cbd oil replace ropinerol for parkinson

CBD for Parkinson's Disease

Parkinson’s disease is a neurodegenerative disorder that progressively causes neurons to die. One function of neurons is to create a neurotransmitter called dopamine, a chemical messenger responsible for sending messages between neural cells in the brain. Parkinson’s disease primarily affects dopamine-producing neurons in an area of the brain called the substantia nigra, causing critically low levels of dopamine that negatively affect motor function.

The result of this is a gradual loss of motor control, with symptoms starting gradually, usually with a noticeable tremor in just one hand. However, people with Parkinson’s disease also often exhibit emotional and behavioral changes, including sleeping problems and depression. Taken together, this makes Parkinson’s a debilitating disease that affects the patient, but also those around them.

The cause of Parkinson’s disease is still unknown and there is no cure for it.

Symptoms of Parkinson’s Disease

People with Parkinson’s typically start experiencing symptoms in the later stages of the disease, after a significant number of neurons have been damaged or lost. Symptoms develop slowly over multiple years, and they differ from person to person. Because symptoms often differ from one person to the next, not all symptoms listed below are necessary for a Parkinson’s diagnosis. Younger people in particular may only exhibit one or two of these symptoms, especially in the earlier stages of the disease.

While a variety of other symptoms may occur, the primary motor symptoms of Parkinson’s disease include:

Tremors that tend to occur at rest, is usually slow and rhythmic, occurring first in the hand, foot, leg, jaw, chin, mouth, or tongue—and eventually spreading across the body

A sensation of internal tremors, which are not necessarily visible to others.

Rigidity including tightness or stiffness of the limbs or torso

Bradykinesia, or “slow movement,” a reduced or mask-like expression of the face, blinking less frequently

Difficulties with fine motor coordination

Postural instability including an inability to maintain a steady, upright posture, or to prevent a fall, that becomes more pronounced in the later stages of the disease, this symptom causes

Walking or gait difficulties that may begin as a small change in the way the arm swings while walking and evolving into a slow, small, shuffling gait, rapid small steps, or freezing episodes in which the feet appear to be glued to the floor

While they are less noticeable—and often overlooked because of the disease being a movement disorder—there are also many associated non-motor symptoms of Parkinson’s. Disturbances in the sense of smell, eye and vision issues, sleep problems, depression, anxiety, pain, psychosis, fatigue, cognitive changes, weight loss, lightheadedness, sweating, melanoma, personality changes, and gastrointestinal, urinary, and sexual issues can all occur in patients of Parkinson’s disease.

Parkinson’s Disease Medications & Treatment

There is no cure for Parkinson’s disease. Because symptoms don’t exhibit themselves until the later stages of the disease, early diagnosis is difficult—but scientists continue to search for ways to identify the early onset of Parkinson’s. While no treatment options currently available can slow or halt the progress of Parkinson’s disease, there are treatments available to improve its symptoms.

Pharmaceutical Interventions
Almost all Parkinson’s patients will eventually require medication to treat their motor symptoms. Several classes of medications are available, and often patients will be prescribed various strengths, formulations, and combinations of medications to improve their symptoms. These include:

Levodopa works by being converted to dopamine in the brain. Side-effects include nausea, usually requiring it to be taken with carbidopa. If symptoms return between doses (OFF periods) an infison of levodopa that is administered through a tube called duopa, a powder form of levodopa which can be inhaled, or the new medication istradefylline (Nourianz) may be prescribed. Levodopa treatments are often delayed as long as possible as its effects wear off over time and it eventually stops working, causing the patient to develop movement problems called “motor fluctuations”.

Safinamide (Xadago) is prescribed when patients taking levodopa and carbidopa have a breakthrough of Parkinson’s symptoms that were previously under control. Side effects include trouble falling or staying asleep, nausea, falls, and uncontrolled, involuntary movements.

Dopamine agonists that imitate the action of dopamine in the brain to treat the motor symptoms of Parkinson’s disease. Examples include pramipexole, rot ropinirole and igotine that can be taken on their own or with levodopa. Side effects can include nausea, orthostatichypotension, hallucinations, somnolence, and impulse control disorders.

Non-Pharmaceutical Interventions
The most common non-pharmaceutical interventions include lifestyle changes that can help slow disease progression and make symptoms more manageable. These include eating a healthy diet and a proper exercise program to help maximize the potential of medications, increase energy, and promote general health and well-being in Parkinson’s patients.

Physical, occupational and speech therapies can help with walking and gait issues, fine motor skills, and speech and language issues that may arise with Parkinson’s disease while deep brain stimulation (DBS) may improve symptoms in certain patients.

CBD for Parkinson’s Disease

Research & Scientific Evidence

A handful of studies have investigated the effects of cannabidiol (CBD) to treat Parkinson’s disease and symptom management. However, the main body of evidence showing that CBD has promise as an effective treatment for this disease lies in studies relating to adjunct actions and complications from the disease including oxidative stress, neural inflammation and neurodegeneration.

One such study is from 2011 in which researchers published the findings of the journal Psychopharmacology. Because of many neurodegenerative disorders involving cognitive deficits, they assessed whether the anti-inflammatory, and neuroprotective effects of CBD could be useful in the treatment of memory impairment associated to these diseases.

Using an animal model of cognitive impairment induced by iron overload, they tested the effects of CBD in memory-impaired rats in both a single dose as well as continued use. In the first experimental condition, the researchers administering a single dose of either 5.0 mg/kg or 10.0 mg/kg of CBD immediately after a training session of the novel object recognition task. They continued a daily intraperitoneal CBD injection for 14 days to examine chronic use and performed object recognition training 24 hours after the last dose and a retention tests 24 hours after training.

They found that a single dose of 10.0 mg/kg of CBD recovered memory while repeated CBD administration of either CBD dose improved recognition memory. They concluded that the evidence suggests that CBD shows potential for the treatment of cognitive decline associated with neurodegenerative disorders.

21 Parkinson’s disease patients without dementia or comorbid psychiatric conditions were assigned to three groups of seven subjects each. The control group was treated with a placebo, the first experimental group with 75 mg/day of CBD and the second experimental group with 300 mg/day of CBD. Participants were assessed in respect to motor and general symptoms, well-being and quality of life, and possible neuroprotective effects one week before and again, during the last week of treatment.

Although they didn’t find a statistically significant different between the group for motor and general symptom outcomes or neuroprotective effects, they did find that the patients treated with 300 mg/day of CBD had a significant improvement in their quality of life. However, the researchers also noted that studies with larger samples and specific objectives are required before definitive conclusions can be drawn.

Bonus:
In contrast, the latest research from 2020 suggests that CBD can help with motor symptoms, specifically tremors. In the Journal of Psychopharmacology, researchers published the results from their study aimed at evaluating the impact of a single dose of 300 mg CBD on anxiety measures and tremors induced by a Simulated Public Speaking Test (SPST) in individuals with Parkinson’s disease. They found that a single dose of 300 mg CBD not only decreased anxiety in patients with Parkinson’s disease but that there was also decreased tremor amplitude in an anxiety-provoking situation.

In a 2015 study published in Toxicology in Vitro, scientists investigated the potential neurorestorative effects of CBD and the pathways that mediate it for the treatment of Parkinson’s disease.

They used rat neurons treated with a neurotoxin that is known to induce Parkinson’s disease in vivo and presents with neuroinflammation, excitotoxicity, mitochondrial dysfunction and reduced neurotrophic support. Cell viability, neuritogenesis (the process of forming of new neurites), neural growth factor (NGF) and neuronal protein expression, and the involvement of NGF receptors after CBD exposure were measured.

The data indicated that CBD has neuroprotective effects on neural cells that involves neuritogenesis, NGF receptors as well as an increased expression of axonal and synaptic proteins leading them to conclude that the neuroprotective effects of CBD might be beneficial in Parkinson’s disease.

Anecdotal Evidence – using CBD oil for Parkinson’s

The scientific evidence seems to indicate that CBD has the potential to improve quality of life for patients with Parkinson’s disease in addition to reducing neuroinflammation and oxidative stress as well as induce neurogenesis and neuritogenesis that can potentially slow or even reverse disease progression. Anecdotal evidence also shows that CBD may improve Parkinson’s disease symptoms in some patients but it would seem that many people find a greater relief and reduction in motor symptoms when using cannabis. In fact, according to this study, while only 4.3% of a self-report survey of patients with Parkinson’s disease used cannabis, it ranked among the most effective complimentary and alternative therapies listed.

