expected for other drug treatments in the medical community, a more well-controlled process leading to FDA and European Medicines Agency (EMA) approval was performed for a pure CBD extract produced by GW Pharma called “Epidiolex.”

The first published study using Epidiolex as an add-on treatment for children with intractable epilepsy was by Devinsky et al. 40 This open-label multicenter efficacy and safety study included 214 patients (aged 1–30 years) with severe childhood-onset, drug-resistant epilepsy (33 patients had Dravet syndrome; 31 patients had LGS). A 36.5% median reduction in monthly motor seizures was found in the 137 patients eligible for analysis.

The following study 32 was already a double-blind placebo-controlled trial looking at the effectiveness of CBD oil (Epidiolex) as an add-on agent compared with placebo in 120 children and adolescents with treatment-resistant seizures related to Dravet syndrome (CBD dosage 20 mg/kg/d). After a four-week titration period, patients were followed for an additional 12 weeks. The main significant effect noted was the rate of reduction in convulsive seizures between CBD-treated patients (43% response rate) and the placebo group (27%), with 5% becoming seizure-free in the treatment versus placebo groups. The difference between groups for non-convulsive seizures was not significant. There was a larger drop-off (15%) in the treatment arm, compared to placebo (5%), as well as a higher rate of side effects (93% versus 85%). The response rate was higher in patients adding CBD to clobazam. 32 , 41

Two multicenter double-blind placebo-controlled trials investigated the short-term effect of CBD in LGS patients: the first one looked at the efficacy of CBD (20 mg/kg/day) as an add-on therapy for drop seizures in 171 patients (2–55 years) with treatment-resistant LGS and found a statistically significant reduction in drop seizure number in the CBD compared to the placebo group. 42 The second study compared two doses (20 mg/kg/day and 10 mg/kg/day) of purified CBD to placebo and demonstrated a significant reduction in drop seizures versus placebo with both dosages. 43

Equally important to double-blind placebo-controlled studies, which are usually short term, is investigation into a drug’s long-term effect on epilepsy. This collected data was lately reported by Szaflarski et al. 44 who reviewed the safety data of 607 patients, and the efficacy data of 580 patients, participating in the extended protocol Epidiolex studies. They found that the improvements experienced during the first 12 weeks of the study were sustained over the 96 weeks of the study, in most of the patients available for this analysis, with no aggravated side effects. The 76% study retention rate compares favorably to other antiepileptic drug trials.

Based on these positive trials the FDA approved pharmaceutical-grade CBD Epidiolex as an oral solution (100 mg CBD/mL) for treating seizures in LGS and Dravet syndrome patients over the age of two years. However, other CBD products remain as schedule I substances under the Controlled Substances Act. The above-mentioned approval was followed by EMA approval of Epidiolex for the same indications and age group, but only when added to clobazam, based on the assumption that because CBD increases blood levels of clobazam active metabolite, its antiepileptic effect in many patients in the randomized studies that led to the FDA approval could be attributed to this effect only.

Smaller-scale studies looked at the effect of Epidiolex in other rare epileptic syndromes and disorders with severe epilepsy, including its positive effect on seizures in tuberous sclerosis patients 45 ; a higher response rate was noted when CBD (Epidiolex) was added to clobazam. A promising effect was also reported in an open-label study in 6/7 patients with febrile infection-related epilepsy syndrome, 46 as well as in Sturge–Weber syndrome. 47

CANNABIDIOL INTERACTIONS

Cannabidiol is a potent inhibitor of CYP2C19, CYP2D6, and CYP2C9, which leads to an increase in the level of several antiepileptic drugs, with the most significant effect being on clobazam and its metabolite N-desmethylclobazam, and a less prominent effect on topiramate, eslicarbazepine, zonisamide, rufinamide, and brivaracetam. 48 – 50

Abnormal elevation in liver enzymes (transaminases) can occur with concomitant use of valproate and CBD without significant changes in the valproate levels, suggesting a pharmacodynamic rather than a pharmacokinetic interaction. 32

