A Study of Tolerability and Efficacy of Cannabidiol on Tremor in Parkinson’s Disease
Persons with Parkinson’s disease (PD) have progressive disabling tremor, slowness, stiffness, balance impairment, cognitive deficits, psychiatric symptoms, autonomic dysfunction, fatigue and insomnia. Tremor may interfere with necessary daily and work functions. The disorder affects approximately seven million people globally. The total economic cost in the US is around 23 billion dollars. In addition to economic costs, PD reduces quality of life of those affected and their caregivers.
Cognitive impairment is a common feature and ranges from delayed recall in early stages to global dementia in up to 80% at end stage. PD with dementia has been associated with reduced quality of life, shortened survival, and increased caregiver distress.
Depression, anxiety and psychosis are also common and are particularly disabling in PD, even at the earliest stages. These symptoms have important consequences for quality of life and daily functioning, are associated with increased carer burden and risk for nursing home admission. Anxiety affects up to 40% of patients with PD, and may predate motor symptoms by several years. The most common anxiety disorders in PD are panic attacks (often during off-periods), generalized anxiety disorder, and simple and social phobias. Psychotic symptoms vary in frequency according to the definition used. If mild forms are included, these affect up to 50% of patients. Visual hallucinations are the most common type. However, hallucinations occur in all sensory domains and delusions of various types are also relatively common. The impact of psychosis is substantial in that it is associated with dementia, depression, earlier mortality, greater caregiver strain, and nursing home placement.
Current therapies are inadequate. Medications have improved the prognosis of PD, but also have problematic adverse effects. Since treatment of PD is often unsatisfactory and since marijuana has recently become legal and readily available in Colorado, persons with PD have been trying it. Patients have heard from the internet, support groups and other sources that marijuana is helpful. Most are doing so on their own, without the supervision or even knowledge of their neurologist. In a survey conducted in the spring of 2014 in University of Colorado Movement Disorders Center (UCMDC) clinic about 5% of 207 PD patients, average age 69, reported using marijuana. In the same clinic, about 30% of the PD patients have asked doctors during their visits over the past 6 months about marijuana. In another study Katerina Venderova and colleagues reported that 25% of PD patients had taken cannabis in the General University Hospital in Prague.
PD mostly affects the elderly, and with the cognitive, psychiatric and motor problems, subjects are prone to falls. Cannabis is well documented to cause psychosis, slowness, and incoordination. Studies have also shown that chronic users have structural and functional CNS alterations. Thus cannabis is expected to be risky in persons with PD. Further, there are many components of cannabis, and the cannabis preparations being sold in Colorado vary widely in composition. There are no definitive data regarding the benefits and risks of these various preparations in PD. Studies on safety and efficacy are greatly needed to protect this fragile Colorado population.
Cannabidiol (CBD) is a cannabinoid that is present to a lesser extent in street marijuana, and limits delta-9-tetrahydrocannabinol (THC)’s psychoactive effect. CBD acts in some experimental models as an anti-inflammatory, anticonvulsant, anti-oxidant, anti-emetic, anxiolytic and antipsychotic agent, and therefore has potential beneficial medical uses. Further, animal studies suggest that CBD is neuroprotective, perhaps due to reported anti-oxidative and anti-inflammatory actions.
Human trials report that CBD decreases anxiety and causes sedation in healthy individuals, decreases psychotic symptoms in schizophrenia and PD, and improves motor and non-motor symptoms and alleviates levodopa-induced dyskinesia in PD. The ratio of THC to CBD plays a role in the preparation’s therapeutic outcome: strains of cannabis with higher concentrations of CBD did not produce short-term memory impairment vs. strains with higher concentrations of THC and lower concentrations of CBD.
Many clinicians who suspect cannabis may have a positive effective upon a particular patient group have no idea of the cannabinoid profile that is being used. Without knowing the composition, it is impossible to draw any conclusions simply because of the huge variety of strains utilised.
Given the current literature regarding CBD: possible neuroprotective effect, good tolerability, anxiolytic and antipsychotic effects and general lack of be well tolerated in PD, including its effect on tremor, the investigators hypothesize that CBD would be well tolerated and would reduce tremor, anxiety and psychosis, and would stabilize cognitive decline in PD. First the investigators will perform an open label study to determine a reasonable dose, and then a randomized, double-blind, placebo-controlled crossover study to evaluate the efficacy and tolerability of oral CBD on tremor and other important aspects of PD. A strength of the study is that it uses well defined form or CBD.
Stage 1: Open Label Dose Escalation Tolerability Study
Primary Specific Aim: To confirm that the dosage regimen of CBD, in the form of GWP42003-P recommended by the study drug manufacturer is safe and tolerated in 10 subjects with PD. GWP42003-P is started at 5 mg/kg/day and is increased by 5 mg/kg at 3 day intervals to a target dose of 25 mg/kg/day.