CBD as a complementary treatment for Parkinson’s

CBD can also play a role as a complementary therapy to help reduce many of the symptoms associated with the pharmaceutical treatments usually prescribed to patients with Parkinson’s disease. CBD can help alleviate gastrointestinal issues like nausea from side effects of levodopa and safinamide. Likewise, CBD has specifically been shown to help improve complex sleep-related behaviors associated with rapid eye movement sleep behavior disorder as well as psychosis in Parkinson’s disease patients.

Bottom Line

The anti-inflammatory, anti-oxidative, neuroprotective and neuroregenaritive effects of CBD can all prove to make it a promising treatment for Parkinson’s disease, for both symptom reduction as well as even potentially slowing down disease progression. In addition, the data shows that CBD is also effective at improving overall quality of life. However, it would seem that high dosages of 300 mg/day produced the best effects, probably due to CBD being a pleiotropic drug that produces different effects through multiple molecular pathways at different dosages. As always, speak to your treating physician before using CBD to monitor dosage, symptom severity, and other clinical parameters. In addition, CBD is contraindicated with use with certain medications, so they can ensure that your CBD treatment is both safe and effective.

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New Research, Medications and CBD for Parkinson’s

There are a lot of medications on the market to treat the symptoms of Parkinson’s and finding the right ones for you can take some trial and error.

In this episode with Dr. Trevor Hawkins, you will learn:

  • About the most common medications that people with Parkinson’s take
  • The biggest problem people with Parkinson’s face when relying on oral medications
  • About current research and clinical trials that may result in better solutions in the future
  • The one proven activity we know about that can slow down the progression of Parkinson’s
  • About marijuana, CBD, how they work and what the research says about their efficacy

Notes

  • One of the biggest issues with oral medications is that you may have a lot of ON and OFF periods
  • Rytary is an extended-release combination of carbidopa-levodopa designed to maintain a steady level of relief and minimize peaks and valleys
  • Duopa is a suspension form of carbidopa-levodopa that is delivered continuously by a pump through a tube into your intestine for up to 16 hours is a continuous flow patch that is in clinical trials and may be available in 2019 is an oral dopamine agonist that’s used to treat the motor symptoms of Parkinson’s is a dopamine agonist that is delivered via a patch is an injection to treat loss of body movement control and it’s currently in clinical trials in the US
  • Current research and clinical trials are focused on developing medications that are more specific and only hit certain receptors so they produce fewer side effects
  • Exercise is the one proven way to slow down the progression of Parkinson’s
  • There are exciting trials being done with the cancer drug Nilotinib to test if it can modulate dopamine in people with Parkinson’s
  • Using CBD oil to treat symptoms of Parkinson’s is becoming more and more common; however, the lack of oversight and inconsistency from batch to batch are big problems
  • There’s a trial going on at the University of Colorado right now for a CBD pill to treat Parkinson’s tremor
  • The biggest hurdle for CBD studies is that there’s no monetary support – unlike the money that big pharma companies get
  • If you want to experiment with CBD oil, make sure that you tell all of your providers about it because there can be serious drug interactions and be aware that each batch you get can be very different
  • There are two species of cannabis – marijuana (15-40% THC) and hemp (.3% THC)
  • THC is what produces the high
  • CBD oil that is derived from hemp is legal in all 50 states
  • CBD oil that is derived from marijuana is not legal in every state
  • There’s new research being done on CBD oil so keep an eye out for it

As with every therapy you try to treat your Parkinson’s symptoms, be sure to consult with your doctor, movement disorder specialist, neurologist and everyone on your care team. Anecdotal evidence is great; however, not everything works the same for everyone. Do your due diligence and make sure all of your experimentation is under the direct and frequent supervision of your doctors.

Concepts Mentioned in this Podcast & Further Reading

[The Parkinson’s Podcast™] Episode Transcript

Kelsey Phinney: Last week, we learned about medications available to treat the motor symptoms of Parkinson’s and how they work in the brain. Just to recap, the three main classes of motor-specific drug therapies for Parkinson’s are carbidopa-levodopa, dopamine agonists and MAO inhibitors.

My interview with Dr. Hawkins was so awesome that I realized I had enough for two podcasts, because after he explained how the medications work, we got to talking about some newer medications available and some trials for potential medications or treatments in the future.

We talked about some research that he was just starting when we initially talked, and then he emailed me to give me an update after the summer about the research that CU Denver is doing on CBD and Parkinson’s.

Today, we’re going to delve into that.

This is the Parkinson’s Podcast™ brought to you by the Davis Phinney Foundation. I’m your host, Kelsey Phinney, and this is episode seven, part two of my interview with Dr. Trevor Hawkins.

Dr. Trevor Hawkins: Part of the reason why there probably hasn’t been an explosion of different varieties of medications working on a variety of different mechanisms, is that it’s really hard to beat levodopa. Dopamine agonists are the closest to it. A lot of the advancements we’re looking at involve fine tuning what we already know about that mechanism between the dopamine agonists and between levodopa, so we can avoid the pitfalls that come from the medication itself.

So number one, when you’re talking about Sinemet, the issue is the fluctuations that occur naturally with different concentrations. You get these peaks and valleys. Ideally, if you’re able to give a steady load, you can fine tune the amount of dopamine that the cells are receiving, so they can send out the appropriate amount of dopamine without getting too high, without getting overwhelmed, and without causing dyskinesias and not being able to produce enough to make up for the deficit. So most of the treatments are kind of trying to hone in on that.

There are some medications that are available on the market now. There’s the true long acting sinemet like Rytari, that’s the name it goes by, and it has both immediate release and the long acting, extended release sinemet.

What that allows it to do is maintain that kind of steady level that the brain is seeing for much longer periods and avoiding those peaks and valleys.

There are other pills that are coming in clinical trials that are trying to do the same kind of thing where they have to sit in your stomach and slowly diffuse out the levodopa over time to again, keep those steady concentrations. The patch is actually a very similar concept. It’s actually very similar to the insulin pumps you may have seen for patients with diabetes. You get a little pump that connects to the skin patch, a little barb that kind of digs into the medication which infuses in a steady level through the skin with the idea again, you know, to maintain that steady state level.

That one is still in clinical trial in terms of the levodopa version.

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They do have one that is available for use with levodopa, which is the duopa or duodopa, which is the gastrointestinal infusion. That one is put into a feeding tube and hooked up to a pump that can infuse medication. The nice thing about that is it goes straight into your gut. So you might not have to worry about absorption issues or anything because it’s getting straight to the system and again avoid those peaks and valleys. Obviously the downside to that one is the complications that do arise from having a feeding tube and managing that.

So, the skin patch version and the pump work and potentially get the same benefit of steady infusion and hopefully, less complications. But ultimately, that’s what the clinical trials will be able to tell us.

Kelsey Phinney: To recap what Dr. Hawkins was just explaining about the levodopa therapies, the main issue with the oral medication is navigating and managing the on/off periods of when the medication is working and when it’s not, and being on that cycle throughout the day.

Dr. Hawkins explains that there are two potentially helpful newer drugs already on the market. I’m not sure how expensive these drugs are, or what that looks like.

One is Rytary, which combines fast acting and long acting carbidopa-levodopa. The other is Duopa, which is a gastrointestinal infusion. And that one’s nice because it goes straight into the gut. But it can be pretty invasive, because there’s a feeding tube involved. And then he also brings up Neuroderm, which is like an insulin pump. But with the levodopa medication in it that would again provide this continuous flow of medication, but would ideally be less invasive than the Duopa. That is in clinical trials. And from what I was reading, it might be on the market as soon as 2019. So it’ll be interesting to see how widely that gets used and if it’s helpful and effective for people navigating ON and OFF periods of Parkinson’s.

Next we get into what options are available for the second class of drugs, the dopamine agonists, and if there’s any research going into future medications for that as well.

