A raft of new study results on medical marijuana are promising, but the message from investigators was loud and clear: No real progress can be made in verifying the safety and efficacy of this treatment until randomized controlled trials are carried out. Such trials are about to get under way early next year.
Meanwhile, though, the results of case reports, surveys and noncontrolled open-label trials presented here at the at the recent American Epilepsy Society (AES) 68th Annual Meeting, suggest that extracts containing cannabinoid (CBD), the element of the marijuana plant believed to reduce seizures, can be effective in some patients.
This appears especially true for children with relatively rare disorders, such as infantile spasms, Lennox-Gastaut syndrome (LGS) and Dravet syndrome. And these products appear to be well tolerated.
One study was based on an anonymous online survey of parents from various locales, including California and Colorado, who were administering CBD-rich extracts to their children. Of the 117 respondents who had been giving a CBD extract for a median of 6.8 months, 53 of the children had infantile spasms or LGS. The others had Dravet syndrome or other epilepsy types.
Most of the children had experienced seizures for many years and had not responded to eight antiepileptic drugs (AEDs) before their parents tried medical marijuana.
It’s not clear what’s in the cannabis extracts that parents give their children, said study researcher Shaun Hussain, MD, pediatric neurologist, UCLA Medical Center. “Even among our highly select responder population, less than half could tell us how many milligrams of CBD their child was receiving each day; as a practitioner that’s frightening.”
Of the families that knew and revealed doses, many reported giving their child about 4 mg/kg CBD per day, which, Dr Hussain pointed out, is quite a bit lower than that proposed for clinical trials.
The study found that of the 53 patients with infantile spasms or LGS, 92% had seizure reduction and 13% had seizure freedom. The only adverse effect reported more often after initiation of CBD was increased appetite. Many patients had improved sleep (53%), alertness (71%), and mood (63%).
Although these survey results “are nothing to scoff at,” they’re not evidence of efficacy, stressed Dr Hussein. These parents are “truly desperate,” he said. “They’re highly invested in finding something that will work, something that will stop the seizures, something that will prevent mental retardation, something that will prevent enduring catastrophic epilepsy.”
So do the positive survey results merely indicate a placebo effect? That was a question researchers in Colorado, a state where medical marijuana as well as recreational marijuana is legalized, are asking themselves. Their retrospective chart review of 75 children receiving various forms of medical marijuana showed that seizures were reduced by half in about a third of patients, but this response rate was almost triple in children who had moved to Colorado to get the treatment than those already living in state (16 vs 9 patients).
One of the researchers on this project, Kevin Chapman, MD, associate professor, pediatrics and neurology, University of Colorado, Denver, said this may be due to a bias by families “really wanting for it to work.”
About 13% of parents reported worsening of seizures while their child was on a medical marijuana product. But even some of these families opted to keep their child on the extract, said Dr Chapman.
“Families seemed to find that it helped in other areas. Some reported that their children are more alert, may be sleeping better, may have improved appetite, et cetera.”
However, as Dr Chapman noted, he and his colleagues were unable to tease out what strain of cannabis worked best. This, he said, underscores the need for a controlled trial that uses “a uniform strain or preparation.”
But whatever the strain, CBD may interact with AEDs patients are already taking. This became apparent in a case report from researchers at Children’s Hospital of San Diego, California, a state where recreational marijuana is not legal and medical marijuana “exists in a bit of a nebulous state,” according to Jeffrey Gold, MD, PhD, Rady Children’s Hospital, San Diego.
The case involved a boy with Doose syndrome, a refractory generalized idiopathic epilepsy syndrome in which children, normally boys 2 to 5 years of age, develop myoclonic and astatic types of seizures, which can lead to learning problems and profound developmental delays.
The boy began receiving levetiracetam and later switched to valproate acid, with good initial response until his seizures returned. Video electroencephalography (EEG) indicated that the boy was at risk for progression of the syndrome, at which point the family chose to pursue CBD, said Dr Gold.
Tests showed elevated levels of valproate acid in the child’s blood, suggesting that the CBD was interfering with the clearance of this drug. After valproate levels were lowered, the parents reported that their son had become seizure-free over about 4 months. Another EEG verified that the boy “was completely normal — honestly to our surprise,” said Dr Gold.
Although resolution of seizures and normalization of EEG have been reported before in Doose syndrome, and this can happen spontaneously or as a result of medication change, “it was very interesting that it happened shortly after the CBD was used, and then the valproate acid was normalized,” noted Dr. Gold.
And it’s not just AEDs that may interact with CBD. Many of these children are receiving multiple other medications, including, for example, blood pressure and cholesterol medications and treatments for various metabolic disorders.
Dr Gold stressed that if families choose to start CBD, “we strongly advocate that they share that information with their physician and that the physician manage the other antiseizure medication the child is receiving.”
