Since its launch in the late 1960s, carbidopa/levodopa (brand name SINEMET®) is still the most effective Parkinson’s disease (PD) motor symptom treatment. However, it doesn’t address all facets of the disease. Medications to bolster its effectiveness and treat PD-related non-motor symptoms are newly available or just on the horizon.

This article is based on a Parkinson’s Foundation Expert Briefings webinar exploring innovative PD treatments by Rajesh Pahwa, MD, Director, Parkinson and Movement Disorder Division, University of Kansas Medical Center, a Parkinson’s Foundation Center of Excellence.

Pioneering Medicine

It’s an exciting time for PD drug advances. While gene therapy benefits are still being studied, many new medications are on the market or are soon to be. These new treatments are designed to tackle Parkinson’s disease challenges, including:

• Psychosis – hallucinations and delusions.
• Orthostatic hypotension – a blood pressure drop when rising or standing.
• “Off” time – when symptoms and movement difficulties increase.
• Dyskinesia – abnormal, involuntary muscle movement.
• Dementia – memory and thinking declines.
• Falls – PD can cause slowness of movements, increasing falling and other risks.

Current Treatments

Parkinson's Disease Psychosis

PD-associated psychosis can be caused by the disease itself or PD medications. Challenging for people with PD and caregivers, symptoms include confusion, delusions and hallucinations. Report any changes to your medical team.

Pimavanserin (Nuplazid®), newer to the market, is the only approved treatment for PD psychosis. It does not block dopamine or worsen motor symptoms. It can improve hallucinations, delusions, night-time sleep and daytime sleepiness. Side effects include nausea, confusion and hallucinations.

Orthosstatic Hypotension

From 20 to 50 percent of people living with PD experience a significant blood pressure drop upon standing, known as orthostatic hypotension; certain medications can worsen this. This drop can cause lightheadedness or fainting, and other symptoms.

Droxidopa (NORTHERA®) treats lightheadedness. It should not be taken within five hours of bedtime. Side effects include headache, dizziness, nausea, fatigue and high blood pressure when lying down.

"Off"-Time Advancements

Levodopa is synthesized in the brain into dopamine, making it key to PD symptom management. But several factors can interfere with steady, accurate dose delivery. When medication is not taken on time, or absorption is delayed, freezing and other sudden and debilitating motor symptoms can occur. These newer medications can help tackle “off” periods.

Carbidopa/Levodopa Enteral Suspension (Duopa™)

Duopa™ therapy, a newer carbidopa/levodopa treatment, can benefit people with advanced PD who respond well to levodopa and experience three or more “off” hours daily. It’s delivered in gel form (called enteral suspension). Duopa™ users must first have surgery to place a tube in their intestine that is later connected to a pump that delivers Duopa™.

Safinamide (XADAGO®)

Safinamide tablets (XADAGO®) are an add-on treatment for people with Parkinson’s taking carbidopa/levodopa and experiencing “off” times. Safinamide is a monoamine oxidase B (MAO-B) inhibitor that can reduce “off” times up to 55 minutes a day, without dyskinesia. Interactions include other MAO-B class drugs, certain antidepressants and the cold medicine dextromethorphan. Anyone taking a PD medication should talk to their doctor and pharmacist about potential drug interactions.

On-Demand Therapy

Levodopa Inhalation (INBRIJA™)

The levodopa inhalation powder INBRIJA™ is an add-on drug for “off” periods in people taking carbidopa/levodopa. Administered via inhaler, it can be used up to five times a day, improving “off” symptoms as soon as 10 minutes and lasting up to 60 minutes. This can improve symptoms for people with decreased gut motility while waiting for oral carbidopa/levodopa to take effect.

Amantadine ER capsules (GOCOVRI®)

This is the only medication to treat dyskinesia and “off” time in people with PD taking carbidopa/levodopa. It must be taken before bedtime and provides control of dyskinesia upon awakening and throughout the day. It can cause hallucinations and lightheadedness. This medication is different from immediate-release amantadine and amantadine ER tablets (OSMOLEX ER™) which are not approved for dyskinesia or “off” time.

IncobotulinumtoxinA (XEOMIN)

More than 50 percent of people with PD can have excessive drooling, causing skin breakdown around the mouth, odors, embarrassment or choking. Two injections on the face, every 3-4 months of XEOMIN, can manage symptoms.

Future Therapies

Sublingual Apomorphine

Apomorphine is administered through injections under the skin. Sublingual apomorphine, dissolved under the tongue, can relieve “wearing off” episodes for people with Parkinson’s disease in 15 minutes and lasts up to 90 minutes. Side effects can include nausea, sleepiness, and dizziness.