Dr. Trevor Hawkins: The dopamine agonist has a similar concept. They actually have true extended release, once a day versions of both the Ropinirole, there’s the patch version with the Neupro patch, for example. And then in Europe since the late 1990s, they’ve had a pump that was very similar to that sinemet pump, the insulin pump, as one of the dopamine agonists called Apomorphine. Nothing to do with the actual drug morphine, it’s a dopamine agonist just like the other ones. And that one, again, is being used in Europe to do the same thing. It gets hooked up to the palm and it fuses to the skin and is a steady level throughout the day to avoid those peaks and valleys. And that’s actually currently in clinical trials here in the US. And hopefully soon, we’ll see it come available on the open market for patients. And again, the only caveat to that one is for me, like the side effects I’ve mentioned before about dopamine agonists, is sometimes that prevents patients from being able to use that but it’s very commonly used in Europe as an option for patients that would benefit from things like Deep Brain Stimulation, but aren’t able to tolerate the surgery for various reasons. And Deep Brain Stimulation is even kind of doing the exact same thing in terms of providing a constant signal in the brain to give that benefit, but give it a steady level to avoid those peaks and valleys from the medications.

Kelsey Phinney: So for dopamine agonist, we have the Nupro patch already available, and that provides that steady stream of medication throughout the day or night. And then the other thing he mentioned is the Apomorphine pump, which is available in Europe, but hasn’t been officially approved to be used in the US. Although, as he says there are clinical trials going on that might make that available soon.

And then that leads him into talking a little bit about Deep Brain Stimulation, which isn’t a drug based therapy, but it also provides continuous support for the brain to offset the symptoms of Parkinson’s. And if you’re a candidate for it, and can handle undergoing a deep brain surgery, it can be really life changing. And amazing, as has been the case with my dad.

Next I was wondering about a lot of times, especially in later stages of Parkinson’s, the OFF periods can happen quite suddenly and intensely. And I wondered what was available to try to get medication into the system quicker than with a pill. Is there anything out there? And is there anything being researched that could help with those OFF periods?

Dr. Trevor Hawkins: The interesting thing about the research is that there’s also a lot of active mechanisms to look into what you do if a patient experiences a sudden OFF, like their medications just drop out or they’re taking medication and it doesn’t really work for them, called dose failure, which tends to happen as you get into later stages of the disease. And sometimes OFF can come on and be pretty debilitating for patients.

It would be nice if we had a way to get them out of it as opposed to having to take their pill and wait a half an hour to kick in and get through their stomach and absorb it. They’ve looked at a lot of different ways – there’s one already, a dopamine agonist called Apokyn. They’re also looking at different formulations of both the dopamine agonists and Levodopa. One looks like an asthma inhaler. That way the medication gets into your lungs and goes directly into your bloodstream, and doesn’t have to sit in your gut waiting to be processed before it can get in. So the early studies, at least when you look at how quickly it kicks in, you’re talking about five to ten minutes. So for patients with that OFF that hits you out of the blue, that’s potentially very, very useful to get patients rescued out of that OFF and jumpstart the system.

Kelsey Phinney: Dr. Hawkins explains that the option already available on the market is the Apokyn injection, which is kind of like an EpiPen with dopamine agonist in it, and that delivers that medication quickly into the system. And then he also talks about the research going into creating an inhaler, similar to an asthma inhaler, that could deliver a dopamine agonist or sinemet into the system much more quickly through the lungs than through the gut. And I’m really excited to see what happens with that research. So next, Dr. Hawkins will explain some newer research going into ways to improve the medicines and their effectiveness within the brain.

Dr. Trevor Hawkins: Most of the medication trials that we have are really trying to hone in on specific receptors that it’s working on. Because levodopa kind of will work everywhere that defers dopamine and will work on all the receptors that dopamine worked on. And so sometimes that can cause the good, but with it also you get the bad if it’s hitting another receptor. It’s the same thing with dopamine agonist.

One example being those impulse control disorders, there is some evidence to suggest that if you can eliminate one type of those dopamine receptors, potentially you lower the risk of getting that side effects. So we are making medications that are more specific. It’s like if you have all these doors on the street to houses – some have red doors and white doors and black doors. If you only want it to go to the red doors, now because that’s where the good receptors are, and they give it to the white or the black, you’re getting the side effect. That’s where we can eliminate giving the message to those and only give it to the right “doors”. So that’s actually pretty fascinating to see if we can maximize the good parts of the medication and really eliminate a lot of side effects. So, I think we’re really close on having a few breakthroughs on that side of it as well.

Kelsey Phinney: I for one am very excited to see this research, I think it’s really cool. And I’m very curious to know more about how they’re able to pinpoint specific receptors or specific locations in the brain, because that would be huge and improving those negative side effects with the dopamine agonist like with a compulsive behavior. And yeah, I’m looking forward to knowing more.

Another thing that I know we’re always curious about is if there’s anything going into ways to slow down the progression of the disease. And so here’s Trevor explaining that.

Dr. Trevor Hawkins: Yeah, there is going to be a lot of active interest looking into potentially developing treatments that slow down the disease, still far and away, the most important thing now is exercise. We know it is the one thing that does slow down progression of disease. There’s definitely a lot of trials that are always ongoing, animal models, and even in the human model, and looking at medications that potentially can do it. Some kind of work in a logical manner to kind of turn down like an overactive immune system. Others have become very weird mechanisms. And some are kind of by accident, either in animal models or other humans, oh, what’s going on here, doing something to slow down progression of symptoms. Certainly we have a couple of trials over at Colorado now. One of which is looking at chemo drugs used for Hodgkin’s lymphoma. One of them showed that maybe it was slowing down the progression of disease. So right now they’re actually going to do a true placebo controlled study to see if that actually is accurate. One tricky thing in Parkinson’s, and it’s true in most diseases, is if you really believe medication is going to work for you, it will, and if you walk out the door thinking it’s not going to work for you, it won’t. Sometimes we have to be cautious about giving too much credit when it’s just the patient’s subjective improvement from the placebo effect.

Kelsey Phinney: The one proven way to prevent the progression of Parkinson’s is exercise. And we’ll actually get into more about exercise and Parkinson’s next week. But that is something to keep in mind. The other interesting research you mentioned has to do with a cancer drug that has been shown to potentially slow down the progression of Parkinson’s by pinpointing a specific protein.

But the issue with the initial study is that the patients knew that they were taking something that could slow down the progression. And so as with most drug therapy research, we have to be careful about placebo effect, which is proven that when people believe that something will work for them, even if they’re given a pill with nothing, if they think that it’s going to work, then a lot of times that’s enough to make something work.

So, they’re still doing trials that will be blind trials so that people won’t know if they’re getting the placebo or the real drug so they can actually accurately test how effective this drug could be in slowing down the progression of Parkinson’s.

We’ll close out today explaining a little bit more about CBD and what it is, why it’s being used with Parkinson’s, what kind of research is going into CBD and any precautions we should be taking about CBD. I’ll let Dr. Hawkins explain. And then I’ll come in with a follow up on some of the preliminary research findings that he emailed me about from this summer.

Dr. Trevor Hawkins: The whole marijuana, CBD, cannabinoid issue is very fascinating. Especially being in Colorado and being kind of on the front line of a lot of it. I think the big takeaway is there’s so much anecdotal evidence out there that it definitely warrants taking a deeper look at what’s actually going on.

Some of the problems with where the field is at is that there are so many different active chemical compounds within marijuana. So it’s about which are the right ones? What’s the right dose? How do you deliver it: do you have to smoke it, is it edible, does it have to be a pill? You do an ointment and with symptoms in particular, is it actually going to be helping?

So, there are still a lot of pieces to be worked out on that front. And certainly the other big problem is that there’s really no oversight. So even the individual, this is where I find a lot of issues with my patients, where they’ll tell me that they found a particular batch or strain or pill that works really, really well for them. Then they’ll get a refill and that same one that was the miracle drug is putting them in the hospital with psychosis. I think part of that is just you have to be buyer beware on a lot of that, with the current state of affairs. But I think it’s going to be an area, you know, that will hopefully take off research wise and really start honing in and hopefully the industry itself will start being a little bit more regulated – kind of similar to what we with herbal supplements and how there are self regulating groups that will still give their medication for testing to the FDA, like the Costco brands and Sam’s Club. But right now, there’s still a lot of variability.

