Medicinal Cannabis in Pediatrics

Medicinal cannabis remains a controversial topic (despite its legalization in 36 US states)—a result of the want for clinical studies proving efficacy and detailing risk. Cannabis use in pediatrics is bathed in greater controversy—a result of even fewer clinical studies.1 And while the image of a child consuming cannabis could make the staunchest cannabis advocate uneasy, it should be remembered that the first FDA-approved cannabis-based drug was for children.2 That drug, Epidiolex, is an oral CBD solution approved in 2018 for patients aged 2 and older for the treatment of Lennox-Gastaut syndrome and Dravet syndrome, two rare and severe forms of epilepsy. Although research is woefully scant and risks should be considered, medicinal cannabis may benefit other pediatric disorders.

Potential Risks of Cannabis Use in Pediatrics
The risks associated with cannabis use have been studied predominantly by evaluating recreational use in adolescents older than 10. These risks—mainly decreased motivation, addiction, mild cognitive decline, and schizophrenia—are increased with earlier onset of use, higher frequency, and greater dosage. However, risks haven’t been studied in clinical trials related to medicinal cannabis in children. Elevated risk may also be related to a higher THC to CBD concentration.3 This is likely due to the direct binding of THC to CB1 and CB2 receptors in the central nervous system, which is credited with the intoxicating effects of cannabis.

Longitudinal follow-up studies of children receiving pure CBD showed high tolerability and safety.4,5 Based on animal studies, the use of CBD during early development appears to be safe; however, THC showed the propensity to impair brain function and structure.6 “The large observational studies that we’ve been able to do in pediatrics are focused on recreation use in adolescents and show an association with negative outcomes later in life. These outcomes are mainly problems with impulse control and the development of social skills,” says Codi Peterson, PharmD, a pediatric pharmacist.

Concerning the effects of cannabis on the developing brain, pediatricians should consider the influence on the endocannabinoid system (ECS), which, Peterson says, “is critical to neurological development, brain growth, and, in the later pediatric years, aids in neurological pruning.” He goes on to explain that frequent and high doses of THC during youth can overload the ECS and downregulate the endogenous ECS. “Because the brain is still developing, you could potentially be solidifying this downregulation of the [ECS].”

The main takeaway is a difference in dosage. “The potential harms of recreational cannabis are not necessarily the same that we would see with a lower dose that is medically supplied,” Peterson says. This isn’t an issue unique to cannabis. Finding the correct doses of many medications is complicated by a lack of pharmacokinetic studies in children.7 Indeed most pediatric doses are extrapolated from adult studies and based on a child’s age and weight. Despite a lack of clear data regarding risk, parents are using cannabis to treat their children. “If you look at surveys, people are self-treating with cannabis and they’re not telling their providers because, first of all, their providers may not endorse it, and second of all, their provider wouldn’t know how to advise them,” says Jill Simonian, PharmD, course chair for “Medical Cannabis Science and Pharmacology” at Skaggs School of Pharmacy and Pharmaceutical Sciences. There’s no doubt more research is necessary, but the rapidly growing use of medicinal cannabis is forcing providers to play catch up, to do their best to measure risks vs rewards.

Potential Uses of Medicinal Cannabis in Pediatrics
Medicinal cannabis for pediatrics has focused predominantly on epilepsy, chemo-induced nausea and vomiting, autism spectrum disorder (ASD), attention deficit disorder, and neurological disorders such as cerebral palsy.8

The FDA has approved four cannabis- related drugs—Epidiolex, Marinol and Syndros (dronabinol), and Cesamet. Dronabinol is a synthetic THC use to treat chemo-related nausea and anorexia associated with weight loss in AIDS patients. Cesamet includes the active ingredient nabilone, which also mimics THC and is approved for the treatment of chemo-induced nausea and vomiting.9 Additionally, nabiximols (Sativex) is a plant-derived cannabis product undergoing FDA-regulated clinical trials. Sativex is used as an add-on therapy to treat spasticity in patients with multiple sclerosis (MS) and is available in most European countries and Canada.10