Rimabotulinumtoxin B (MYOBLOC®)

Rimabotulinumtoxin B is currently approved for dystonia and used off-label for drooling. It is undergoing trials to treat drooling. Side effects include dry mouth, mild swallowing difficulty, mild chewing weakness and saliva thickness changes.

Adenosine A2 Antagonist: Istradefylline

A group of brain circuits called the basal ganglia play a role in causing PD symptoms. The basal ganglia have adenosine A2A receptors that are located next to dopamine receptors. Scientists believe that activating the dopamine receptor or blocking the adenosine A2 receptor can improve PD symptoms.

Istradefylline, an adenosine A2A receptor antagonist shows mild motor symptom fluctuation improvements. Approved for use in Japan, Istradefylline has also received U.S. FDA approval.

Subcutaneous Apomorphine Infusion

Available in Europe, subcutaneous apomorphine treatment offers a less invasive motor fluctuation treatment option. A small delivery tube placed under the skin is connected to an apomorphine-filled pumping device. It can reduce daily “off” time and possibly dyskinesia by reducing needed levodopa dose. Those with hallucinations and dementia might not be candidates.

Subcutaneous Carbidopa/Levodopa Pump

Two companies are currently developing pumps for continuous under-skin carbidopa/levodopa therapy to reduce “off” times and motor symptom fluctuations. The pumps can be used around the clock and don’t require surgery.

Carbidopa/levodopa extended release

New tests are underway for extended-release carbidopa/levodopa therapy to reduce “off” times and motor symptom fluctuations.

• Accordion Pill™, Carbidopa/Levodopa (AP-CD/LD) maker, will begin its Phase 3 clinical trial of new delivery technology. The Accordion Pill slowly releases treatment in the stomach for more steady absorption.
• IPX203, an investigational extended-release oral carbidopa/levodopa formulation that increases “on” time, is currently enrolling participants in its Phase 3 clinical study.

Opicapone

Experimental opicapone is a COMT (catechol-o-methyl transferase) inhibitor. This drug class can extend levodopa benefits. Available in Europe, opicapone reduces “off” time for people with PD experiencing levodopa effectiveness fluctuations.

If you have any questions about managing Parkinson’s, PD medications or caregiving, call our Helpline at 1-800-4PD-INFO (473-4636) on weekdays from 9 a.m. to 8 p.m. You can also check out these resources:

• Prescription Medications
• For Caregivers
• Episode 6: New Levodopa Delivery Methods for Parkinson’s
• Parkinson’s Treatment

This Parkinson’s Awareness Month, we asked our Parkinson’s disease (PD) community to share their keys to Parkinson’s with us. We received hundreds of keys to living well with Parkinson’s!

Whether you are living with PD, are a caregiver or a healthcare professional, thank you for sharing your tips that make life a little easier. We will be posting your keys at Parkinson.org/Blog throughout the year but check out our top 10 keys submitted by YOU.

Exercise

“I listen to audiobooks and love good thrillers. I tease myself into exercising by allowing myself the satisfaction of hearing what happens next only when I’m exercising.”
- Patricia

“Create a playlist for walking. My symptoms get worse towards the end of long walks as I tire. By creating a playlist of songs with a good strong walking beat, the muscle memory kicks in and helps my body finish the walk strong instead of dragging one heel and not having one arm swing.”
- Fred

“For me, I have been blessed to be part of the Rock Steady Boxing (RSB) family for the last 3 plus years. Our coaches encourage us to push ourselves to continue to improve our strength, balance, movements, stamina and endurance. We have class 4 times a week and what a great and supportive new family of friends we have in each other! If you had told me that I would be doing a boxing workout at age 71 for an hour 3-4 times a week, I probably would have laughed. Rock Steady Boxing has given me a whole new positive outlook on my Parkinson's.”
- Wayne

Medication

“I use a black container to put all my husband’s medications in when I get them ready for him to take. I used to use little clear plastic cups that fruit snacks come in, but since most of his pills are white or light colored it was sometimes for him to see if he took them all. Then I found some black sauce cups from an Italian restaurant and he said he could see the pills much better against the black.”
- Susan

“Planning. I am the live-in caregiver for my mom with PD. I set aside a few hours one day a month to set up her pills in four, seven-day containers. That way in case something comes up with her or me at least we have her pills ready. I also set alarm timers in her phone and mine for her pill times. Such a big help!”
- Megan

Daily Living

“My key to living well with Parkinson’s is a metronome. When I get up in the morning, I have trouble walking because of freezing issues. It is very frustrating. There are ways to trick your brain into walking, but the best thing I have found is a metronome. The tick, tick, tick helps me to get going. Now I don’t want to carry a metronome around and as they say, ‘there’s an app for that.’ I have it on my phone and it is my key to get my morning moving!”
- Joyce

