Introduction
Raising a young daughter was more difficult for the Rodriguez family than for most. Instead of arranging playdates and dance lessons, Grace’s parents had to count how many seizures their daughter had in a single day.
Nearly 2 years of hospital stays, doctor appointments, and failed medications were taking their toll on the family [1]. Tired of not getting answers, Grace’s mother worked with a new pediatric neurologist who enrolled Grace in a clinical trial of a cannabidiol (CBD) pharmaceutical. Suddenly, the seizures decreased in frequency and Grace began to enjoy regular activities with her family [1].
The medication that continues to bring some normalcy to her life was approved by the FDA in 2018 and is called Epidiolex®. Because of stories like Grace’s, cannabidiol has increased in popularity over the last few decades, and with it, a new body of evidence is emerging to support its use in clinical practice.
Background
CBD is an important phytocannabinoid component of the cannabis sativa plant and is illustrated in Figure 1. In contrast to delta-9-tetrahydrocannabinol (THC), CBD is non-psychoactive, has less adverse effects, and is therefore a desirable drug candidate.
It interacts with the endocannabinoid system as well as with other molecular targets, which is believed to mediate anti-inflammatory, anti-emetic, and anti-epileptic mechanisms [3].
The current landscape of standardized, therapeutic CBD availability in the US is still in its early phases. To date, Epidiolex® is the only FDA-approved purified CBD product currently indicated for seizures associated with Lennox-Gastaut syndrome, Dravet syndrome, or tuberous sclerosis complex [4].
However, innovative pharmaceutical approaches and robust clinical trials are paving the way for new indications to be approved. The present review describes clinical evidence supporting the medical use of CBD in neurological disorders, specifically in Lennox-Gastaut syndrome, peripheral neuropathy, and Parkinson Disease.
Research and Findings on Seizures Associated with Lennox-Gastaut Syndrome
Lennox-Gastaut syndrome is a severe form of epileptic encephalopathy. It is characterized by specific electroencephalographic patterns, severe cognitive impairment, and recurrent seizures of different types.
Drop seizures, for instance, are widely observed in this disorder and are the main cause of sudden falls and injury [5].
Current therapy includes anti-epileptic medications such as valproic acid, lamotrigine, clobazam, among others. Despite multi-drug therapy, many patients continue to experience several seizures every day.
Based on animal and open-label studies, randomized control trials (RCT) have assessed the efficacy and safety of oral cannabidiol in this population [6].
Addition of cannabidiol at 10-20 mg/kg/day reduces seizure frequency
A 2018 study by Orrin Devinsky, et al. evaluated the effects of adding cannabidiol to standard treatment regimens in patients with Lennox–Gastaut syndrome.
This double-blind, placebo-controlled trial was conducted at centers in the US, Spain, the United Kingdom, and France [7].
The inclusion criteria consisted of the following: 2 to 55 years of age, diagnosis of Lennox–Gastaut syndrome, frequent drop seizures for at least 6 months prior to screening, and patients taking one to four antiepileptic drugs on a stable basis. Key exclusion criteria included an unstable medical condition, history of substance abuse, and use of cannabis [7].
A total of 225 children and adult patients were randomized to receive cannabidiol at 10-mg/kg/day, 20-mg/kg/day, or matching placebo. Figure 2 shows the study timeline including a baseline phase, a 14-week treatment period, and a safety follow-up [7].
The active treatment was a plant-derived oral solution of purified CBD and was administered orally twice a day in equally divided doses. The patients and/or caregivers were trained to use a voice-response system to record the daily frequency and type of seizures. Any side effects and concomitant medications were also documented in diaries [7].
Study results indicated that adding cannabidiol to existing Lennox-Gastaut therapy further decreased the frequency of seizures. Of note, patients across the three groups were taking a median of 3 concomitant antiepileptic medications, with the most common drug being clobazam [7].
