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CBD for Neurologic Conditions in Children

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Current evidence for treatment of pediatric neurologic conditions with FDA- and non-FDA-approved cannabidiol (CBD), a chemical constituent of the cannabis plant

Epidiolex, a pharmaceutical-grade CBD medication, was approved in 2018 for treatment of refractory epilepsy in children with Dravet syndrome or Lennox-Gastaut Syndrome. In 2020, the medication was further approved for the treatment of seizures associated with Tuberous Sclerosis Complex (TSC) in children greater than 1 year of age. It is the first cannabis-derived medication to gain approval from the FDA. This resource helps medical home clinicians understand the safety and side effects of Epidiolex and address families’ questions and popular beliefs about non-FDA-approved CBD and other marijuana-derived products.

Other Names

"Hemp" often refers to low-THC (tetrahydrocannabinol) cannabis plants.
"Marijuana" usually refers to plants containing high-THC concentrations. Medical marijuana” (sometimes spelled marihuana) is not a single drug but a spectrum of preparations based on the concentrations of cannabinoids.
Other terms:
  • Cannabidiol
  • CBD oil
  • Hemp extract
  • Hemp oil

Key Points

Legality
Only 1 form of CBD, Epidiolex, has FDA approval. As of April 2020, Epidiolex is no longer a controlled substance. CBD in forms other than Epidiolex remains a Schedule 1 drug at the federal level and is illegal to prescribe. As of February 3, 2022, 37 states, 3 territories, and the District of Columbia allow the medical use of cannabis products. Marijuana and its derivatives (other than Epidiolex) remain illegal at the federal level, despite legalization in certain states.

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 may:

  • Vary in the amount of CBD they contain, if any, and they may not contain the amount of CBD that the label states.
  • Contain up to 80 other cannabinoids, including THC, unlisted ingredients, and contaminants. [Bonn-Miller: 2017]

Discontinuation of 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 without guidance or against the advice 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
Aside from Epidiolex, CBD is illegal to prescribe at the federal level, despite being legal and readily available in many states. In addition, there is no 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. See Complementary and Alternative Medicine (CAM).

Evidence
The use of CBD products in children with neurologic conditions other than 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 the treatment of refractory epilepsy and understand the long-term consequences of CBD and other cannabis preparations. Since the FDA approval and re-scheduling of Epidiolex, increasing studies have become available regarding usage, dosage, and safety. Research within the field is expected to flourish rapidly.

Epidiolex: Prescribing, Dosage, Safety

Epidiolex consists of purified cannabidiol and is the first cannabis-derived medication to gain approval from the FDA for treatment of refractory seizures in children with Dravet syndrome, Lennox-Gastaut syndrome, or tuberous sclerosis complex. (See FDA Approval for Epidiolex (FDA) for the press release.)

Prescribing

When first FDA approved, Epidiolex was a Schedule V controlled substance, meaning it was classified as a drug that can be misused or cause dependence, and the federal government regulated its use. As of April 2020, Epidiolex is no longer a controlled substance. Yet, barriers remain in prescribing the medication. Such barriers include dispensing at specialty pharmacies, limited insurance coverage, and high co-pays. Off-label use of Epidiolex to treat other types of refractory epilepsies may be covered by insurance. However, this typically requires pre-authorization with considerable effort by the prescribing physician to justify use.

Dosing

Dosing guidelines are available on the manufacturer's website at Epidiolex: Recommended Dosage (Greenwich Biosciences). Dosing recommendations differ depending on the individual’s underlying diagnosis and degree of hepatic impairment, with higher doses for efficacy suggested for treatment of seizures in children with tuberous sclerosis complex than for Dravet or Lennox-Gastaut syndromes. Guidelines for use in Dravet syndrome are based on a 2020 randomized controlled clinical trial that reported similar efficacy between 20mg/kg/d dosing and 10mg/kg/d dosing, with the latter demonstrating a better safety and tolerability profile. [Miller: 2020] There is limited data reflecting dosing comparisons in Lennox-Gastaut syndrome and tuberous sclerosis complex literature. Primary care clinicians are strongly advised to consult with a pediatric neurologist, particularly an epileptologist, rather than starting this medication independently.

Safety & 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.
Monitoring of transaminase and bilirubin levels is recommended by some authorities 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. (Bilirubin Screening & Testing in NewbornsI)
In a dose-dependent study, all cases of elevated transaminases occurred in participants taking concomitant valproate sodium. Transaminitis also occurred significantly more frequently in the higher dose subset of participants. [Miller: 2020] Other medications metabolized through the cytochrome P450 system may have altered concentrations when taken with CBD. [Filloux: 2015]
In particular, CBD interferes with the metabolism of desmethylclobazam, the primary active metabolite of clobazam, potentially leading to excessive sedation. Consequently, dose reductions of clobazam are often needed when adding epidiolex to a patient’s regimen. 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]
Concerns have also been raised regarding dietary habits that may impact the metabolism of Epidiolex, specifically the ketogenic diet commonly utilized by patients with refractory epilepsy. Eating meals high in fat can increase the amount of Epidiolex the body absorbs, which can increase the level of Epidiolex in the patient’s system. In clinical studies, Epidiolex levels were increased up to five times when the drug was taken with a high-fat meal, leading to adverse drug reactions, including somnolence and GI upset. [Schaiquevich: 2020]
The potential changes in metabolism of anti-epileptic medications other than valproate sodium or clobazam are possible but generally do not require further monitoring. 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 unavailable 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”