“I have rather severe tremors and eating gets pretty messy. I find that if I put my plate of food on top of a large bowl, the distance from plate to mouth is much reduced, which makes more food stay on the spoon or fork during that journey. It is a very small thing but for me, it makes a big difference.”
- Carole

“Use supermarket gift cards so you don't have to sign for a credit card or fumble with paper money and coins.”
- Sandra

“To decrease my leg pain/stiffness when I go to sleep, I do an Epsom salt soak. Heat the water as hot as you can stand it (without sustaining a burn). Add two cups of Epsom salts (there are some that are infused with lavender) and 1/2 cup baking soda. To enhance the experience, light a candle and/or play soothing music. Soak for 20 to 30 minutes.”
- Moises

"Since my hands are weak, I use a Waterpik, face scrubber, button hook, electric toothbrush and hair dryer holder to help me get dressed and out the door faster. My best tip is using a seat belt extender in my car so that I can buckle up with my right hand. These things are small but make life so much easier. Also, it's important to have a 'happy place' and parrots are mine!"
- Martha

Many people with advanced Parkinson’s disease (PD) suffer from gait (walking) dysfunction, freezing of gait and postural instability. These symptoms can cause falling, resulting in a multitude of injuries, a loss of personal freedom, caregiver stress and a reduction in the quality of life (Pirker & Katzenschlager, 2017; Samotus, Parrent, & Jog, 2018). Medications, such as levodopa, rarely helps with these specific motor symptoms, while deep brain stimulation (DBS) results are limited and unpredictable for these particular symptoms. The fact is, current PD medications, therapies or surgical procedures do not effectively address this debilitating unmet need. This lack of options might be changing, due to an intervention called spinal cord stimulation (SCS).

Surgically implanted, SCS is a device that alters nerve activity by sending a low-voltage electrical current to select areas of the spinal cord. These voltage settings are adjustable post-implantation, which allows for personalized optimization. SCS is currently used to treat people with chronic back and nerve pain, as well as for neuropathic pain, such as diabetic neuropathy, and chemotherapy or radiation induced neuropathy. Exploring its usefulness for people with PD has just begun.

Recently published in the journal of Movement Disorders, a study titled, “Spinal Cord Stimulation Therapy for Gait Dysfunction in Advanced Parkinson's Disease Patients” (Samotus et al., 2018), a six-month pilot study recruited five PD participants with advanced PD. These participants were chosen based on convenience. Participants were an average age of 71 with average disease duration of 14 years. Participants who had a stroke (or any other neurological diseases) and moderately severe parkinsonism in the context of unstable medication treatment (Samotus et al., 2018) were not included in the study. All five participants underwent mid-thoracic spinal cord stimulation surgery and a dorsal spinal cord stimulator was implanted in the epidural space (near the lower back).

This study evaluated SCS efficacy by clinical evaluation and objective gait analysis before and after surgery. A 20-foot gait detection mat equipped with pressure sensors — a relatively new technology (Muro-de-la-Herran, Garcia-Zapirain, & Mendez-Zorrilla, 2014) — was used to measure various features of gait such as step length, stride width, stride velocity, step time, stance, swing, and percentage of time one or two feet are on the ground. To measure freezing of gait, a timed sit-to-stand test was used, as well as an automated freezing detection program that measured changes in foot pressure.

The study also evaluated different frequency and pulse width combinations via gait analysis multiple times 1-4 months after surgery. Eleven frequency and pulse width SCS combinations were tested. Of note, the freezing questionnaire, the Unified Parkinson’s Disease Rating Scale (UPDRS) motor items, Activities-specific Balance Confidence Scale (ABC), and Parkinson’s Disease Questionnaire (PDQ-8) were given to all five participants at every visit.

Results

• Six months post-implantation, there was an average improvement of 33.5%, in the UPDRS motor score, 26.8% in the FOG questionnaire and 71.4%, in the ABC score.
• Significant improvement in all participants’ confidence to complete daily activities, especially around and outside the house, occurred in week six and improvements were maintained following week 10, resulting in an average improvement of 71.4% in week 24 compared to before the SCS implantation.
• The number of freezing episodes captured on the gait mat dropped quickly from an average of 16 before surgery to zero six months after surgery, per study participant, on levodopa and off stimulation.
• Stride velocity significantly improved by 42.3%, mean step length improved by 38.8% and the time in seconds for a participant to arise from a chair to a standing position improved by 50.3%.
• By week 24, two of the five participants were able to walk without assistance whereas they needed it before surgery, and three of the five participants reported that their activities of daily living were now only moderately affected by gait dysfunction, whereas they were severely affected before surgery.
• One participant reported no longer needing to use his wheelchair and was solely using a walker by the end of the study,
• No adverse effects were reported.

