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Dr Schuman, section editor for Peds v2.0, is clinical assistant professor of Pediatrics, Geisel School of Medicine at Dartmouth, Lebanon, New Hampshire, and editorial advisory board member of Contemporary Pediatrics.
There is little evidence of efficacy and safety of the cannabidiol (CBD) products flooding the market when it comes to use in children. Here’s what pediatricians should know and what to tell parents.
Pediatricians are being asked by parents about treating their children with cannabidiol (CBD) products obtained via local shops, online sellers, and national pharmacy chains. As many parents are using CBD regularly, it is likely that children are being given these products without pediatricians’ endorsement, convinced by the national media and word of mouth that they are both safe and effective for conditions such as anxiety, sleep problems, and pain.
The purpose of this article is to examine the evidence relating to the safety and therapeutic benefit of CBD for pediatric patients, and to offer suggestions how pediatricians should respond to queries from parents regarding its use.
Cannabis: CBD and THC content
Cannabis contains over 100 different chemicals identified as cannabinoids. The major psychoactive component in cannabis is delta-9-tetrahydrocannabinol (THC), which produces euphoria, changes in perception and mood, as well as an increase in appetite. In contrast, CBD alone produces sedation, without the psychoactive effects associated with THC.1
Marijuana consists of the dried flowers, leaves, and stems of the female cannabis plant and contains between 3% to 20% THC. Different subspecies of cannabis contain different ratios of THC to CBD, with the highest ratios in Cannabis sativa and the lowest in Cannabis indica.2 “Hemp” is a term used to classify varieties of cannabis with 0.3% or less of THC and is the source of most CBD products available commercially. Cannabidiol is sold for inhalation by smoking or vaping; ingestion via a spray, pill, oil, or tincture; as a CBD-infused edible; or to be used topically as a cream or balm.
Delta-9-tetrahydrocannabinol exerts its effects by binding to 2 cell membrane receptors called the cannabinoid type 1 (CB1) receptor and type 2 (CB2) receptor. Cannabinoid type 1 receptors are mainly concentrated in brain tissues and CB2 receptors are found in immune and hematopoietic cells. Through its effects on these receptors, THC affects pain, perception, anxiety, learning, memory, and motor control.
In contrast, CBD has no effect on CB1 and CB2 receptors and exerts its sedative activity by affecting numerous other neurotransmitters. It also has been demonstrated to reduce the euphoric effects of THC by inhibiting its effects on the CB1 and CB2 receptors and modulating the metabolism of THC.2
To date, the US Food and Drug Administration (FDA) has approved only one CBD medication, Epidiolex, for treatment of refractory seizures in patients aged 2 years and older with Lennox-Gastaut syndrome or Dravet syndrome. Epidiolex, approved just last year, is synthetic CBD and contains no THC. Extensive clinical trials with this drug have been conducted and results provide significant insight regarding its benefits and adverse effects.3,4 More on this in a moment.
Medical cannabinoids in pediatric patients
Wong and Wilens published a systematic review of medical cannabinoids in pediatric patients in 2017. Of 2743 citations examined to identify the evidence base of cannabinoids for children and adolescent patients, they identified 22 studies meeting inclusion criteria. They found sufficient evidence that THC-derived products are effective for chemotherapy-induced nausea as well as CBD for epilepsy. They also reported insufficient evidence for cannabinoids for spasticity, Tourette syndrome, neuropathic pain, and posttraumatic stress disorder. They advocated for further research regarding CBD and THC, given that recreational cannabis has potential psychiatric and neurocognitive adverse effects, including lower intelligence quotient scores, deficits in memory, psychomotor performance, and attention.5
CBD and the marketplace
In spite of warnings issued by the FDA (see “Current status of FDA-approved cannabis or cannabis-derived compounds”), many Americans are using CBD, convinced that it is effective for anxiety, pain, and sleep problems. It is even being used for cancer treatment, arthritis, and mood disorders, in place of or in addition to prescribed medications. It is no surprise that CBD is growing in popularity, as 22% of adolescents and young adults use marijuana regularly and 22 million Americans use marijuana at least once per month.6,7
Cannabidiol is poised to be a multibillion- dollar industry in the United States over the next few years. What is most disconcerting is that many online sellers are promoting the use of CBD-infused gummies to calm overactive and “fussy” children and CBD-infused oils are now being sold as a teething remedy for infants. We don’t know how many children receive CBD on a regular or sporadic basis.