Legality

Marijuana and products derived from cannabis are regulated at both the state and federal levels. In recent years, substantial differences have developed between state and federal regulations, with some states legalizing marijuana for medical or personal use. 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 at the federal level. [Mead: 2017]
Schedule I drugs are defined as those with high abuse potential and no accepted medical use per the federal government. As of April 2020, Epidiolex is no longer a controlled substance. CBD in forms other than FDA-approved Epidiolex remains a Schedule 1 drug at the federal level and is 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: Marijuana and its derivatives (other than Epidiolex) remain illegal at the federal level, despite legalization in certain states.

Safety & Side Effects

Cannabis containing products pose a concern for neurotoxicity that may impact neurophysiology and development. However, it is important to note that the limited information regarding neurotoxicity refers to THC-containing products, which do not apply to pure CBD products such as Epidiolex. Existing evidence suggests that CBD has very limited, if any such toxicity. Further concerns regarding the safety of cannabis products are outlined below.
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 as effective, they might decrease or stop other anti-epileptics without consulting a physician, which could 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 significantly increased 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 CBD; 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. The long-term effects of cannabis products in children and adolescents are unknown.
Inability to monitor for safety
Evaluating and safely monitoring cannabis use is difficult because the formulations parents give their children are often unknown. For example, some preparations may have much higher 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] This puts children currently using CBD products at risk of worsening 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 or other medical conditions.

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 reported 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 considered a psychoactive agent 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 non-standardized medical marijuana products 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 at the federal level, despite being legal and readily available in many states. Because of this, physicians should avoid making specific recommendations about use, dosing, and places to purchase non-pharmaceutical-grade products.

Evidence for Therapeutic Value of CBD

Childhood Epilepsy
Literature about cannabinoids and childhood epilepsy has shown that pure CBD has more evidence for efficacy than other preparations, and its use significantly improved seizure control for patients in most of the few studies conducted. s use significantly improved seizure control for patients in most of the few studies conducted. [Wong: 2017] [Devinsky: 2014] [Thiele: 2018] [Thiele: 2018]
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

  • Thiele EA, Bebin EM, Bhathal H, Jansen FE, Kotulska K, Lawson JA, O'Callaghan FJ, Wong M, Sahebkar F, Checketts D, Knappertz V.
    Add-On Cannabidiol Treatment for Drug-Resistant Seizures in Tuberous Sclerosis Complex: A Placebo-Controlled Randomized Clinical Trial.
    JAMA Neurol. 2020. PubMed abstract / Full Text

  • Miller I, Scheffer IE, Gunning B, Sanchez-Carpintero R, Gil-Nagel A, Perry MS, Saneto RP, Checketts D, Dunayevich E, Knappertz V.
    Dose-Ranging Effect of Adjunctive Oral Cannabidiol vs Placebo on Convulsive Seizure Frequency in Dravet Syndrome: A Randomized Clinical Trial.
    JAMA Neurol. 2020;77(5):613-621. PubMed abstract / Full Text

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 syndrome, Lennox-Gastaut Syndrome, and Tuberous Sclerosis Complex (TSC). Ongoing clinical trials can be found at ClinicalTrials.gov.

Remaining studies have lacked appropriate controls and large sample sizes. They are subject to significant bias, especially since 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 than parents already living there. [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]

Under the 2014 Farm Bill, which allows the 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. 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.

Other Neurological 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] ] Efficacy of cannabis products in the treatment of complex motor disorders has also been studied in randomized controlled clinical trials but was not found to demonstrate significant benefit. [Libzon: 2018] 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. Given the paucity of literature on the topic, the American Academy of Pediatrics (AAP) opposes the use of medical cannabis outside of FDA-approved pharmaceutical products but does acknowledge that providers may support use of medical marijuana products in desperate cases. [Ammerman: 2015] They recommend higher-quality research in the field.

Research Potential

FDA approval of cannabis in various conditions is often limited by a lack of controlled research studies specific to that condition or population. For many years, bipartisan legislature has struggled to see eye to eye on the best direction of cannabis reform to further promote quality research efforts within the medical community. In a landmark victory on December 2, 2022, President Biden signed into law the “Medical Marijuana and Cannabidiol Research Expansion Act, H.R. 8454.” This bipartisan legislation marks the first cannabis reform bill to pass both the House and Senate, paving the way for future research and applications of medical cannabis.
It should be noted that the new law does not change marijuana’s status as a schedule 1 substance. This legislation primarily intends to:
  1. Further characterize the medical risks and benefits of cannabis and its synthetic equivalents.
  2. Expand sources of medical-grade cannabis.
  3. Encourage commercial development of marijuana and CBD derivatives approved by the FDA.
  4. Ensure that physicians are prepared to appropriately discuss the risks and benefits of marijuana and CBD with patients and their families.
  5. Clarify and streamline the rolls of governing bodies, s including the FDA, NIDA, and DEA, in cannabis research.
By increasing the supply of cannabis available for research potential and streamlining the approval process for research in medical cannabis, future studies are predicted to drastically expand the uses and applications of cannabis in pediatric neurologic conditions in the coming years.