CANNABIDIOL AND CANNABIDIOL-ENRICHED CANNABIS ADVERSE EVENTS AND POSITIVE NON-EPILEPSY-RELATED EFFECTS

The adverse events reported in the well-controlled trials of both artisanal cannabis use and Epidiolex were qualitatively similar and included fatigue, decreased appetite, somnolence, vomiting, diarrhea, and seizures. Somnolence was more frequently reported in patients treated with Epidiolex in addition to clobazam. 47 , 48 In the extensive chart review by Sulak et al., related to artisanal cannabis use, the main side effects were somnolence and fatigue in up to 20% of patients. 39 The same side effects with similar or slightly higher rates were reported in the other artisanal cannabis studies, 34 , 38 while various Epidiolex studies showed a significantly higher side effects rate. In the open-label study by Devinski et al., 40 a 79% adverse event rate was reported, with 25% somnolence, 19% decreased appetite, 19% diarrhea, 13% fatigue, and 11% convulsions; 3% of patients discontinued treatment because of an adverse event. Serious adverse events as defined by the research protocol were reported in 30% patients; in 12% these effects were possibly related to cannabidiol use, the most common of which was status epilepticus (6%). For LGS treatment, a comparison study of two CBD dosage groups, 10 mg and 20 mg, reported adverse events in 84% and 94%, respectively, but a significant adverse event rate of 72% was also reported in the placebo arm. The investigators judged 89% of the events to be of mild or moderate severity. The most common adverse events were, again, somnolence, decreased appetite, diarrhea, upper respiratory tract infection, pyrexia, and vomiting. 43

Elevations of liver transaminases were reported only in the Epidiolex studies, mainly during the first two months after treatment initiation, and were primarily dose-related; delayed transaminase elevations have also been noted, particularly with concomitant valproate use, and less frequently with concomitant clobazam use. The transaminase elevation was reversible with discontinuation or reduction of CBD oil and/or concomitant valproate. 32

The significantly higher rate of adverse events reported in the Epidiolex well-controlled trials compared to the open-label artisanal cannabis reports may be partially related to bias effect of the artisanal retrospective reports; the high rate of adverse events reported in the placebo group of the Epidiolex studies supports this assumption. But it could also be related to the much higher dose and rapid titration rate of CBD used in the Epidiolex studies as compared to artisanal cannabis use. The possibility that differing amounts of other constituents in artisanal cannabis oil, such as THC, other cannabinoids, and terpenes, have a protective effect merits further investigation.

It is interesting to note that the artisanal cannabis reports and the short- and long-term Epidiolex studies reported other positive side effects not directly related to seizure control. The beneficial effects of CBD-enriched cannabis, other than reduced seizures, were reported in all studies related to artisanal cannabis use and included: increased alertness (>50%); improved sleep (25%–68%), behavior (33%), language (10%), and motor skills (10%–20%); and decreased self-stimulation (32%). 34 , 35 , 37 – 39 Although there is no specific reference to these effects in the Epidiolex studies, a recent report on quality of life (QoL) in pediatric patients enrolled in a CBD (via Epidiolex) study has shown significant improvement in caregiver-reported QoL in multiple domains, as well as in general. This may be related to both better seizure control as well as additional positive changes noted in the patients’ conditions. 51

THOUGHTS, PRECAUTIONS, AND CONCLUSIONS

Pure CBD (i.e. Epidiolex) and CBD-enriched cannabis oil extracts were found to be effective for epileptic seizure control in pediatric patients and young adults, particularly in the specific epileptic syndromes, Dravet syndrome and LGS, as was the case in larger more varied groups of patients with intractable epilepsy. Based on the current data, it is essential that drug formulations contain as low a THC content as possible, since the anti-seizure activity of THC is equivocal and it can potentially aggravate seizures; moreover, it can be associated with additional short- and long-term side effects, especially related to memory as well as other aspects of cognition and behavior. 52

We should be aware that artisanal and other commercially available products are currently not well controlled. This has been proven through in-depth chemical profiling of cannabinoids, terpenes, and oxidation products of commercially available CBD oils used for treating epilepsy in the United States, which found that 9/14 of the samples studied (64%) had concentrations that differed from the declared amount, with only five maintaining optimal concentrations. 53 Strict regulations for manufacturing, packaging, and labeling are warranted to ensure safe administration and efficient use of cannabis extracts, and would enable wider use for treatment of intractable epilepsy in the pediatric and possibly the adult population.

On the other hand, future research on the role of cannabis in epilepsy should keep in mind that the controlled, randomized trials have revealed that the actual reduction in seizure frequency in response to CBD is comparable to that achieved in response to other antiepileptic drugs, and have failed to meet the 60%–85% responder rates in unblended web-based surveys and chart reviews based on parental reports. In addition the rate of side effects was higher in the well-controlled Epidiolex studies compared to artisanal cannabis use. Although these differences may primarily be related to the positive bias of the open-label retrospective studies and higher CBD dosages used in the controlled pure CBD trials, there is still room for debate regarding the role of other phytocannabinoids present in artisanal cannabis extracts, which may have an “entourage effect” on both the anticonvulsant potency and their protective role, which points to the need for further research in this direction. 54