Shown in Figure 3 is the median percent reduction from baseline in monthly seizure frequency. For the primary endpoint, drop seizures specifically were reduced by 41.9% in the 20-mg CBD group, 37.2% in the 10-mg CBD group, and 17.2% in the placebo group.
Furthermore, the median difference in seizure reduction between the 20-mg and placebo groups was 21.6% (CI 6.7 to 34.8, p = 0.005), and the difference between the 10-mg and placebo groups was 19.2% (CI 7.7 to 31.2, p= 0.002) [7].
These results are statistically significant and demonstrate that cannabidiol as an add-on therapy, compared to placebo, decreases the number of seizures in patients with Lennox-Gastaut syndrome in a dose-dependent manner.
In terms of safety results, the 20-mg/kg/day CBD group experienced the greatest number of side effects. The most common adverse events included somnolence, decreased appetite, and diarrhea [7].
Of note, elevation in aminotransferase concentrations greater than 3 times the upper limit of normal occurred in 9% of patients. Additional safety data is currently being collected from patients who opted to continue in the open-label extension trial [7].
This study and another similar RCT supported the FDA approval of Epidiolex® for reducing seizures in patients with Lennox-Gastaut syndrome [7,8].
Research and Findings on the Treatment of Peripheral Neuropathy
Peripheral neuropathy is a debilitating condition that affects more than 20 million individuals in the United States. It is characterized by damage to the peripheral nervous system, which causes symptoms such as muscle weakness, pain sensations, and heat intolerance [9].
Causes can be idiopathic or related to a number of conditions including diabetes, vascular problems, physical trauma, and more. Current treatment is limited to pain relievers and topical anesthetic patches, which have unwanted side effects and do not always control symptoms [9].
Cannabidiol has become a potential modulator of neuropathic pain based on its efficacy in pre-clinical trials. For instance, a study on mice with diabetic neuropathy showed that CBD may prevent microglial cell activation in the dorsal spinal cord, which in turn limits neuropathic pain [10].
Patients with underdiagnosed or uncontrolled peripheral neuropathy are in desperate need of treatments that will both relieve symptoms and limit adverse effects.
Cannabidiol oil for symptomatic relief of peripheral neuropathy
A recent RCT by Dixon Xu, et al. investigated the effects of cannabidiol oil, compared to placebo, in patients suffering from neuropathy of the lower extremities [11].
Participants were enrolled in this study if they met the following criteria: experienced at least 3 months of symptomatic neuropathy and had at least one underlying condition (e.g. diabetes). Key exclusion criteria included history of substance abuse, fibromyalgia, and psychiatric disorders.
Following baseline vascular and neurological exams, 29 patients were randomized to receive either a CBD cream containing 250mg per 3oz or a placebo emu oil cream [11].
Patients were instructed to apply these formulations to symptomatic areas up to 4 times per day for 4 weeks. As seen in Figure 4, after the trial period, participants taking placebo were given the option to cross-over to the CBD group to receive active treatment for 4 weeks [11].
The main outcomes of interest were measured using the Neuropathic Pain Scale (NPS), which was collected every 2 weeks throughout the study.
The NPS evaluates the location and intensity of pain and other sensations (e.g. sharp and itchy) in a scale of 0 to 10, with 0 being no pain and 10 being worst pain imaginable [11].
Investigators identified a statistically significant decrease in NPS scores when comparing the CBD and placebo groups. For instance, as visualized in Figure 5, mean decreases from baseline in intense pain (p = 0.009) and surface pain (p = 0.013) were greater in the CBD group versus the placebo group.
Other domains with similar results included sharp, itchy, cold, and unpleasant pain [11].
Safety outcomes showed that no local or systemic adverse events were reported in this study [11]. This is likely due to the localized application of topical CBD, which is known to have decreased systemic distribution and therefore cause fewer side effects.
A potential limitation of these results is the varied quantity of CBD applied by different patients, thus future studies must perform thorough monitoring in order to standardize results.