Neurophysiology of Cannabinoids

The cannabis plant contains at least 60 different phytocannabinoids with variable proportions of these biochemicals based on the strain of plant. [Koppel: 2014] These cannabinoids are structurally related yet distinct and easily cross the blood-brain barrier due to their lipophilic nature. Within the central nervous system, they function through the complex endocannabinoid system, which is composed of chemicals called endocannabinoids and their receptors. Activation of this system through endogenous (endocannabinoids) or non-endogenous (cannabis-derived chemicals) results in multifactorial neuro-modulatory effects with modulation of region-specific, long-term synaptic potentiation and depression. [Rosenberg: 2015]

The 2 main cannabinoid receptors are CB1, which is widely distributed and primarily inhibits neurotransmitter release, and CB2, which is less prevalent and not as well understood. [Fine: 2013] Some believe that phyto- and endo- cannabinoids also work on additional target sites and receptors, which adds to the complexity of a process. Furthermore, the system is felt to be dynamic, with chronic hyperexcitability leading to changes in the pathway. [Rosenberg: 2015] Cannabinoids work through synaptic depolarization and hyperpolarization, which activate receptors that then modulate the release of other neurotransmitters. [Fine: 2013] The endocannabinoid system, and its ability to function as feedback inhibition, thus presents an inherent potential target for the management of neurologic disease.

While the complex nature of the system makes cannabis an attractive potential therapy for multiple ailments, it also creates difficulties in targeting the correct receptors and desired effects. This is further complicated by the variability of strains, preparations, and ratios of phytocannabinoids. The most studied phytocannabinoids are tetrahydrocannabinol (THC) and cannabidiol (CBD).

THC is a partial agonist of cannabinoid receptors. It is felt to be responsible for the majority of cognitive and psychotropic effects of cannabis. Functioning mainly through CB1 and CB2, it has been shown to be involved in the regulation of neuronal excitability and the release of anti-inflammatory cytokines. [Rosenberg: 2015]

CBD, on the other hand, seems to function through non-CB receptor signaling, with antioxidant, anti-inflammatory, and neuroprotective properties. [Devinsky: 2014] The effect of a cannabis preparation, therefore, depends on the ratio of THC to CBD, and CBD in and of itself is thought to modulate the psychoactive effects of THC. [Koppel: 2014]

Resources

Information & Support

For Professionals

Epilepsy, Medical Marijuana and CBD: Myths and Facts (AES)
From the 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.

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

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/revision: June 2023
Current Authors and Reviewers:
Author: Reilly F Philliben, DO
Reviewer: Francis M. Filloux, MD
Authoring history
2023: update: Reilly F Philliben, DOA; Reilly F Philliben, DOA; Carey A. Wilson, MDSA
2020: update: Lynne M. Kerr, MD, PhDR
2019: update: Francis M. Filloux, MDR
2018: first version: Jennifer Goldman, MD, MRP, FAAPA; Melissa Wright, MDA; Carey A. Wilson, MDCA; Francis M. Filloux, MDSA
AAuthor; CAContributing Author; SASenior Author; RReviewer

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

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

Fine PG, Rosenfeld MJ.
The endocannabinoid system, cannabinoids, and pain.
Rambam Maimonides Med J. 2013;4(4):e0022. PubMed abstract / Full Text

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

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

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.

Libzon S, Schleider LB, Saban N, Levit L, Tamari Y, Linder I, Lerman-Sagie T, Blumkin L.
Medical Cannabis for Pediatric Moderate to Severe Complex Motor Disorders.
J Child Neurol. 2018;33(9):565-571. PubMed abstract

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

Miller I, Scheffer IE, Gunning B, Sanchez-Carpintero R, Gil-Nagel A, Perry MS, Saneto RP, Checketts D, Dunayevich E, Knappertz V.
Dose-Ranging Effect of Adjunctive Oral Cannabidiol vs Placebo on Convulsive Seizure Frequency in Dravet Syndrome: A Randomized Clinical Trial.
JAMA Neurol. 2020;77(5):613-621. PubMed abstract / Full Text

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.

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.

Schaiquevich P, Riva N, Maldonado C, Vázquez M, Cáceres-Guido P.
Clinical pharmacology of cannabidiol in refractory epilepsy.
Farm Hosp. 2020;44(5):222-229. PubMed abstract

Thiele EA, Bebin EM, Bhathal H, Jansen FE, Kotulska K, Lawson JA, O'Callaghan FJ, Wong M, Sahebkar F, Checketts D, Knappertz V.
Add-On Cannabidiol Treatment for Drug-Resistant Seizures in Tuberous Sclerosis Complex: A Placebo-Controlled Randomized Clinical Trial.
JAMA Neurol. 2020. PubMed abstract / Full Text

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.