What Does This Mean?

First presented at the 21st International Congress of Parkinson’s Disease and Movement Disorders, this is the first study to use objective gait technology to assess SCS efficacy for people with advanced PD.

Ranging from significant improvement in all study participants’ confidence in performing activities of daily living, to one of the participants no longer needing a wheelchair, to sustained improvements in gait, the pilot study results are encouraging. Stride velocity improved by 42.3%, average step length improved by 38.8% and the time in seconds for a participant to stand up from a chair improved by 50.3%. Perhaps most impressive was the reporting of zero freezing episodes six months after SCS surgical implantation with no adverse effects.

Further, SCS technology proved to be personalized, as doctors were able to adjust technology after implantation in order to provide the optimal therapeutic value. Unlike most surgical procedures, SCS is reversible. Also, important to note, SCS runs on batteries — some are rechargeable, and others last up to 5 years (NIH, 2019).

Although it is a small pilot study, it nonetheless demonstrated that SCS may offer some significant therapeutic value for people with advanced PD. A larger and longer clinical study is warranted to see if these rather remarkable preliminary results can be replicated.

Learn More

The Parkinson’s Foundation believes in empowering the Parkinson’s community through education. Learn more about freezing, balance, gait and falls and Parkinson’s in the below Parkinson’s Foundation resources or by calling our free Helpline at 1-800-4PD-INFO (473-4636).
• Walking with Parkinson’s: Freezing, Balance and Falls
• Expert Briefings: Gait, Balance and Falls in Parkinson's Disease
• Podcast Episode 18: Stall the Fall

Over the next three years the Parkinson’s Foundation will invest more than $50 million to Parkinson’s disease (PD) research and clinical care. At the heart of our research initiatives are scientists and researchers who have received Foundation awards to improve our understanding of Parkinson’s, which will ultimately lead us to a cure.

Alpha-synuclein (αSyn)is a protein central to Parkinson’s. In Parkinson’s, this protein misfolds, forming a clump in the brain. Large clumps are known as “Lewy bodies” and disrupt the brain’s normal functioning in people with PD.

Alpha-synuclein is also involved in the regulation of lipids and fatty acids, which help to prevent disease-associated changes in the brain. In Parkinson’s, alpha-synuclein is destabilized. This makes the protein more likely to break down and clump together. What triggers the destabilization of alpha-synuclein in the human brain remains one of the most critical questions in the study of Parkinson’s.

Tim Bartels, MSc, PhD, from Brigham and Women's Hospital Inc., received a Parkinson’s Foundation research grant to gain a better understating of alpha-synuclein in Parkinson’s. He and his research team will analyze the interactions of lipids with different forms of alpha-synuclein in human brain samples. Dr. Bartels hopes to discover which lipids and fatty acids prevent alpha-synuclein aggregation and which ones promote aggregation.

He will also investigate the normal interaction of alpha-synuclein with fatty acids and lipids. Together, these approaches should suggest how to develop drugs that stabilize alpha-synuclein by mimicking the beneficial lipids and fatty acids.

Dr. Bartels team may also find a signature of specific lipids and fatty acids that are associated with PD. This could be an easily accessible biomarker — a biological molecule that is a sign of disease — for Parkinson’s. Having a biomarker for Parkinson’s could lead to earlier diagnosis of the disease. This can improve outcomes for people living with PD.

The Parkinson’s Foundation Stanley Fahn Junior Faculty Award helps ensure promising early career scientists stay in the PD research field. This award provides junior investigators the support they need to develop their own independent funding source.

What’s Next: Reporting Our Findings
Parkinson’s Foundation research awards fund Parkinson’s studies than can span up to three years. Scientists submit yearly progress reports to the Parkinson’s Foundation, and we report findings once the studies have concluded. Stay up to date with our latest research findings at Parkinson.org/Blog.

A new study resulting from a partnership of Parkinson’s organizations and industry partners reveals that the economic burden of Parkinson’s disease (PD) in the U.S. is $51.9 billion – nearly double previous estimates.

Study Highlights 

• $25.4 billion is attributable to direct medical costs, such as hospitalizations and medication.
• $26.5 billion is attributable to non-medical costs, such as missed work, lost wages, early forced retirement and family caregiver time.
• The U.S. government accounts for nearly $25 billion in spending related to PD, with $2 billion through Social Security and the remaining $23 billion through Medicare.

Why is this study important?