But not all parents are willing to admit to giving their child CBD. They’re concerned about the legal, social, and other ramifications. Dr Gold has heard stories of patients being told not to come back to the doctor’s office after revealing that they were treating their child with “a nonapproved therapy.”
“We don’t support that; we want families to feel like they can share their treatment with their physician because we don’t know what that treatment might be doing to other treatments the child might be receiving, and it’s imperative that families stay in contact with their physician,” said Dr Gold.
The effect of adding CBD to AEDs was also investigated in an observational study of patients enrolled in an expanded access compassionate use of CBD program. These patients were taking a purified 98% oil-based CBD extract (Epidiolex, GW Pharmaceuticals) in addition to their baseline AEDs.
Researchers carried out blood tests at baseline and every 4 weeks for 12 weeks after addition of CBD. They also tested serum levels of this clobazam’s active metabolite (NDMC) in a subset of patients taking this drug.
Blood tests in 57 patients (median age, 12 years) showed that they were taking 10 to 20 mg/kg of Epidiolex per day. Almost 44% were also receiving clobazam and about a third (33.3%) were receiving valproate acid.
“Patients were on a background regimen of at least one to four medications in addition to CBD,” noted researcher Daniel Friedman, MD, assistant professor, New York University School of Medicine.
Blood level changes from baseline to 1 month were variable following the addition of CBD. Some patients experienced decreases while others experienced increases, said Dr Friedman.
“Especially for the most common drugs, we found that the ranges were pretty wide. There were people who had elevations in drug levels, especially CBD and valproate, that the physician caring for them felt were related to toxicity of those medications.”
About a quarter of those receiving clobazam had to have their clobazam dose reduced and about a third of those receiving valproate had to have that drug reduced.
Researchers also found that CBD interferes with clearance of the clobazam active metabolite.
Grain of Salt
These results, however, “should be interpreted with grain of salt,” said Dr Friedman. “Until formal drug interaction studies are done, we refrain from any specific advice except to make sure that if your patients are on CBD, whether they’re getting it through artisanal preparations or as part of a compassionate use study, background AEDs should be monitored,” and if they’re taking clobazam, the metabolite levels should also be checked.
Yet another study, an open-label, investigator-initiated trial of Epidiolex (25 mg/kg per day) in children and young adults with treatment-resistant epilepsy, was carried out by Orrin Devinsky, MD, also at New York University, and his colleagues.
The researchers collected efficacy data on 58 patients followed for 3 months. Of these patients, almost 40% had a greater than 50% reduction in seizures. For patients with Dravet syndrome, this reduction was just over 50% while for all other patients, it was about 30%.
Seizure freedom at 3 months was also highest for patients with Dravet syndrome (22%) compared with other patients (10%).
“These rates were much higher than we would expect from a placebo response alone,” noted Dr Devinsky. “But until we do randomized, controlled trials, we won’t truly know what the safety and efficacy will look like vs a placebo.”
Researchers followed 40 of the patients to 4 months and found no “drop off” in effectiveness from 3 months, said Dr Devinsky. “There does not appear, from this preliminary snapshot we have in this open-label study, that there is tolerance or loss of effectiveness over time.”
Again, the drug was very well tolerated, said Dr Devinsky. The most common adverse effects, reported by more than 10% of patients, were somnolence (19%) and fatigue (11%). The only other adverse effects, reported in more than 5% of children, were diarrhea, weight loss, and convulsions.
Of the 26 serious adverse events, only 1 (prolonged status epilepticus) was considered possibly related to the drug.
The “critical take-home message” from this study, stressed Dr Devinsky, “is that these are early promising results, but we need controlled trials to know how to move forward.”
Several researchers stressed how difficult it is to carry out studies of CBD because of the legal issues and tight security involved. Marijuana comes under Schedule I of the Controlled Substances Act, which means that because of the potential for abuse, doctors can access it only for research purposes and with the approval of the federal government.
“It’s a tragedy that we’re being held back by bureaucracy when these patients, parents, and practitioners are so desperate,” commented Dr Hussein.
Many also stressed that the myriad artisanal products patients can access — sometimes at a very high cost — are different from agents used in clinical trials. Ben Whalley, professor, neuropharmacology, School of Pharmacy, University of Reading, United Kingdom, pointed out that artisanal preparations contain about 500 different chemical compounds, and many have high amounts of tetrahydrocannabinol, the psychoactive element of the marijuana plant.
In contrast, he said, preparations such as Epidiolex that are approved for clinical trials are 98% CBD and are specifically formulated as a conventional medicine.
The multicenter trial of Epidiolex will include patients with infantile spasms and LGS. It is set to begin next year.
Dr Hussain and Dr Devinsky have received research support from GW Pharmaceuticals.
American Epilepsy Society (AES) 68th Annual Meeting. Posters 2.372, 1.326, 2.104, 2.309, 3.303
Source: Med Scape