We are going to be potentially doing a clinical trial, the second phase at the University of Colorado, hopefully sometime in the summer looking at CBD as a kind of a pill, oil suspension, and its treatment of Parkinson’s trauma. We are starting to hopefully unravel the mystery, so to speak.

We went through the phase one part of that already, which was really just looking at dose. But there are certainly a lot of hurdles when you’re talking about trying to do studies on this method. One practical point is that unlike with the medications, where you have the drug companies who are willing to fund the big trial and kind of look at if they’re working, there’s really no monetary support for looking at whether or not the CBD and marijuana products work.

That’s where some of this is being dragged out is that it’s really not as big of a push to get some of those big drug trials going. And all the federal hoops you have to jump through to make sure that that’s okay. We’ll see. We are very excited to be able to start putting together what is the right form and looking at potential CBD products and then seeing what is it going to do for us for our Parkinson patients.

The only caveat is that I tell all my patients two very important things about it:

If they are using CDB or marijuana, make sure you’re telling all your providers that you’re doing it because it is a drug that has a lot of drug to drug interactions. So it’s important to make sure that they’re dosing their other medications correctly. Just because it’s natural doesn’t mean it’s safe. Same as arsenic, it’s natural and not safe. So treat it like it’s a medication just like anything else you’re being prescribed by your doctor. That means that if you’re going to take it, you’re not immediately jumping behind the wheel of a car, you’re not down by yourself to take a bath, not putting yourself or anything in harm’s way where you wouldn’t do that with your other medications as well.
Buyer beware. Each batch is like getting a brand new medication. You don’t know 100% what it’s going to do for you; so, you’ve got to treat it as if you’ve never taken it before.

But I think it’s a very exciting time to be in Colorado. As this field is taking off, I think we’re very close to hopefully figuring out some of these things in a more scientific way about what they can potentially do for us.

Kelsey Phinney: One thing I want to reiterate is that Dr. Hawkins cautions all of us and all of you that it’s important to treat CBD like any new medication, tell your doctor if you want to try it, or if you’re already taking it. And please make sure it doesn’t interact with any of your other medicines.

Never try it before doing anything potentially dangerous like driving a car and treat every new batch you get, even from the same company, as if you’re trying it for the first time.

If you aren’t in Colorado or another state where all marijuana is legal, recreationally and medicinally, you may be wondering if CBD is even legal. I’ve done some research on CBD and we’ve come to use the terms cannabis, marijuana and hemp interchangeably in popular culture. But it turns out that those are three distinct plants. Marijuana and hemp are two species of cannabis. And the plants look different and have different chemical properties. And because of this, they have different definitions and are legal in different places.

The important thing and the primary difference chemically and medically between hemp and marijuana has to do with the two primary cannabidiol compounds found in the plants, THC and CBD. So hemp by definition contains less than 0.3% THC concentration, while marijuana can contain between 15 and 40% THC concentration. Both of these plants contain CBD as well.

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THC, if you don’t know, is the psychoactive compound in cannabis. It’s what produces that high feeling when someone takes it recreationally or for medical purposes. So what does this mean? CBD oil derived from hemp is legal in all 50 states. On the other hand, CBD oil derived from marijuana is not legal in every state. So you need to research your own state’s laws, and make sure that whatever you want to take is legal and then chat with your doctor about if they think it could be beneficial and doesn’t interact with any of your current medicines.

When I reached out to Dr. Hawkins about how the research was going on CBD at CU Denver and what they’ve discovered, he got back to me in an email and explained that Dr. Leheay had completed the analysis on the phase one open label trial they did. And they were just getting started on the phase two to trial which will be the placebo controlled study.

He said that the first study showed improvement in motor scores, and the sleep and mood control portion of the Parkinson’s disease rating scale. The biggest side effects were likely in part related to the fact that they use an oil based supplement and they included diarrhea and abdominal pain. Additionally, two thirds of patients reported sleepiness and one third did have elevation in liver enzymes. He goes on to say, “My take is it most likely does have true treatment benefits, including helping with mood and sleep, and perhaps motor symptoms.” He says that it’s maybe unclear if these motor symptoms improve because of the improved sleep or mood, or if there is an independent effect on the actual motor symptoms. And he concludes his sentiment by saying “however, the adverse effects reflect the potential risks and lack of unified understanding of best dose as well as how it is prepared”.

So a couple takeaways from all of this is to hopefully give all of you a little bit more information so that you can ask your doctor questions about alternative therapies for your motor symptoms and other symptoms. And keep an eye out for new research and hopefully feel some hope that new things are in the works.

And you never know what could be truly helpful. As always, because everyone’s Parkinson’s is a little different and everyone responds differently to medications, it is so important to have an open dialogue with your doctors about anything that you even try, or take. Especially if you’re adding in a supplement like CBD, you need to be careful and check in with your doctor about it. So that’s all for this episode. Thank you so much to Dr. Hawkins for all the information. Please tune in next Wednesday for an episode about exercise. And thank you for listening.

Safety and Tolerability of Cannabidiol in Parkinson Disease: An Open Label, Dose-Escalation Study

1 Department of Neurology, University of Colorado School of Medicine, Aurora, Colorado, USA.

Ying Liu

1 Department of Neurology, University of Colorado School of Medicine, Aurora, Colorado, USA.

Felecia Hart

2 Department of Clinical Pharmacy, University of Colorado School of Medicine, Aurora, Colorado, USA.

Christen Epstein

1 Department of Neurology, University of Colorado School of Medicine, Aurora, Colorado, USA.

Mary Cook

1 Department of Neurology, University of Colorado School of Medicine, Aurora, Colorado, USA.

Stefan Sillau

1 Department of Neurology, University of Colorado School of Medicine, Aurora, Colorado, USA.

Jost Klawitter

3 Department of Anesthesiology, University of Colorado School of Medicine, Aurora, Colorado, USA.

Heike Newman

4 Regulatory Compliance Office, University of Colorado, Aurora, Colorado, USA.

Cristina Sempio

3 Department of Anesthesiology, University of Colorado School of Medicine, Aurora, Colorado, USA.

Lisa Forman

5 Department of Gastroenterology, University of Colorado School of Medicine, Aurora, Colorado, USA.

Lauren Seeberger

1 Department of Neurology, University of Colorado School of Medicine, Aurora, Colorado, USA.

Olga Klepitskaya

1 Department of Neurology, University of Colorado School of Medicine, Aurora, Colorado, USA.

Zachrey Baud

1 Department of Neurology, University of Colorado School of Medicine, Aurora, Colorado, USA.

Jacquelyn Bainbridge

2 Department of Clinical Pharmacy, University of Colorado School of Medicine, Aurora, Colorado, USA.

Abstract

Background: Cannabis is increasingly used in Parkinson disease (PD), despite little information regarding benefits and risks.

Objectives: To investigate the safety and tolerability of a range of doses of cannabidiol (CBD), a nonintoxicating component of cannabis, and it’s effect on common parkinsonian symptoms.

Methods: In this open-label study Coloradans with PD, substantial rest tremor, not using cannabis received plant-derived highly purified CBD (Epidiolex ® ; 100 mg/mL). CBD was titrated from 5 to 20–25 mg/kg/day and maintained for 10–15 days.

Results: Fifteen participants enrolled, two were screen failures. All 13 participants (10 male), mean (SD) age 68.15 (6.05), with 6.1 (4.0) years of PD, reported adverse events, including diarrhea (85%), somnolence (69%), fatigue (62%), weight gain (31%), dizziness (23%), abdominal pain (23%), and headache, weight loss, nausea, anorexia, and increased appetite (each 5%). Adverse events were mostly mild; none serious. Elevated liver enzymes, mostly a cholestatic pattern, occurred in five (38.5%) participants on 20–25 mg/kg/day, only one symptomatic. Three (23%) dropped out due to intolerance. Ten (eight male) that completed the study had improvement in total and motor Movement Disorder Society Unified Parkinson Disease Rating Scale scores of 7.70 (9.39, mean decrease 17.8%, p=0.012) and 6.10 (6.64, mean decrease 24.7%, p=0.004), respectively. Nighttime sleep and emotional/behavioral dyscontrol scores also improved significantly.