Nevertheless, the work by Dixon Xu, et al. points to the efficacy and safety of transdermal CBD for patients with peripheral neuropathy and makes way for future, hopefully larger, RCTs in this population.
Research & Findings for Treatment of Parkinson Disease
Parkinson Disease (PD) is one of the most common neurodegenerative diseases in the US, usually affecting individuals over the age of 70.
PD causes unintentional and uncontrollable movements of the body with the main symptoms including tremor, rigidity of the muscles, bradykinesia (i.e. slow movements), and postural instability [12].
Currently, this chronic and progressive disease is effectively treated with levodopa (L-DOPA). However, this medication can cause long-term movement abnormalities (e.g. dyskinesias) and further exacerbate poor quality of life.
In recent years, CBD has shown to have neuroprotective effects in animal models of PD due to its action on the endocannabinoid system [13]. Nevertheless, clinical trials are still attempting to find similar results in human patients.
Cannabidiol may improve quality of life in patients with Parkinson Disease
In a clinical study published in 2014, Marcos Chagas et al. investigated the effects of adding cannabidiol to standard treatment in Brazilian patients with PD [14].
Key enrollment criteria included a diagnosis of PD and stable use of anti-PD medications for at least 1 month prior to screening, while the exclusion criteria were comprised of psychiatric disorders, dementia diagnosis, and comorbid use of cannabis.
After psychiatric and neurologic baseline assessments, patients were randomized to receive either placebo, 75-mg CBD/day, or 300-mg CBD/day, for 6 weeks [14]. The active treatment consisted of gelatin capsules formulated with powdered cannabidiol (99.9% purity) and corn oil.
The Unified Parkinson’s disease rating scale (UPDRS) and the Parkinson’s Disease Questionnaire – 39 (PDQ-39) were then used to assess improvement in PD symptoms and overall wellbeing, respectively [14].
Although there were no statistically significant differences in UPDRS scores, the results did reveal improvement in patient quality of life. The difference in the overall PDQ-39 scores between the placebo group and the 300-mg CBD group was statistically significant (p <0.05) [14].
More specifically, patients in CBD groups had more improvement in activities of daily living (ADL) and decreased reports of stigma compared to the placebo group. Included in Table 1 are the p-values of the analysis of variance (ANOVA), which demonstrate that there was a statistically significant difference in these categories between the three study groups [14].
Despite the lack of response in terms of motor symptoms of PD, it can be argued that well-being and quality of life are valid, clinically significant, and patient-oriented outcomes.
The question clinicians must answer is whether results like these provide enough evidence to change the way they treat patients with PD.
This study indicates that further research in larger patient cohorts is necessary to determine other possible effects of CBD in patients with Parkinson Disease.
Conclusion
The popularity of CBD for medical purposes is evolving rapidly, not only because of potential application in many disease states, but also because of its non-psychoactive safety profile.
As discussed earlier, a significant amount of evidence exists for the treatment of seizure disorders with oral CBD, specifically Lennox-Gastaut syndrome and Dravet syndrome.
For patients like Grace, the approval of Epidiolex ® in 2018 meant significant relief of daily seizures and better access to CBD.
The study by Dixon Xu, et al. was an interesting example of CBD use that resulted in decreased peripheral neuropathic pain while causing no local or systemic adverse effects.
In patients with Parkinson Disease, Chagas et al. did not find statistically significant changes in motor symptoms, but they did observe improvement in overall quality of life after use of CBD capsules.
There may not be clear-cut answers for CBD’s specific place in therapy, however there is enough data to support a new wave of clinical studies in neurologic diseases.
The benefits of CBD will need to outweigh the possible risks before new indications are approved. Even though controversial opinions and the current legal landscape of cannabis pose barriers to this area of research, patients like Grace who have uncontrolled symptoms despite active treatment deserve innovative therapy options.
Research investigators, lawmakers, and clinicians alike will need to collaborate in order to continue to grow the body of evidence supporting the use of CBD.
References
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