Knupp KG, Rice JD, Helmkamp LJ, Galinkin J, Sempio C, Jost
K, Chapman KE. Prospective evaluation of oral cannabis extracts in children
with epilepsy. Seizure. 2019 Nov;72:23-27.
Abstract
PURPOSE:
Interest in the use of artisanal cannabinoids in pediatric
epilepsy has increased but safety and utility data are lacking. Our aim was to
prospectively characterize the use of oral cannabis extracts (OCE) in a
refractory pediatric epilepsy population.
METHODS:
Families considering the use of an OCE were enrolled in a
prospective observational study. Baseline seizure frequency was assessed over a
period of 4 weeks. Seizure frequency, CBD and THC-COOH levels were assessed
every 4 weeks during a 12-week treatment period. Response was defined as at
least a 50% reduction in seizure frequency over the final 8 weeks of the study
relative to baseline.
RESULTS:
Consent was obtained in 32 children; 11 were excluded from
analysis (3 failed to complete baseline data, 3 started OCE before completing
baseline period and 5 did not start OCE) leaving 21 to be included in
subsequent analyses. Median age was 10.3 years (IQR 6.8-12.6), 13 (62%) were
male and median seizure frequency was 2.7 seizures/day during the baseline
period. The median of the high dose of CBD that was administered during the
observation period was of 0.9 (0.6-2.2) mg/kg/day. Of the 21 subjects who were
included in the analysis, 5 (24%) were responders. OCE was stopped early in 3
subjects (14%) due to a perceived increase in seizures. THC-COOH and CBD blood
levels did not have a significant association with response status (p = 0.95
CBD, p = 0.53 THC-COOH, N = 14).
CONCLUSION:
The observed response rate in this study is similar to
placebo rates in prospective randomized trials of pharmaceutical grade products
and the withdrawal rate is greater than rates obtained with retrospective
methods. Doses of OCE administered were lower than doses used in randomized
trials.
Mitelpunkt A, Kramer U, Hausman Kedem M, Zilbershot Fink E,
Orbach R, Chernuha V, Fattal-Valevski A, Deutsch L, Heffetz D, Sacks H. The
safety, tolerability, and effectiveness of PTL-101, an oral cannabidiol
formulation, in pediatric intractable epilepsy: A phase II, open-label, single-center
study. Epilepsy Behav. 2019 Sep;98(Pt A):233-237.
Abstract
INTRODUCTION:
Several works have reported on the antiepileptic impact of cannabis-based
preparations in patients with treatment-resistant epilepsy (TRE). However,
current formulations suffer from low bioavailability and side effects. PTL-101,
an oral formulation containing highly purified cannabidiol (CBD) embedded in
seamless gelatin matrix beadlets was designed to enhance bioavailability and
maintain a constant gastrointestinal transit time.
METHODS:
This phase II, prospective study was open to pediatric
patients with TRE on stable antiepileptic drugs' (AEDs) doses, who experienced
≥4 seizures within four weeks of enrolment and with a history of ≥4 AEDs
failing to provide seizure control. Following a 4-week observation period,
patients began a 2-week dose-titration phase (up to ≤25mg/kg or 450mg, the
lower of the two), followed by a 10-week maintenance treatment period.
Caregivers recorded seizure frequency, type, and severity and ranked their
global impressions after 7 and 12weeks of treatment. Responders were those
showing a ≥50% reduction from baseline monthly seizure frequency. Safety
assessments monitored vital signs, adverse effects, physical and neurological
exams, and laboratory tests.
RESULTS:
Sixteen patients (age: 9.1±3.4) enrolled in the study; 11
completed the full treatment program. The average maintenance dose was
13.6±4.2mg/kg. Patient adherence to treatment regimens was 96.3±9.9%. By the
end of the treatment period, 81.9% and 73.4±24.6% (p<0.05) reductions from
baseline median seizure count and monthly seizure frequency, respectively, were
recorded. Responders' rate was 56%; two patients became fully seizure-free. By
study end, 8 (73%) caregivers reported an improved/very much improved
condition, and 9 (82%) reported reduced/very much reduced seizure severity.
Most commonly reported treatment-related adverse effects were sleep
disturbance/insomnia, (4 (25.0%) patients), followed by somnolence, increased
seizure frequency, and restlessness (3 patients each (18.8%)). None were
serious or severe, and all resolved.