A recent Harris Poll survey of 2000 Americans indicated that 7% of those surveyed use CBD regularly.8 Another survey of over 4000 CBD users performed by Consumer Reports revealed some interesting findings9:
· 26% of those surveyed have tried CBD at least once in the past 2 years.
· 14% use it daily.
· 47% used CBD preparations to replace over-the-counter medications.
· 30% used it to supplement their regular medications.
· 22% used CBD to replace their medications entirely.
The same survey9 also found that 37% reported using CBD for relaxation or stress/anxiety reduction, 24% for joint pain, 11% for recreation, and 10% as a sleep aid. In addition, 40% of users obtained CBD from cannabis dispensaries, 34% from retail stores, and 27% from online sellers with the remainder from unspecified outlets. The most popular forms were infused edibles (35%), drops or sprays (30%), and vaping devices (30%).
What the Epidiolex trials reveal
In controlled trials, Epidiolex was administered to pediatric patients aged 2 years and older with Lennox-Gastaut syndrome or Dravet syndrome in a dosage range of 5 to 20 mg/kg/day. The drug reduced the frequency of seizures by 36% to 41% compared with a reduction of 14% to 16% seen in patients receiving placebo. According to the package insert, adverse effects seen in at least 10% of Epidiolex-treated patients included elevated liver enzymes, somnolence, decreased appetite, diarrhea, fatigue, sleep problems, and malaise. An increase in suicidal ideation was also seen.
The trials also showed that Epidiolex interfered with the metabolism of many drugs including propofol, bupropion, morphine, clobazam, lorazepam, and phenytoin.3,4 The incidence of dose-related liver transaminase elevations were seen in 13% of patients treated with Epidiolex compared with 1% in placebo-treated patients, and extreme elevations were much more common in patients taking other seizure medications. The package insert for Epidiolex cautions that bilirubin levels and liver function tests should be obtained prior to starting treatment, and at 1 month, 3 months, and 6 months, as well as at 1 month following a dosage change.
The Epidiolex trials provide evidence that CBD in appropriate dosages can be effective for refractory seizures in children with either Lennox-Gastaut syndrome or Dravet syndrome. Epidiolex may prove to be a useful antiepileptic drug for refractory seizures in other conditions as well. However, Epidiolex’s adverse effect profile is significant, and although some trials were as long as 2 years, the long-term effects of Epidiolex are not known.
What’s in CBD products: A cautionary tale
Most CBD sold to consumers is hemp derived and contains small quantities of THC, usually less than 0.3%. However, depending on the strain used to prepare the product, some CBD preparations will contain a higher content of THC, of the order of 1.5% to 3%.
In researching this article, I made some interesting observations relating to commercial CBD products. Many CBD products are labeled with claimed health benefits including reducing pain, facilitating sleep, and reducing stress and anxiety. Many also display that they are preservative free and rich in vitamins. Online shops that cater to CBD users usually contain more information regarding the CBD content and many display the chemical analysis of the hemp used to manufacture the product, displaying the CBD and THC percentages by weight.
OTHER INTERESTING OBSERVATIONS:
· CBD gummies contain from 25 mg to 50 mg CBD per candy, so it would only take a few gummies per day to reach the dosages associated with Epidiolex use that produce the adverse effects listed above-and no one tests children or adults using CBD regularly for liver enzyme elevations!
· An interesting study was published 2 years ago in which researchers analyzed purchased CBD products from shops and online sellers, finding that many were labeled incorrectly.10
· Between 2017 and 2018, Utah reported 52 cases of poisoning from ingestion of CBD oil that produced symptoms that included hallucinations, nausea, vomiting, seizures, and loss of consciousness.11
· Last year, there were 518 CBD poisonings reported by the American Association of Poison Control Centers, and as of May 31 of this year there have been 492 poisonings reported.