Understanding the annual economic toll on people with PD, their families and the government helps when advocating for more federal funding for Parkinson’s research. It also allows us to better serve people with PD and their families with programs to help them live better with the disease, touching on areas they are most concerned about and where we can have the most impact.

How was the study performed?

The study, The Economic Burden of Parkinson’s Disease, was sponsored by The Michael J. Fox Foundation, with support from the Parkinson’s Foundation, several industry groups (ACADIA, Adamas, AbbVie, Acorda and Biogen), the American Parkinson Disease Association and The Parkinson Alliance.

The Michael J. Fox Foundation, with support from the Parkinson’s Foundation and other community organizations and industry partners, used data from public databases including Medicare, the Centers for Disease Control and Prevention and the Census Bureau. Several Parkinson’s organizations, including the Parkinson’s Foundation, assisted with data collection through sharing a survey across websites, social media networks and email communications. This joint effort resulted in the most comprehensive assessment illustrating the annual economic toll on the Parkinson’s community and the U.S. government in history.

How can I get involved in Parkinson’s research?

People with PD and their loved ones can help speed the cure and find medications to reverse its course. The Parkinson’s Foundation pairs people in the PD community as primary research partners with scientists, industry and government to prioritize research areas, improve studies and influence stakeholders. Learn more about our Research Advocates program.

Learn More

Another recent large-scale study about Parkinson’s disease is the Parkinson’s Foundation Parkinson’s Prevalence Project. This study established accurate estimates of the prevalence of Parkinson’s throughout North America, which will help the Parkinson’s Foundation attract the attention of federal and state government as well as the pharmaceutical industry to the growing need and urgency in addressing PD.  Read more about the prevalence of Parkinson’s.

In this month’s What’s Hot in Parkinson’s disease? column, I review what is becoming a hot topic: a Sinemet shortage. Recently, many people with Parkinson’s disease (PD) have been informed by their pharmacy that there is a shortage of Sinemet or that their brand of Sinemet has been “discontinued.” What should you do?

In 2010-2011 there was a national shortage of Sinemet. This occurred as the brand was transitioned from Merck and Company, Inc. to Mylan Pharmaceuticals, Inc. In 2019 Merck announced that it would no longer be manufacturing Sinemet CR (extended release). These national news stories led to panic.

Generic formulations cause worry. We field many calls to the Parkinson's Foundation Helpline about this topic. Callers are concerned about a wide range of topics from weaker efficacy of the generic, worsening of Motor fluctuations, dyskinesia, allergy and skin rash. When switching to a generic form, people with PD should keep in mind that there may be as much as a 20% difference in treatment effect. However, a generic may sometimes be desired, especially in people with Parkinson’s who experience dyskinesia from tiny medication dosages (some people have referred to these cases as “brittle” PD).

Keep in mind that the U.S. Food and Drug Administration (FDA) approval of a brand name drug requires demonstration of its pharmacokinetics, efficacy, safety and tolerability in both a healthy population and in the Parkinson’s population. In contrast, approval of a generic drug only requires demonstrating its bioequivalence in the blood, but not its clinical treatment effect in Parkinson’s disease.

It is important not to panic when your “brand” or “generic” Sinemet become unavailable. There are many alternatives. Here are a few tips:

• If you have had Parkinson’s more than five years, in many cases the CR (extended release) tablets offer little to no advantage over standard regular release for many people.
• Sometimes a CR tablet can be useful for “peak dose” dyskinesia, but it rarely helps extend the life of Sinemet after the first few years following a PD diagnosis.
• While individuals cannot control the manufacturer that their pharmacist chooses for their medications, talk to your pharmacist and let him/her know how helpful it is for you to have a consistent version of carbidopa/levodopa.
• If you are able to maintain a pill made by the same manufacturer; then you can adjust the timing and the dose (by as little as ½ or ¼ tablets) to achieve an optimal strategy.

The Eight Sinemet Limit

Another important issue has been the “eight Sinemet limit.” Pharmacies and insurance companies have been citing the language in the original FDA approval of Sinemet and denying prescription requests for people with PD who request more than eight tablets a day. The advent of electronic medical records has worsened this difficult issue for people with PD, as automatic limits are now being set by nationalized computer systems. Once limits are in computer systems, they can be challenging for patients to change. If your insurance carrier or pharmacy blocks filling of your Sinemet prescription purely based on the number of daily pills, we suggest you contact your doctor, send an appeal letter and also contact the Parkinson's Foundation Helpline at 1-800-4PD-INFO (473-4636), as we are here to assist you.