CONCLUSIONS:
PTL-101 was safe and tolerable for use and demonstrated a
potent seizure-reducing effect among pediatric patients with TRE.
____________________________________________________________________
Just how confident are pediatric neurologists about
prescribing the use of cannabidiol (CBD) for young patients with severe
epilepsy syndromes? Answers from a session at the annual meeting of the Child
Neurology Society earlier this year suggest the answer is not clear-cut.
Pediatric neurologists on the panel and in the audience said
they are still largely confronted with a “Wild West” environment when it comes
to deciphering how to proceed with requests for CBD from their patients and
families—especially in light of the tangle of federal and state regulations
that govern the use and legality of marijuana-related products.
But there was consensus on this point: Emerging data on one
such product, the cannabidiol product known as Epidiolex in epilepsy and the
explosion of “artisanal” CBD products—from CBD oils to truffles to balm that are
grown and sold without FDA regulation—has led to rampant interest from
neurology patients and the general public.
“Everyone has encountered patients asking about CBD,
thinking it can help with anything and everything that ails them,” said Kathryn
McVicar, MD, assistant professor of clinical pediatrics in neurology at Yale
University and the moderator of the session.
“We really need to understand what these preparations
entail,” she said. Legal cannabis, she said, is huge business—constituting
$12.2 billion in consumer spending around the world in 2018 and projected to be
$31.3 billion in 2022.
The Legal Issues
Bennett L. Lavenstein, MD, FAAN, chair of the legislative
affairs committee of the Child Neurology Society, recounted the ongoing
perplexity involving cannabis in US marijuana has been classified as a Schedule
I substance, along with heroin and other drugs, but 33 states allow medical
marijuana use for qualifying patients.
“According to federal law, any level of state legislation is
still illegal under federal law he noted and therein lies the conundrum,” he
said.
The 2018 Farm Bill removed hemp and all its derivatives with
less than 0.3 percent tetrahydrocannabinol (THC) concentration—the psychoactive
compound in cannabis—from the Controlled Substances Act, effectively legalizing
hemp cultivation, sale, transport and possession of hemp-derived products as a
high regulated crop. But any cannabis product marketed with a claim of
therapeutic benefit must be approved by the US Food and Drug Administration
(FDA) for its intended use before being sold in interstate commerce.
A comprehensive review by the National Academies of Science
and the National Academy of Science Engineering and Medicine found that
marijuana had various degrees of effectiveness for several conditions but was
specifically effective for chronic pain in cancer, chemotherapy-induced nausea,
and alleviation of some symptoms of multiple sclerosis. But it reported limited
or no effectiveness in other conditions.
In August 2019, the US Surgeon General issued an advisory on
known and potential harms for the developing brain. Published literature
reports potential risks of fetal growth restriction, low birth weight, pre-term
birth, neonatal intensive care admission and stillbirth.
Clinical research—and therefore FDA approval of—
cannabis-related products has been slow largely because research requires
registering with the Drug Enforcement Agency and getting cannabis from the
National Institute on Drug Abuse (NIDA), which comes from just one grower, the
University of Mississippi. But the FDA doesn't object to the clinical
investigation of cannabis for medical use, Dr. Lavenstein said. Other potential
growers have applications pending.
Patients can potentially get access to cannabis or
cannabis-related products through expanded access in serious or
life-threatening cases. Another possible option outside of conventional avenues
is Right to Try, a federal act designed to help with access to certain
investigational drugs, for those with life-threatening illnesses who have tried
all other medical options and are not able to enter a clinical trial. These
decisions don't involve the FDA.
Frustration has been building over the lack of oversight of
CBD. In July, a group from the American Epilepsy Society presented written
comments to the FDA, authored by the Council on Clinical Activities, Dr.
Lavenstein noted. Those comments were published in Epilepsy Currents in
October, suggesting that CBD and cannabis-derived compounds be viewed as drugs
as defined by the FDA. This would place CBD and cannabis-derived compounds
under the full regulatory control of the FDA and would lead to an appropriate
path forward, with all the associated scientific data, safeguards, warnings,
marketing and labeling, he said.
What the FDA Approval Means
The FDA-approved cannabidiol-based drug, which became
available for use in October of 2018, was a welcome development, said Amy R.
Brooks-Kayal, MD, FAAN, chief of pediatric neurology at the University of
Colorado, who works in a state where poorly regulated artisanal CBD products
were widely used.