Conclusions: CBD, in the form of Epidiolex, may be efficacious in PD, but the relatively high dose used in this study was associated with liver enzyme elevations. Randomized controlled trials are needed to investigate various forms of cannabis in PD.

Introduction

Parkinson disease (PD) is a common neurodegenerative disorder characterized by motor symptoms of resting tremor, bradykinesia, rigidity, and impaired balance that often has nonmotor symptoms of cognitive dysfunction, anxiety, and psychosis. Since standard treatments may only partially relieve symptoms many patients are turning to complementary and alternative medications. In many states across the United States, cannabis use has been permitted medicinally and recreationally, so increasing numbers of PD patients are using formulations with a myriad of cannabinoid components. In an anonymous web-based survey, 47.8% of PD patients reported that cannabis reduced their use of prescription medication. 1 Since the major component of the cannabis plant, Δ-9 tetrahydrocannabinol (THC), is known to sometimes cause psychosis, 2–4 cognitive dysfunction, 4–6 anxiety, 7–9 and balance impairment, 10,11 it may be especially harmful in PD. Conversely, cannabidiol (CBD), the next largest cannabinoid plant constituent, may have neuroprotective, anxiolytic, and antipsychotic effects, 12 as well as relatively good tolerability; thus, it may have benefits in PD. The purpose of this study is to begin investigating the effects of cannabis in PD by focusing on the safety of a range of doses of a purified CBD formulation, Epidiolex ® . In addition, the effect of CBD on common PD symptoms was studied.

Review of the literature shows that CBD is well tolerated at doses up to 1500 mg/day, 13–15 or ∼13 mg/kg/day, and most definitively has a central nervous system effect, for example, reduction of seizures, at 25 mg/kg/day. 16 However, the literature is sparse and inconclusive, and most studies used much lower doses, usually in combination with THC, and have shown a range of effects. A study in Huntington’s disease using purified CBD at 10 mg/kg/day showed no effect. 17 Thus, we designed this study to evaluate doses ranging from 5 to 25 mg/kg/day.

The U.S. governmental policies at the time this study was conducted required that human interventional cannabis research uses a study drug that is obtained from the National Institute on Drug Abuse (NIDA) or another Drug Enforcement Administration (DEA)-registered source. NIDA did not have a cannabis product with the desired dose of CBD that also had low enough THC content. Thus a highly purified form of CBD with minimal THC content was used for this study that was obtained from a DEA approved source.

Methods

Study participants

The trial was conducted at the University of Colorado Movement Disorders Center, an academic, tertiary referral center. Participants were eligible if they were 45–78 years old; lived in Colorado; met U.K. PD Society Brain Bank Clinical Diagnostic Criteria for idiopathic PD; and had resting tremor with at least an amplitude of ≥1 cm, that is, score of ≥2 on item 3.17 of the Movement Disorder Society Unified Parkinson Disease Rating Scale (MDS-UPDRS), in any limb while taking their usual PD medication, that is, while in the ON state. Participants had to agree not to operate a motor vehicle while taking the study drug, as required by the FDA. Key exclusion criteria included the following: cannabis detectable at the screening visit or THC detectable at the baseline visit; history of drug or alcohol dependence; use of dopamine antagonists within 180 days; and currently taking specified medications that are known to increase the risk of hepatotoxicity.

Written informed consent was obtained from all participants. This study is registered with ClinicalTrials.gov, <"type":"clinical-trial","attrs":<"text":"NCT02818777","term_id":"NCT02818777">> NCT02818777, and approved by the Colorado Multiple Institutional Review Board. Study progress and safety were monitored by its Colorado Clinical & Translational Sciences Institute Drug Safety and Monitoring Board.

Study design and procedures

Participants in this open label, dose escalation study had a screening visit, a baseline visit within 3 weeks, a final assessment visit on their maximal dose, and a safety visit 2 weeks later. From the baseline visit, qualified study participants took a pharmaceutical formulation of highly purified CBD derived from Cannabis sativa L. plant in oral sesame oil solution (100 mg/mL, Epidiolex in the United States; GW Research Ltd., Cambridge, United Kingdom) with ≤0.15% THC twice daily. CBD was started at 5 mg/kg/day and was titrated by adjusting the dose every ≥4th day, by up to 5 mg/kg/day, until the maximum targeted (20–25 mg/kg/day) or tolerated dose was achieved. Participants maintained their maximal dose, as tolerated, for 10–15 days, and then stopped it the next day. A registered nurse or nurse practitioner interviewed participants using a standardized phone script at each dose regarding study drug effects and at 3 days after stopping CBD to check for signs of withdrawal. At study visits, efficacy assessments were conducted when the participants’ PD medications were in optimal effect, that is, when participants were in their ON state. To monitor study drug compliance, participants filled out home diaries and study drug bottles were weighed. Participants maintained the same PD medications throughout the study period.

CBD analysis

Cannabinoid concentrations were measured in plasma samples collected during the screening visit, baseline visit (before the first dose was administered), at final assessment visit (3 h after the maximal dose was administered), and at the safety follow-up visit. A previously validated high-performance liquid chromatography atmospheric pressure chemical ionization mass spectrometry-based assay determined cannabinoid levels. 19

Outcomes

The primary outcome was safety and tolerability of CBD and was measured in four ways: (1) the frequency and severity of adverse effects, using Common Terminology Criteria for Adverse Events terminology and grading, at each dose level; (2) vital signs, orthostatic blood pressures, physical examinations, electrocardiograms, and laboratory values (hematology, complete metabolic liver function tests, and urinalysis); (3) standardized assessment tools on relevant symptoms of PD; and (4) the proportion of participants that dropped out of the study due to study drug intolerance.

The prespecified major secondary outcome was the effect of CBD on severity and duration of tremor: the change from baseline to the maximal dose in the total of scores on items 3.17 and 3.18 in part III of the MDS-UPDRS in the ON state if the participant was taking anti-PD medication. Item 3.17 measures rest tremor amplitude, ranging from 0 (no tremor) to 4 (>10 cm in maximal amplitude) for each extremity and ranging from 0 (no tremor) to 4 (>3 cm in maximal amplitude) for lips/jaw. Item 3.18 measures constancy of rest tremor, ranging from 0 (no tremor) to 4 (present >75% of the examination). Other secondary outcomes were other motor signs and the common nonmotor symptoms of PD. The other motor signs were evaluated with the MDS-UPDRS parts II, III, and IV, as well as the Unified Dyskinesia Rating Scale (UDysRS). The effect of CBD on common nonmotor symptoms was measured using the following tools: MDS-UPDRS part I, Montreal Cognitive Assessment (MoCA), parts of Quality of Life in Neurological Disorders (Neurol-QOL) short forms for anxiety, depression, and emotional and behavioral dyscontrol, the Neuropsychiatric Inventory Questionnaire (NPI, © JL Cummings, 1994), Scales for Outcomes in PD-Sleep Scale (SCOPA-Sleep), 20 Fatigue Severity Scale (FSS, © Lauren B. Knupps), the Patient Reported Outcome Measurement Information System (PROMIS) pain intensity and pain interference short forms, Impulsive-Compulsive disorders in Parkinson’s disease Rating Scale (QUIP-RS), the Columbia-Suicide Severity Rating Scale (C-SSRS), 21 International Restless Legs Syndrome Study Group Rating Scale (IRLS), 22 and REM (rapid eye movement) sleep behavior disorder screening questionnaire (RBDSQ). 23

Statistical analysis

Proportions presented for each adverse event type are the number of patients with any instance of the event divided by the total number of patients. Mean severity and standard deviation were calculated by averaging all the severity scores for each adverse event type across all the occurrences of the event within each patient and then taking the mean and standard deviation of the patient means, weighted by number of events. The same procedure was performed on any event type and by dose for any event type and several of the most common adverse event types. Generalized estimating equations (GEE) logistic regression models and Cochran-Mantel-Haenszel statistics were used to investigate the effect of dosage on the odds of adverse events.