Reasons to try Sinemet CR (ER) or Rytary

1. Medication dosages taking too long to “kick in” and start working
2. Medication wearing off before the next scheduled medication dose
3. Severe on-off medication fluctuation periods (e.g. rapid cycling during the day ranging from feeling completely on medication to completely off medication)
4. Dyskinesia (too much movement, usually resulting from too high of a blood level of dopamine)
5. Too many pills
6. Too many medication dosage intervals (e.g. taking medications every 1-2 hours throughout the waking day)

The below conversion may be useful if trying the extended release Rytary (Hauser et. al.):

Finally, doctors are here to optimize the timing and medication combinations that work best for each patient ― a critical part of that is finding the best dopamine replacement therapy. The “timing is critical principle” from Parkinson’s Treatment: 10 Secrets to a Happier Life should be considered during dose adjustments for any person living with Parkinson’s. Timing is an important element to the success of any Parkinson's treatment. If your formulation changes or a manufacturer discontinues your medication, your care team is here to help you find the best and most positive path forward.

Selected References

Go CL, Rosales RL, Schmidt P, Lyons KE, Pahwa R, Okun MS. Generic versus branded pharmacotherapy in Parkinson's disease: does it matter? A review. Parkinsonism Relat Disord. 2011 Jun;17(5):308-12. Epub 2011 Mar 1. Review.

Okun MS. Parkinson's disease patients cannot get their dopamine replacement: The 8-sinemet limit. Mov Disord. 2011 Dec 9. doi: 10.1002/mds.24038. [Epub ahead 
of print].

Pahwa R, Lyons KE, Hauser RA, Fahn S, Jankovic J, Pourcher E, Hsu A, O'Connell M, Kell S, Gupta S; APEX-PD Investigators. Randomized trial of IPX066, carbidopa/levodopa extended release, in early Parkinson's disease. Parkinsonism Relat Disord. 2014 Feb;20(2):142-8. doi: 10.1016/j.parkreldis.2013.08.017. Epub 2013 Sep 5. PubMed PMID: 24055014.

Hauser RA, Hsu A, Kell S, Espay AJ, Sethi K, Stacy M, Ondo W, O'Connell M, Gupta S; IPX066 ADVANCE-PD investigators. Extended-release carbidopa-levodopa (IPX066) compared with immediate-release carbidopa-levodopa in patients with Parkinson's disease and motor fluctuations: a phase 3 randomized, double-blind trial. Lancet Neurol. 2013 Apr;12(4):346-56. doi: 10.1016/S1474-4422(13)70025-5. Epub 2013 Feb 26. PubMed PMID: 23485610.

Hauser RA. IPX066: a novel carbidopa-levodopa extended-release formulation. Expert Rev Neurother. 2012 Feb;12(2):133-40. doi: 10.1586/ern.11.195. Review. PubMed PMID: 22288668.

Okun MS. Parkinson’s Treatment: 10 Secrets to a Happier Life. Createspace, 2013.

You can find out more about our National Medical Director, Dr. Michael S. Okun, by also visiting the Center of Excellence, University of Florida Health Norman Fixel Institute for Neurological Diseases. Dr. Okun is also the author of the Amazon #1 Parkinson's Best Seller 10 Secrets to a Happier Life and 10 Breakthrough Therapies for Parkinson's Disease.

Parkinson’s disease (PD) results in the loss of dopamine-producing cells in the brain. Because dopamine cannot cross the blood-brain barrier (a safety feature of the brain), people cannot simply take dopamine pills. The drug levodopa (L-dopa) — a precursor to dopamine and the gold standard for treating PD — does have the ability to cross the blood-brain barrier, where it successfully converts into the much-needed dopamine.

Since 1971, scientists were aware that one or more of the many microorganisms living in the human gastrointestinal tract prematurely convert the L-dopa into dopamine before it gets into the brain― but they didn’t know which ones. To combat some of this loss, L-dopa is usually combined with carbidopa to help block the premature metabolism, as well as help with the common side effects of nausea and vomiting.

Only about 44% of the L-dopa makes it to the brain. There are many different types of microorganisms, such as bacteria, viruses and fungi. Understanding which ones may affect this process could help improve the efficiency of levodopa as a treatment for PD.

A study titled, “Discovery and inhibition of an interspecies gut bacterial pathway for Levodopa metabolism” (Maini Rekdal, Bess, Bisanz, Turnbaugh, & Balskus, 2019), sought to decipher the molecular mechanisms by which gut bacteria might be responsible for this degradation of L-dopa en route to the brain. A complex undertaking, researchers used several, highly sophisticated methods, from running tests on the microbiome (trillions of microorganisms that help keep the body running smoothly) to evaluating inhibitors and testing the gut microbiota of people with and without PD.