“The FDA approval really got rid of issues that we saw with
variation in strains and in potency,” she said. “Variations in purity were a
major issue for us—and complete lack of information, often, on the specific
concentrations, how to dose, interactions, efficacy and safety.... This was a
real advance for those of us that had been managing those things.”
The cannabidiol product, Epidiolex, is highly purified and
meets FDA standards of consistent concentrations and lack of contaminants, with
a regulated manufacturing process. Being available by prescription, and
eligible for prescription coverage, has been helpful to families who have been
covering the big expense of artisanal products.
CBD has produced significantly greater seizure-reduction
rates in Dravet syndrome and Lennox-Gastaut patients compared to placebo, but
adverse event rates—most commonly gastrointestinal effects and fatigue—are seen
in a lot of patients, Dr. Brooks-Kayal said. These effects usually didn't
require patients to leave the trials, she pointed out.
Greenwich Biosciences, which developed Epidiolex, recently
announced in a release that researchers saw a reduction in seizure-frequency
compared to baseline compared to placebo in tuberous sclerosis patients, but
publication of the data is pending.
Doses of first 5 mg per kg per day, then increased to 10 mg
per kg per day, tend to give maximal efficacy, with higher doses possible if
done “judiciously,” Dr. Brooks-Kayal said.
She cautioned, however, that CBD can have significant drug
interactions with some CYP enzyme inhibitors and it also increases sedation
with clobazam dosing.
“You may well need to adjust clobazam dosing if you're
adding Epidiolex to a patient who is already receiving clobazam,” she said. But
there are also data suggesting a synergistic effect with clobazam, “so it may
be that that's really a great combination to use if carefully monitored.”
Questions Remain
Neurologists are learning more and more about Epidiolex but
important questions are still unanswered, she said, including medications it
will work with best.
“What we really don't know—and continues to keep many of us
up at night—are what are the long-term development and cognitive effects of
cannabidiol, and specifically Epidiolex over time? And that is something that
will require continued study.”
In the world of artisanal CBD products, confusion still
reigns, said Anup D. Patel, MD, FAAN, chief of pediatric neurology at
Nationwide Children's Hospital. “There is no monitoring of these ‘street-based’
[artisanal] products and little data on their efficacy and long-term risks,”
Dr. Patel said. Even though these artisanal products are often thought of as
“natural,” that's a misleading label, he said, much as St. John's Wort came to
be found to cause serious interactions with prescription drugs.
CBD products are not legally allowed to make medical
claims—and FDA testing of them has found that half contained no cannabinoids
and others had less CBD content, or higher THC content, or both, than what was
on the label, Dr. Patel said. Still, the general public has been trusting of
the products.
A study in Colorado looking prospectively at families who
were considering oral cannabis extracts to treat seizures, following them for
12 weeks, saw an observed response rate of 24 percent, with 14 percent stopping
use of the products because of an increase in seizures. The median age of the
21 patients was 10 years old. Concentrations were labeled in just nine of the
cases and eight used products without concentration information available. The
other four used a combination of products that had labeled and unlabeled
concentrations.
“What that says is that parents were willing to give their
children a product without actually knowing what was in it—nor was there
advertising of what was in it,” Dr. Patel said.
An oral CBD formulation called PTL101—manufactured with a
proprietary gelatin matrix made with a natural and digestible polymer soluble
at body temperature—includes CBD derived from a highly purified extract that is
more than 93 percent CBD and less than 0.2 percent THC. At an initial dose of
50 mg up to a maximum of 25 mg/kg per day or 450 mg, whichever was lower,
patients had an average 73 percent reduction in monthly seizure frequency. But
five of the initial 16 patients withdrew, two because of worsening seizures and
one, due to mild adverse events. The most common effects were nervousness and
sleep disturbances, each reported by four patients, as well as sleepiness and
increased epileptic seizures.
Another study, STAR 1—in which 188 patients were randomized
to a CBD transdermal gel or placebo, with 174 completing the trial—found no
statistically significant reduction in monthly seizure frequency, with a high
rate of placebo response.
Dr. Patel said it's important to remember that the products
are grossly understudied, so claims made about them are mostly not backed by
data.
“They will tell you—you will hear this from your
families—there's no side effects to these products, and there's side effects to
the FDA-approved product Epidiolex,” he said. “The absence of side effects is
only because those were not tested in these products, so therefore you can't
say they're without.
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