FDA trials are also underway investigating CBD oral solutions. One such study sponsored by GW Research Ltd is a phase 2 exploratory trial investigating the and efficacy of a strawberry-flavored CBD oral solution (Epidiolex) in children and adolescents with ASD.11

According to one systematic review, cannabis for epilepsy has been studied more than all other pediatric conditions combined, with studies suggesting CBD has greater efficacy than THC. An open-label trial showed that CBD reduced seizure frequency in child-onset, treatment-resistant epilepsies by 37% over a 12-month period.12

For the treatment of chemo-related nausea and vomiting, THC (or a synthetic THC) seems to be an active component of treatment,8 with dronabinol showing efficacy in children. For the treatment of nausea and vomiting, the recommended pediatric dosage is the same as the adult dosage, whereas caution is recommended regarding the use of nabilone in children due to a lack of safety guidelines and effectiveness. “Cannabis has an established role in alleviating chemo-related nausea,” Peterson says.

There’s growing interest in the use of cannabis for ASD. According to Peterson, “I’ve consulted parents who are using cannabis with their children with ASD and have reached out for advisement. The consensus is that children with ASD respond better to full-spectrum cannabis products. According to Peterson, anecdotal evidence shows that some children exhibit improved socialization; in some cases, verbal communication is reported in previously nonverbal children.” However, he notes the need for clinical studies.

Interest in medicinal cannabis for ASD comes from both anecdotal evidence and studies (animal, in vitro, and in vivo) that show a relationship between dysregulation of the ECS and ASD.13,14 This dysregulation seems to have neuroinflammatory and immunoinflammatory consequences. The influence of cannabis on neuroimmune function and neuroinflammation also is a likely regulator of other metabolic and cellular pathways involved in ASD, such as food intake, energy metabolism, and control of the immune system. However, there are still potential risks when using THC. Animal models have indicated the potential for brain dysfunction and memory impairment when cannabis is abused. CBD seems generally safe and shows several positive therapeutic activities, such as neuroprotection, immunomodulation, and antioxidative and anti-inflammatory properties.14

Peterson acknowledges these potential risks and focuses on individual cases and doses. “The lower the dose, the lower the risk for adverse effects,” he says, adding that a parent would typically give their child one dose of cannabis during a behavioral outbreak and wait 20 minutes to gauge the response. Clinicians are trying to weigh risks vs rewards, but research on the effects of medicinal doses is simply lacking. “The changes we see are resulting from recreational use and are not necessarily the same changes we would see in a lower dose medicinally supplied,” Peterson says.

There’s also an increasing interest in cannabis in the treatment of ADHD, although Peterson describes this research as less robust. A qualitative analysis of online forum discussions on the effects of cannabis on ADHD was performed to systematically characterize the information users may encounter regarding cannabis use for ADHD. The results indicated that 25% of posts reported cannabis as helpful for ADHD management. Eight percent believed it was harmful, 5% reported that it was both beneficial and harmful, and 2% believed it had no effect.15 “There’s just very little data on ADHD. I think some people try it, but I don’t think any provider would recommend it for that. Personally, I couldn’t recommend cannabis for ADHD,” Simonian says.

“The majority of spasticity we see in pediatrics involves cerebral palsy or other neurological conditions,” Peterson says, explaining that MS is usually diagnosed later in life. There’s little research regarding the use of cannabis for spasticity in pediatrics. A randomized controlled trial of 72 pediatric patients measured the efficacy of nabiximols to reduce spasticity in pediatric patients with cerebral palsy. The drug was deemed unsuccessful, as it didn’t significantly reduce spasticity.16 During the 12-week trial, nabiximols was well tolerated, although there were three reported cases of hallucinations and one suicide attempt. However, hope comes from adult studies that show that nabiximols decreased spasticity in MS patients.17

Treating Pediatric Patients
In all US states with legalized medicinal cannabis programs, use by minors is legal with consent from a legal guardian and certification from a physician. Laws vary slightly by state, with some requiring certification from a second physician. Only four states specifically require certification by a pediatrician.1

Treating pediatric patients is almost always more complicated than treating adults. In every pharmacological situation, the developing brain must be considered. With children, it’s not always as simple as weighing risks vs rewards; the risks may not be seen until later in life. However, the rewards may appear in the moment, and, for concerned parents, relief can be the holy grail.