Pre–Post changes in the motor and nonmotor scores were analyzed by performing permutation paired t-tests, with a univariate alpha=0.05 considered statistically significant. The Benjamini–Hochberg procedure was considered to control the false discovery rate (FDR) at alpha=0.05.

Findings

Participant characteristics

Between October 17, 2016 and June 19, 2017, 15 participants were enrolled, one was a screen failure due to electrocardiogram changes, one withdrew consent before starting treatment, thus 13 started study drug. Safety data are presented on these 13 participants. Three dropped out due to treatment related adverse events, thus 10 completed the study. Efficacy data are presented on these 10 participants. Note that these 10 participants are also in the Safety Group. Baseline characteristics of the 13 participants that took at least 1 dose of study drug, the Safety Group, and of the 10 participants, the Efficacy Group, that finished the study are described in Table 1 .

Table 1.

Characteristics of the Participants at Baseline

  Safety analysis group (n=13) Efficacy analysis group a (n=10)
Age, years, mean (SD) 68.1 (6.05) 68.7 (6.65)
Male, n (%) 10 (77) 8 (80)
Total MDS-UPDRS score, mean (SD) 39.2 (13.3) 43.2 (12.2)
Motor MDS-UPDRS score, mean (SD) 22.9 (9.3) 24.7 (8.9)
Disease duration, years, mean (SD) 6.1 (4.0) 6.3 (4.5)
H&Y, mean (SD) 1.73 (0.56) 1.75 (0.59)
MoCA, mean (SD) 28.2 (1.6) 27.9 (1.6)
Levodopa daily dose equivalent, b mean (SD) 398.3 (331.0) 443.8 (349.0)

H&Y, Hoehn and Yahr scale; MDS-UPDRS, Movement Disorder Society Unified Parkinson Disease Rating Scale; MoCA, Montreal Cognitive Assessment.

Safety and tolerability

Due to adverse events experienced by the first five enrolled participants, the maximal targeted dose was reduced from 25 to 20 mg/kg/day. The mean maximum CBD dose was 19.4 (SD 5.2) mg/kg/day, that is, 1623.0 mg/day (range 552.5–3458.8 mg/day) in the safety analysis group and 20.3 (3.4) mg/kg/day in the efficacy analysis group, that is, 1731.4 mg/day (range 1014.0–3458.8 mg/day). The mean maximum volume of sesame oil taken per participant per day was 16 mL (range 5.5–34.5 mL) in the safety analysis group. The average length of time on study drug was 26.8 (8.0) days in safety group and 28.5 (3.4) days in efficacy group.

Adverse events, shown in Table 2 , reported in all participants, were transient and mild (1.17±0.49) on average. The adverse events reported at each dose are shown in Figure 1 . There were no serious adverse events and no withdrawal symptoms. The percentage of participants reporting diarrhea directly correlated with dosage, as shown in Figure 1 . A GEE logistic regression model found that each 5 mg increase in the dosage increased the odds of diarrhea by an estimated factor of 2.32 (95% CI: 1.46–3.69, p=0.01).

Adverse event frequency by dosage.

Table 2.

Adverse Effects Reported in Safety Group Analysis (n=13)

Adverse effects a Frequency, n (%) Severity, mean (SD)
Any 13 (100) 1.17 (0.49)
Diarrhea 11 (84.6) 1.24 (0.68)
Somnolence 9 (69.2) 1.10 (0.31)
Fatigue 8 (61.5) 1.17 (0.22)
Weight gain 4 (30.8) 1.17 (0.33)
Abdominal pain 3 (23.1) 1 (0)
Dizziness 3 (23.1) 1 (0)
Weight loss, nausea, anorexia, increased appetite, headache b 2 (15.4) N=6 (46.2%) 1.29 (0.37)
Vomiting, flatulence, gastroesophageal reflux disease, allergic reaction, spasm, fever, weakness b 1 (7.7) N=6 (46.2%) 1.13 (0.27)

There were no clinically significant adverse changes in other outcome safety assessments, except for increases in liver enzymes, especially alkaline phosphatase. Liver enzymes were measured at baseline and not again until the final assessment visit when participants were on their highest tolerated or the targeted dose. Elevations, shown in Table 3 , occurred in five (38.5%) participants, one symptomatic and four asymptomatic, all on 20–25 mg/kg/day. The symptomatic participant, ID 02, developed moderate anorexia, diarrhea, somnolence, mild abdominal pain, dizziness, fatigue, fever, headache, and weight loss; had a cholestatic pattern of liver enzyme changes; and his liver ultrasound was normal. All symptoms and laboratory changes resolved after discontinuation of study drug.

Table 3.

Liver Function Test, Final Dose, and Medications

ID Age Sex ALT (normal 7–52 U/L) BL, final, SF AST (normal 12–39 U/L) BL, final, SF GGT (normal 9–64 U/L) BL, final, SF ALP (normal 39–117 U/L) BL, final, SF, FU T. Bili (normal 0.1–1.3 mg/dL) BL, final, SF Final dose, mg/kg/day Medications known to cause ANY hepatotoxicity a Other medications
02 b 70 M 11, 150, 49 16, 58, 23 9, 206, 116 99, 503, 247, 103 0.9, 1.4, 1.0 25 Aspirin, celecoxib, rasagiline None
06 b 71 M 36, 64, 34 27, 46, 25 49, 101, 75 54, 81, 60 1.3, 1.8, 1.2 25 Acetaminophen, fish oil, lisinopril, rasagiline, sildenafil, vitamin B6 Biofreeze, glucosamine chondroitin, loperamide, magnesium, potassium citrate, vitamin B12, vitamin D3
08 b 70 M 12, 41, 9 17, 80, 29 29, 229, 229 12, 317, 182, 94 0.7, 0.9, 0.4 20 Acetaminophen, aspirin, atorvastatin, doxazosin, esomeprazole, meloxicam Carbidopa/levodopa, finasteride
09 b 68 M 13, 29, 11 19, 22, 16 46, 129, 68 108, 137, 107 0.7, 0.7, 0.4 20 Aspirin, ibuprofen, lisinopril, methylphenidate, ropinirole, selegiline, trazodone Melatonin, vitamin D3
10 b 68 M 16, 20, 12 15, 30, 18 20, 162, 62 75, 134, 84 0.6, 0.6, 0.6 20 Amantadine, aspirin, atorvastatin, citalopram, ibuprofen, omeprazole, Ropinirole Carbidopa/levodopa, coQ10, folic acid, melatonin, vitamin C
01 68 F 4, 8, N/A 17, 20, N/A N/A, 13, N/A 62, 53, N/A 0.4, 0.4, N/A 17.5 Escitalopram, fish oil, gabapentin, lansoprazole, lorazepam, ropinirole, prasterone Carbidopa/levodopa, CoQ10, garlic, magnesium, melatonin, MiraLAX ® , nystatin, senna, turmeric, vitamin B complex, vitamin D2
03 75 M 13, 14, N/A 15, 19, N/A 17, 16, N/A 33, 31, N/A 0.8, 1, N/A 25 Amlodipine, aspirin, hydrochlorothiazide, metoprolol, telmisartan Docusate, calcium, etanercept, magnesium, vitamin B12
04 74 M 3, 8, N/A 17, 25, N/A 20, 24, N/A 38, 38, N/A 0.4, 0.5, N/A 25 Diclofenac, hydrochlorothiazide, docosahexaenoic acid, propranolol, selegiline Carbidopa/levodopa, coQ 10, Heart Burn Relief ® , multivitamin, stool softener.
05 62 M 25, 25, N/A 21, 29, N/A 54, 51, N/A 53, 49, N/A 1, 0.8, N/A 5 Fish oil, ibuprofen (Advil ® ), meloxicam, olmesartan, rasagiline Albuterol, coQ10, fluticasone, melatonin.
07 74 M 3, 4, N/A 19, 17, N/A 13, 11, N/A 54, 49, N/A 0.5, 0.7, N/A 20 Aspirin, clonazepam, entacapone, loratadine, omeprazole, simvastatin, tramadol Carbidopa/levodopa, Centrum ® , ocuvite, omega 3, pramipexole, vitamin D3
11 58 F 20, 26, N/A 18, 18, N/A 15, 20, N/A 57, 63, N/A 0.5, 0.4, N/A 20 Estradiol, lisinopril, prasterone, progesterone, rasagiline CoQ10, magnesium, melatonin, pramipexole
13 73 M 25, 37, N/A 26, 42, N/A 24, 56, N/A 52, 64, N/A 0.7, 0.7, N/A 12.5 Acetaminophen, gabapentin, Ibuprofen, niacin/chromium Carbidopa/levodopa, coQ10, ferrous sulfate
14 56 F 4, 6, N/A 19, 20, N/A 11, 14, N/A 80, 84, N/A 0.4, 0.4, N/A 20 Conjugated estrogens, naproxen, nortriptyline, sumatriptan Bone Nutrient ® , carbidopa/levodopa, cellular vitality, diphenhydramine, essential oil, Food Nutrient ®

ALP, alkaline phosphatase; ALT, alanine transaminase; AST, aspartate transaminase; BL, baseline visit; final, final visit; FU, follow-up visit, participants had ALP checked until it was in the normal range; GGT, gamma-glutamyl transferase; M, male; mg/dL, milligrams per deciliter; SF, safety follow-up visit 2 weeks after final visit; T. Bili, total bilirubin; U/L, units per liter.