What to tell parents: one pediatrician’s perspective
As you can see from the previous discussion, CBD has only been shown to be an effective therapy for refractory seizures associated with 2 uncommon medical conditions. For the duration of the trials, CBD was well tolerated but adverse effects were frequent. Cannabidiol has not been studied adequately via randomized clinical trials for medical problems for which CBD distributors claim significant benefit, including anxiety, attention-deficit/hyperactivity disorder (ADHD), pain, inflammation, and sleep disorders. Although many individuals report symptomatic improvement from CBD, only randomized controlled trials can exclude the placebo effect as being responsible for the results observed by consumers.12
Marijuana’s former Schedule I status hampered research regarding cannabinoids. Currently, there are now more than 100 ongoing clinical trials regarding the use of CBD products for conditions that include refractory seizures, anxiety, and cannabis abuse disorder (clinicaltrials.gov; key word: cannabidiol). In the near future, we will have more clinical data upon which to base our advice. Meanwhile, the FDA and many states are at odds regarding the legality of CBD products, so for the time being individuals can buy and vendors can sell products without fear of prosecution. (See “Current status of FDA-approved cannabis or cannabis-derived compounds”)
I would encourage pediatricians to ask parents if they are using CBD to treat their children for autism, anxiety, or ADHD. In my experience, many adolescents do not acknowledge using marijuana, but according to the statistics above, 1 in 5 do. If parents are giving CBD in addition to prescribed medication, this situation may complicate and confound treatment. Parents of children with ADHD who are not responding optimally to their prescribed medications may be tempted to medicate or supplement with CBD as it is inexpensive and universally available. So, too, with aggressive children with autism who are not doing well on prescribed medications. (See “CBD and autism”)
In my opinion, it would be inappropriate and irresponsible for pediatricians to encourage the use of CBD until more studies are available, particularly regarding its long-term safety, and it is endorsed for specific conditions by the FDA.
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2. Campbell CT, Phillips MS, Manasco K. Cannabinoids in Pediatrics. J Pediatr Pharmacol Ther. 2017;22(3):176-185.
3. Devinsky O, Patel AD, Cross JH, et al. Effect of cannabidiol on drop seizures in the Lennox-Gastaut syndrome. N Engl J Med. 2018;378(20):1888-1897.
4. Chen JW, Borgelt LM, Blackmer AB. Cannabidiol: A new hope for patients with Dravet or Lennox-Gastaut syndromes. Ann Pharmacother. 2019;53(6):603-611.
5. Wong SS, Wilens TE. Medical cannabinoids in children and adolescents: a systematic review. Pediatrics. 2017;140(5):e20171818.
6. Johnston LD, Miech RA, O’Malley PM, Bachman JG, Schulenberg JE, Patrick ME. Monitoring the Future: National Survey Results on Drug Use 1975-2017. Overview: Key Findings on Adolescent Drug Use. Ann Arbor, MI: Institute for Social Research, University of Michigan; 2018.
7. Substance Abuse and Mental Health Services Administration (SAMHSA); Center for Behavioral Health Statistics and Quality (CBHSQ). Results from the 2015 National Survey on Drug Use and Health: Detailed Tables. Available at: http://www.samhsa.gov/data/sites/default/files/NSDUH-DetTabs-2015/NSDUH-DetTabs-2015/NSDUH-DetTabs-2015.htm. Accessed August 14, 2019.
8. Kopft D, Avins J. Harris Poll: New data show Americans are turning to CBD as a cure-all for the modern condition. Available at: https://theharrispoll.com/new-data-show-americans-are-turning-to-cbd-as-a-cure-all-for-the-modern-condition/. Accessed August 14, 2019.
9. Gill LL. CBD goes mainstream. Consumer Reports. April 11, 2019. Available at: https://www.consumerreports.org/cbd/cbd-goes-mainstream/. Accessed August 14, 2019.
10. 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.
11. Horth RZ, Crouch B, Horowitz BZ, et al. Notes from the Field: Acute poisonings from a synthetic cannabinoid sold as cannabidiol-Utah, 2017-2018. MMWR Morb Mortal Wkly Rep. 2018;67(20):587-588.
12. Colloca L. Preface: the fascinating mechanisms and implications of the placebo effect. Int Rev Neurobiol. 2018;138:xv-xx.