“I think it’s important that we don’t bypass the medications that could treat a child’s condition, but if the child is refractory or if the treatment has severe side effects, I may recommend medicinal cannabis,” Peterson says.

Despite the lack of research, medicinal cannabis is appealing to patients who want to feel better and parents who believe the current drug market isn’t meeting their needs. How drugs are studied matters, and the majority of studies regarding cannabis have focused on potential harm rather than potential benefit. Hence, there’s an inherent bias regarding cannabis use in pediatrics based on what’s been studied.

“We use medicines that aren’t studied in pediatrics all the time, and these medications have very real side effects, but we use them because they’ve been approved,” says Peterson, who also addresses the difficulty in recommending cannabis. “We don’t have control over how much cannabis will be administered or what strain will be used,” he says. But Peterson isn’t concerned about cannabis having greater toxicity than other drugs that are prescribed to children. “We give selective serotonin reuptake inhibitors to children, and those come with a warning that they increase suicidality. We give benzodiazepines to children for anxiety. Frankly, we’re in a difficult situation where we steer away from cannabis because of unknown risks, but we prescribe other medications—simply because we know the risks,” he says.

Peterson and Simonian agree that cannabis wouldn’t be the first treatment option they’d recommend. However, parents often request it. Second to treating seizures, cannabis is most widely accepted to alleviate nausea and vomiting related to chemotherapy. In five randomized controlled trials of children receiving chemotherapy, THC-based treatment was more effective in treating nausea and vomiting than were prochloperazine, metoclopramide, and domperidone. The predominant side effects were limited to dizziness and drowsiness.8 “I would say if a child is on a high medic type of chemotherapy, that they might want to try a small amount of THC,” Simonian says.

In many cases, the best thing a provider can do is encourage open dialogue with the parent and be as informed as possible. Children will fare better using cannabis under an informed physician’s care than they will on use based on social media recommendations.

Dosage, Contraindications, and Side Effects
As is true with adults, THC to CBD ratio, route of administration, strain, and amount are all factors that should be taken into consideration. “For medicinal use, the doses are small, maybe 0.5 mg to 1 mg or maybe 5 mg,” Simonian says. Those doses will differ depending on the individual response—another challenge of recommending cannabis.

Peterson explains that the majority or parents are gravitating toward full-spectrum cannabis products, using the whole plants. Monitoring the ratio of CBD to THC is an important factor when making this decision, which depends on what the product is being used for.

Because of the effects of cannabis on the central nervous system, it isn’t recommended for people with a family history of psychosis, although this, too, is a conclusion based on what is known about recreational use. The most common side effects of medicinal cannabis are fatigue and lethargy.18

Finally, cannabis shouldn’t be used in place of potentially life-saving treatments. Peterson notes that some parents prefer cannabis to chemotherapy—a choice he doesn’t recommend. As an adjunct therapy to treat nausea, cannabis can be helpful, but it shouldn’t be seen as a cure for cancer.

It’s difficult to “do no harm” when doing nothing can be the most harmful approach. Providers can work with parents to keep them informed on best safety practices, new research, and complementary treatment options. Cannabis may not be a first-line treatment, but it’s surely part of the line-up, and its usage is likely to increase.

— Jennifer Lutz is a freelance journalist who covers health, politics, and travel. She’s written for both consumer and professional medical magazines as well as popular newspapers. Her writing can be found in Practical Pain Management, Endocrine Web, Psycom Pro, The Guardian, New York Daily News, Thrive Global, BuzzFeed, and The Local Spain. In addition to journalism, Lutz works as a strategies and communication consultant for nonprofits focused on improving community health.

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