Three participants (23%) stopped study drug due to intolerability, one due to rash at 5 mg/kg/day, one to abdominal pain and gas at 17.5 mg/kg/day, and one, described above, to fatigue, diarrhea, and elevated liver enzymes, that is, hepatitis, at 25 mg/kg/day.

Efficacy

The mean decreases in the total and motor MDS-UPDRS scores at the maximal dose compared with baseline were a 17.8% (p=0.012) and 24.7% (p=0.004) improvement, respectively. Two nonmotor assessments also showed significant improvement, the SCOPA-Sleep nighttime and the emotional and behavioral dyscontrol short form. At 2 weeks follow-up, the total MDS-UPDRS and nighttime sleep assessments remained improved; the other two assessments did not. Enrolled subjects had minimal levodopa induced dyskinesia, cognitive dysfunction, restless leg syndrome symptoms, REM sleep behavior disorder, and impulsivity at baseline, and these assessments did not change on study drug. Table 4 shows the data for all assessments.

Table 4.

Change in Motor and Nonmotor Scores Among Efficacy Analysis Group (n=10)

  Baseline, mean (SD) Final, mean (SD) Change from baseline to final, mean (SD) p a Follow-up, mean (SD) Change from baseline to follow-up, mean (SD) p a
Rest Tremor b 3.10 (2.23) 2.70 (2.31) −0.40 (1.26) 0.471 4.20 (2.10) 1.10 (2.56) 0.109
Total MDS-UPDRS 43.20 (12.21) 35.50 (14.31) −7.70 (9.39) 0.012 a 35.70 (14.97) −7.50 (6.74) 0.008 a
Motor MDS-UPDRS 24.70 (8.93) 18.60 (9.66) −6.10 (6.64) 0.004 a 27.40 (10.51) 2.70 (4.74) 0.188
H&Y 1.75 (0.59) 1.80 (0.89) 0.05 (0.76) 1.000 1.95 (0.685) N/A N/A
SCOPA-Sleep NS 5.70 (2.95) 2.90 (2.60) −2.80 (3.91) 0.040 a 3.30 (2.36) −2.40 (3.66) 0.023 a
SCOPA-Sleep DS 2.60 (2.27) 2.20 (1.69) −0.40 (1.65) 0.575 2.10 (2.42) −0.50 (1.84) 0.453
Emotional and behavioral dyscontrol SF 44.39 (7.91) 39.70 (6.75) −4.69 (6.14) 0.047 a 40.17 (7.08) −4.22 (7.24) 0.125
NPI 0.78 (1.20) 0.75 (1.39) −0.13 (1.55) 1.000 N/A N/A N/A
Anxiety SF 46.24 (6.35) 46.57 (7.27) 0.33 (3.57) 0.783 45.99 (7.05) −0.25 (4.11) 0.945
Depression SF 43.09 (6.03) 42.24 (7.04) −0.85 (3.13) 0.440 41.1 (5.85) −1.99 (4.55) 0.500
Fatigue Severity Scale 28.50 (15.54) 28.00 (14.49) −0.50 (11.46) 0.907 27.4 (14.91) −1.10 (9.85) 0.648
Pain interference SF 52.25 (8.63) 49.93 (8.99) −2.320 (6.008) 0.253 49.94 (9.16) −2.31 (6.99) 0.438
Pain intensity SF 44.64 (7.36) 42.78 (9.20) −1.860 (4.711) 0.311 42.96 (9.78) −1.68 (5.20) 0.469

NPI, Neuropsychiatric Inventory Questionnaire; SCOPA-Sleep DS, Scales for Outcomes in Parkinson’s Disease-Sleep, Daytime Sleep; SCOPA-Sleep NS, Scales for Outcomes in Parkinson’s Disease-Sleep, Nighttime Sleep; SD, standard deviation; SF, Short Form.

Applying the Benjamini–Hochberg procedure to control the FDR at alpha=0.05 found none of the tests to be statistically significant. The small sample size severely limits power for multiple testing adjustment.

CBD plasma levels

Three hours after the final dose was administered, the participant on 12.5 mg/kg/day had a CBD plasma level of 181 ng/mL, while those on 20 mg/kg/day, n=7, showed plasma levels of 376±78 ng/mL (mean±SEM) and those on 25 mg/kg/day, n=2, showed plasma levels of 340±4 ng/mL. Fourteen days after discontinuation of CBD, the values were 13, 24±5, and 39±14 ng/mL for the 12.5, 20, and 25 mg/kg/day treatment groups, respectively.

Discussion

This is the first study of the effects of relatively high dose, ∼20 mg/kg/day, purified CBD in humans with PD. The purpose of the study was to determine tolerability of a range of doses in the PD population and explore efficacy. The study found that relatively high dose CBD, ∼1600 mg/day, with <0.15% THC, that is, Epidiolex, taken orally, is associated with mild adverse effects, especially somnolence, fatigue, and diarrhea, and perhaps hepatotoxicity in persons with PD. In this dose ranging study somnolence occurred early in dose titration, but improved, diarrhea was common and increased with higher doses, and the 25 mg/kg/day dose was poorly tolerated. These adverse effects were similar to those reported in prior studies in pediatric epilepsy at this dose. 16,24 However, they were more frequent in our population, perhaps due to different characteristics of the PD population or the smaller sample size in the present study. The only dose-related adverse event was diarrhea, which could be related to sesame oil. In three controlled trials conducted by GW Pharmaceuticals, manufacturer of Epidiolex, diarrhea was reported in 9% of participants on placebo, 9% on 10 mg/kg/day, and 20% on 20 mg/kg/day. a This suggests that the diarrhea is related to the CBD rather than sesame oil.

In this study five participants (38%) had transient elevated liver enzymes, one symptomatic and four asymptomatic, resolving after discontinuation of the study drug. In this study, the pattern of enzyme changes, particularly in the symptomatic patient, was consistent with a cholestatic rather than hepatocellular process. The drug may have caused idiopathic or bland cholestasis and, much less likely, granulomatous hepatitis or vanishing bile duct syndrome, since all liver tests normalized. Liver biopsy was not performed. None of these participants had significant elevated bilirubin or internalized normalized ratio, suggesting no change in liver function.

While liver enzyme elevations in a hepatocellular pattern have been reported with Epidiolex 16 on doses similar to those taken by the present study participants, the cholestatic pattern has not. Single or multiple factors, such as older age, having PD, concomitant medications, and relatively high CBD dosage, may contribute to this. To date Epidiolex has been used primarily in pediatric populations. Perhaps older age and/or pathologic mechanisms that underlie PD, for example, mitochondrial dysfunction, are relevant factors. Regarding concomitant medications, most of the participants in prior epilepsy studies on Epidiolex were also on valproate; and while none in this PD study was, they were taking concomitant medications with potential hepatotoxicity, as shown in Table 3 . Generally medications specific for PD have little potential for hepatotoxicity, with the exception of tolcapone, which none of the study participants was taking. There was no apparent diffence in the overall hepatotoxic potential of concomitant medications being taken by those that did and did not develop liver enzyme changes. Table 3 also shows the final CBD dose of participants, and again there was no apparent difference between those that did and did not have liver enzyme changes. Thus, it is unlikely that the liver enzyme elevations were solely due to hepatotoxicity of concomitant medications or CBD dose. Regarding dose, in this study liver enzymes were tested at the final, that is, highest dose, and not at lower doses, so the dose at which liver enzymes started to change is unknown. Perhaps persons with PD would have better tolerability of lower doses. Taken in whole, it is likely that multiple factors contributed to the liver enzyme changes that occurred in this study, with older age and relatively high CBD dosage being particularly relevant.