Results

• In the gut, some of the L-dopa was converted into dopamine by an enzyme from the common gut bacteria (Enterococcus faecalis).
• Then, the dopamine (still in the gut) was further metabolized into a compound called m-tyramine, by an enzyme from a second bacterium (called Eggerthella lenta).
• The enzymes from these two bacteria (Enterococcus faecalis and Eggerthella lenta) appear to be responsible for L-dopa metabolizing first into dopamine and then into m- tyramine, prior to reaching to blood-brain barrier, thereby diminishing how much L-dopa and the dopamine treatment successfully makes it to the brain.
• Carbidopa is successful in inhibiting the metabolism of L-dopa by human enzymes, but not by the bacterial enzymes in the human gut.
• When L-dopa was given to lab rodents orally along with a bacterial enzyme inhibitor called AFMT, this prevented metabolism of L-dopa and resulted in improved bioavailability of the drug in the animals’ blood stream.  

What Does This Mean?

Using a complex set of steps, this study identified two enzymes in human gut microbiota (called  Enterococcus faecalis and Eggerthella lenta) that are key to impeding a significant portion of the L-dopa from reaching the brain.

Further, in lab rodents, researchers increased the amount of L-dopa reaching the brain, by manipulating the activity of these enzymes in the gut with a drug, AFMT. This suggests that this approach (inhibiting bacterial enzymes) could possibly be developed for human use. In short, they may have found a drug that can reduce the premature metabolism of L-dopa into dopamine in the human gut, ultimately improving the efficiency of L-dopa treatment.

Medical marijuana, or cannabis, is one of the most popular topics among the Parkinson’s disease (PD) community ― for people with PD, health professionals and researchers, alike. Earlier this year, the Parkinson’s Foundation hosted its first-ever convening on marijuana and Parkinson’s. Among the 46 attendees, of which 17 gave presentations, there was a reoccurring theme: what are the biggest hurdles the PD community faces when it comes to medical marijuana? 

This is the second article in a two-part series. Read part one here.

Adverse Effects

Some of the most common side effects of cannabis-based products include:

• drowsiness and fatigue
• dizziness
• dry mouth
• anxiety
• nausea
• cognitive effects

Specifically, for smoked forms, side effects include cough, increased phlegm and bronchitis. Some rare but important side effects to note include: orthostatic hypotension, paranoia, depression, worsening of coordination of movement and rapid beating of the heart.

Specifically, regarding cognitive function, one review article of several studies found that attention and concentration were impaired in the short term (0-6 hours after use) but largely returned to normal in the longer term (three weeks or longer after use). However, decision making and risk taking were impaired three weeks or more after last cannabis use. Working memory was impaired shortly after use, but did not see any residual or long-term effects. Mixed results were seen as to whether there are long-term effects on impulsivity and verbal fluency after cannabis use.

→ Danny Bega, MD, MSCI, from Northwestern University Feinberg School of Medicine, spoke about this topic at the marijuana convening.

Finding the Right Formula

Physicians and pharmacologists are constantly trying to define the limits of their practice when it comes to cannabis. Not only must researchers find the right formula, they must also find the right delivery method. Cannabis can be delivered in various forms, from liquids to e-liquid (vapor) and inhalers to patches. 

One additional challenge is that cannabis products are not highly regulated, so there can be a lot of variation from product to product and even from batch to batch within a single product. This needs to be regulated more so that people can know what is in the product they are purchasing and trust that it is safe.

→ Bill Arnold, CEO of Cannoid, LLC, spoke about this topic at the marijuana convening.

The Effects of Cannabis and Pain on Men VS Women

Of the 20 common conditions that qualify for medical marijuana, chronic pain has substantial evidence supporting the use of cannabis. People with PD report pain as one of the most common non-motor symptoms, which is not always responsive to pain medications.

PD-related pain is most common among women. Differences between men and women specifically in their susceptibility to intoxication and abuse liability have not been studied. Preclinical evidence suggests that female laboratory animals are more sensitive to cannabinoid (THC) relative to males in terms of treating pain, but they are also more sensitive to the abuse-related effects of these drugs. However, female animals develop tolerance to the pain-relieving effects of THC at a faster rate than males, rendering THC close to ineffective in females.

Ziva D. Cooper, PhD, and her colleagues tested cannabis to see if these findings in animals would translate to humans. Her study found that women who heavily smoke cannabis did not show a pain-relieving response, whereas men did. Regardless of pain response, women reported feeling as intoxicated as men and reported liking the cannabis as much as men.

Future studies investigating the use of cannabis and cannabinoids for PD-related pain are warranted.  These studies should consider differences between men and women, cannabis experience and adverse effects.