Secondary Specific Aim: To examine the effect of CBD on severity & duration of tremor and other conditions that are problematic in PD.
The dose escalation tolerability study will be conducted in 10 subjects (the investigators will be recruiting up to 15 subjects to end up with 10) as an open label study lasting approximately 3 weeks followed by a 2-week safety follow up. Subjects are closely monitored as the dose is titrated. Subjects will have a screening visit, a baseline visit within the next three weeks, a visit when subjects are on 20 mg/kg/day, a final assessment visit when subjects have been on the maximal tolerated or the targeted dose for 10-15 days, and a safety visit 2 weeks later. The subject is to be on the maximal tolerated or targeted dose for 10-15 days. Subjects will be called on the 3rd day of each dose. During phone calls subjects are monitored for adverse events, especially excessive daytime sleepiness, symptoms of hepatotoxicity, as well as changes in medical history and concomitant medications. Subjects are also called 3 days after stopping the study drug to check for signs of withdrawal.
New Study: CBD May Ease Public Speaking Fears—And Lead to a Better Parkinson’s Drug
Glossophobia, the fear of speaking in public—and subjecting your personhood, thought processes and self-worth to the withering scrutiny of the marketplace of ideas—is a common-enough affliction to be “treatable” by both pharmaceutical interventions and a panoply of hack cures.
More effective than picturing your audience in a state of undress is cognitive-behavioral therapy, or anti-anxiety medication, or—since this is 2020—what about some CBD? A big fat dose of CBD ought to quell your qualms just fine, a new study out of Brazil suggests. However, there’s one large caveat: The findings are limited to patients with Parkinson’s disease—which means that the findings have value for both how that disease is treated and for understanding how CBD acts on the brain.
As outlined in an article published in the Journal of Psychopharmacology, researchers at the Federal University of São Carlos and the University of São Paulo subjected 24 people to two separate “simulated public speaking tests,” 15 days apart. Twenty-two out of the 24 patients were men, and most were on other medications, most commonly levodopa.
Each time, half were given 300 milligrams of CBD, the other half a placebo. (The next time out, the placebo-receivers were administered CBD, and vice-versa.) Test subjects had their heart rates, blood pressure and tremor frequencies monitored.
And in patients who received the CBD, both anxiety as well as tremors—a common sign of Parkinson’s which can be exacerbated with stress—were reduced.
“These observations suggest that CBD may be an alternative treatment for patients with [Parkinson’s] and anxiety,” the researchers wrote. “Thus, the chronic administration of CBD could be tested in future studies.”
For some, the maleness of the study might be problematic, but the aforementioned caveat stems from the fact that the 24 research subjects in the study all suffered from Parkinson’s disease—a very serious but rare affliction that affects 3.3% of adults 64 and older. Why limit a research study in this way?
Anxiety and attendant tremors afflict 67% of Parkinson’s patients—and a main goal of this research study was to build off of prior research and discover whether CBD did anything to calm tremors as well as more “subjective” signs of anxiety.
That’s good. Also valuable, and more widely applicable, is understanding the role of the endocannabinoid system in both anxiety disorder as well as Parkinson’s.
As the researchers noted, the disease is most often treated by pharmaceutical drugs with side effects that include tremors, impaired cognition and increased risks of falls.
Finding an alternative treatment to pharmaceutical drugs with deleterious side effects would add value—as well as figuring out any link between decreased symptoms and endocannabinoid receptors. Other research suggests that CBD reduces inflammation in the brain and enhances neuroplasticity, thus aiding brain function (and, possibly, treating symptoms of Alzheimer’s). So did CBD calm tremors because it calmed anxiety, or did it do something else to the motor controls of the body?
The short answer is that we aren’t quite sure yet. The endocannabinoid system, recall, is the network of receptors in the brain and body that send and receive signals that, in turn, regulate key functions including mood, appetite, sleep and memory. Whether CBD would have any effect on motor signs triggered by anxiety was the “novelty” of the study, as the researchers wrote. And while there’s not enough data to posit anything definitive, researchers did suggest that the presence of CBD may reduce activity at one specific receptor, 5-HT1A , which in turn may dampen tremors.
Currently, it is “not possible to conclude whether CBD had a direct effect on the amplitude of the tremors or whether the reduction in anxiety levels led to the differences observed,” the researchers wrote.
However, the benefit from a drug with limited side effects for patients with Parkinson’s, and the initial signs that CBD may indeed trigger functions in the brain that reduce anxiety symptoms like tremors, would seem to more than justify the study—and future CBD research, more of which is absolutely coming.