This was an open label study so no conclusions can be drawn regarding efficacy. However, assessments were done to check for hints of efficacy to inform future studies. The results suggest that CBD has a beneficial effect on total and motor MDS-UPDRS scores, nighttime sleep, and emotional and behavioral dyscontrol. Interestingly, the p-values on these assessments were still significantly or close to significantly improved 2 weeks after stopping CBD, compared to baseline. It is possible that CBD was still having some effect, since participants still had low plasma levels at that time.

A review of the literature of clinical studies of cannabinoids in PD shows that four randomized, blinded controlled studies have been reported, one Class 1 25 (according to the American Academy of Neurology Classification of Evidence for Rating of a Therapeutic Article, © 2014 American Academy of Neurology, AAN.com/guidelines), one Class 2, 26 and two Class 3. 27,28 Other studies were open label, 29–31 case reports, 32,33 or surveys. 34–36 These other studies mostly evaluated cannabis; one included CBD, 25 and three studied 99% pure CBD. 26,29,32

The presented study is the first study of the effects of relatively high dose, ∼20 mg/kg/day, purified CBD in humans with PD. There were three prior studies of purified oral CBD, with reports of effects of lower doses. A double-blind study in 21 participants using ∼4.5 mg/kg/day found no change in UPDRS and other outcomes, except improved scores on the PD Questionnaire-39, which assessed functioning and well-being. 26 An open label study in six patients found an improvement in total UPDRS scores and psychotic symptoms on ∼5 mg/kg/day of pure oral CBD. 29 The third study was open label and reported that four participants taking ∼1–4 mg/kg/day had improvement in REM sleep behavior disorder, that is, reduction in acting out dreams. 32 These three studies reported no adverse events. Other studies in PD examined the use of cannabis: two measuring the acute effects of smoked cannabis, total n=42, reported significantly improved motor UPDRS scores and reduced pain, 30,31 another administered a medium dose of oral THC (0.25 mg/kg/day) and very low dose of CBD (0.125 mg/kg/day), n=17, and showed no significant change on all measured outcomes. 25 Adverse effects of cannabis included somnolence, dizziness, decreased concentration, palpitations, and altered taste. Accumulating literature suggests that CBD may reduce psychosis, 29,37 which is a frequent debilitating symptom in PD.

Most previous pre-clinical studies using animal models of PD have focused on cannabinoid receptor 1 (CB1) agonists and antagonists, rather than pure CBD. The studies show evidence of therapeutic effects, improving motor symptoms, and levodopa induced involuntary movements, that is, dyskinesia. However, these effects were found with both CB1 agonists and antagonists. Furthermore, there is a dose dependent effect: low doses of CB1 antagonists have been reported to improve motor function and dyskinesia more consistently than CB1 agonists, while high doses of both CB1 agonists and antagonists have no effects or impair motor function. 38–47 Regarding CBD, a study using the 6-hydroxydopamine rat model of PD found that CBD, and also THC, attenuated neurodegeneration from the toxin, perhaps through antioxidant or anti-inflammatory mechanisms. 48 Another study with the same toxin inducing PD, but in mice, studied pain thresholds and suggested that CBD modulated analgesic effects by increasing anandamide, a major endocannabinoid, levels and acting on CB1 and the transient receptor potential vanilloid receptor 1 (TRPV1) and that lower doses are more effective than intermediate doses. 49 Evidence from pre-clinical studies to date suggests that there is more to learn about the effects of different types of cannabinoids on the motor signs of PD. 38–47,50–54

How CBD influences PD is unclear, as its effect in humans is complex. CBD has low affinity for the endogenous cannabinoid receptors, but it can upregulate the levels of anandamide, by inactivation of fatty acid amide hydrolase, which metabolizes anandamide. Equally important, CBD interacts with many noncannabinoid signaling systems, and these functions may vary depending on its concentration. 55 Activation of the serotonin 5-HT1A receptor may underlie improvement of motor signs. 56 Other theories involve actions at G-protein coupled receptor 55, 57,58 TRPV1, 59,60 and GRP6 receptors. For example, the G-coupled protein receptor GPR6 is highly expressed in the basal ganglia. Depletion of GPR6 causes an increase of dopamine. By acting as an inverse agonist at the GPR6 receptor, CBD boosts dopamine levels in pre-clinical studies. 61 A neuroprotective effect has been proposed due to studies showing anti-oxidant activity, for example, upregulating superoxide dismutase mRNA levels in the substantia nigra, 62–65 and through anti-inflammatory activity, for example, activating peroxisome proliferator-activated receptor gamma. 62,66–69

The plasma concentrations of CBD in our participants were consistent with prior pharmacokinetic studies of Epidiolex. Taylor et al. 70 showed in a multiple ascending dose study of Epidiolex at 750 mg and 1500 mg twice daily (21.4 and 42.8 mg/kg/day for a 70 kg person) a tmax of ∼3–5 h after administration, depending on fasting versus nonfasting state. The Cmax was also dependent on the fasting state: 335 ng/mL when subjects were fasting versus 1628 ng/mL when subjects received a high-fat breakfast. In our study CBD plasma peak concentrations 3 h after the last administration of study drug of the treatment period (10–15 days) were 376±78 ng/mL (mean±SEM) for the 20 mg/kg/day (n=7). This is consistent with the Epidiolex PK study 70 where 290 ng/mL (in the morning, fasting) and 732 ng/mL (in the afternoon, not fasting) were reported in the 750 mg (∼21 mg/kg/day) twice daily group. However, relatively high interindividual variabilities were observed in our study, likely because we did not control for food intake.

This study has some limitations. First, conclusions about adverse effects, but especially efficacy, are limited by the absence of a placebo arm. Also rater bias can occur in an open label design, both with regard to noting adverse effects, as well as rating scale assessments. Note, however, that the data that showed improved sleep and emotional and behavior dyscontrol were collected from participant questionnaires, rather than a rater. Furthermore, the number of participants was small and those included had minimal dyskinesia, cognitive dysfunction, restless leg syndrome, REM sleep behavior disorder, and impulse control disorder. These important problems may be altered by CBD treatment, but they were not addressed in this study. Furthermore, efficacy did not achieve significance when adjusted for multiple testing.

There was not a significant change in the major secondary outcome, tremor. Tremor was chosen because of the author’s clinical experience: persons with PD in clinic frequently reported reduction in tremor with CBD, but rarely reported changes in other motor symptoms. Participants had to have a tremor amplitude in the ON state of at least 2 cm to be in the study, but tremor is variable from time to time and thus may be a less reliable motor symptom to measure. Quantifying tremor at home with a device may yield a more accurate measurement.

Further study of the effects of cannabinoids in PD is greatly needed, since presently these persons are trying products with various cannabinoid compositions despite little data regarding safety and efficacy. The usual dose of CBD in dispensary products is quite variable, for example, 2–200 mg/day, is much lower than that used in this study, and the CBD is often combined with clinically relevant doses of THC. Besides dosage, routes of administration might alter outcomes, for example, smoking or vaping would likely cause more immediate intense and shorter lasting effects. As increasing numbers of persons with PD visit cannabis dispensaries, they are presented with a wide range of choices. Randomized controlled studies are needed to confirm this study’s findings and to investigate lower doses of CBD, CBD in combination with THC at varying compositions, and the effects of routes of administration.

Acknowledgments

The authors are grateful to Emil Diguilio, Sarah Fischer, and Candace Ellman for their assistance in preparation of this article, to Nicole Gendelman and the University of Colorado Department of Neurology Core Clinical Trials Team for their help with all aspects of conducting this study, and especially thank the patients that participated in this study.

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