→ Ziva D. Cooper, PhD, from the UCLA Cannabis Research Initiative, spoke about this topic at the marijuana convening.

The medical marijuana convening brought together a diverse group of experts from academia, clinics, industry, government and the Parkinson's community to establish a consensus on medical marijuana use in PD. The Parkinson’s Foundation will publish its findings on the convening in summer 2020. 

Learn more about Parkinson’s and marijuana at Parkinson.org/Marijuana.

Medical marijuana, or cannabis, is one of the most popular topics among the Parkinson’s disease (PD) community ― for people with PD, health professionals and researchers, alike. Earlier this year, the Parkinson’s Foundation hosted its first-ever convening on marijuana and Parkinson’s. Among the 46 attendees, of which 17 gave presentations, there was a reoccurring theme: what are the biggest hurdles the PD community faces when it comes to medical marijuana?  

This is the first article in a two-part series. Read part two here.

Treating Parkinson’s Symptoms with Cannabis

There is not enough evidence yet to support that medical marijuana can help manage Parkinson’s symptoms, however there are studies on the topic. Unfortunately, they have mixed results. Generally, the studies have been small and some with no control groups. The effects of medical marijuana are not completely understood, especially in the PD population. The bottom line is that more studies are needed, specifically larger and more rigorously conducted studies.

Based on some observational studies, cannabinoids (the active molecules in marijuana) may potentially benefit some non-motor symptoms of PD including pain, anxiety, sleep problems (insomnia, RBD, RLS), weight loss and nausea. Potential adverse effects include dizziness, blurring of vision, loss of balance, mood and behavioral changes, hallucinations, and impaired cognition and motivation. Better studies are necessary to confirm these benefit and adverse effects for people with PD.

Controlled clinical trials of cannabinoids (where some people receive the drug and some do not) have  reported mixed results for treating motor symptoms and levodopa-induced dyskinesia as well as improving quality of life.

While stories and videos exist showing that marijuana can treat PD symptoms, the challenge is showing that cannabis is better and safer than treatments that are currently available. A recent survey shows that the health community does not have a consensus on using cannabis as a treatment. This reflects lack of data, knowledge and training on the subject.

Future studies about medical marijuana and Parkinson’s should follow the highest standards of clinical trials to focus on:

• Delivery type: do specific strains, soft gels, tinctures (alcohol-based cannabis extract), e-liquid (vapor), topicals, infused food, flower products, inhalers and patches treat symptoms differently and have different side effect profiles?
• Dosage: what is the minimum dosage to guarantee effectiveness, what is the maximum dose tolerated and what dose will have a sustained benefit? Furthermore, how does this differ by strain and formulation?
• Effect on motor vs non-motor symptoms: which symptoms can improve, worsen or stay the same with cannabis use?
• Interaction with PD medications: how does cannabis interact with medications taken for PD symptoms?
• Key component: What components of cannabis/marijuana provide the best response in PD with the least risk of side effects?  What is the optimal CBD (Cannabidiol) to THC ratio?
• PD-specific side effects: are people with PD uniquely susceptible to certain side effects that are not seen in the general population?
• Population: studies that involve participants in difference stages of the disease.

Lastly, there needs to be a widespread physician education on using cannabis as a treatment ― almost all physicians surveyed agreed that medical school curriculums should include education on cannabis.

→ Danny Bega, MD, MSCI, from Northwestern University Feinberg School of Medicine; Joseph Jankovic, MD, from Baylor College of Medicine; and Karl Kieburtz, MD, MPH, from the University of Rochester, spoke about this topic at the marijuana convening.

Potential Drug Interactions

One surprising fact shared at the meeting is that cannabis-based products have the potential to interact with other medications. Given that people with Parkinson’s may be on multiple medications for other conditions, it is important to be aware of these interactions to avoid complications.

Epidiolex® is the first FDA-approved cannabinoid prescription drug. It is an oral solution of cannabidiol most commonly used to treat rare forms of epilepsy. It has been shown to have interactions with many anti-seizure medications, some antibiotics and medications for lowering cholesterol, pain, anxiety, depression and blood pressure. In some cases, Epidiolex can make these medications more or less potent. In other cases, these medications can make Epidiolex more or less potent. Because Epidiolex largely contains cannabidiol, there is the possibility that other cannabis-based products may also interact with medications in a similar way.

Delta-9-tetrahydrocannibinol (THC) is the primary psychoactive component of marijuana (the part that gives a “high”). It can take a long time to take effect and cannot be easily measured for a therapeutic or medicinal dose. THC can also interact with certain medications such as valproic acid (for bipolar disorder, seizures, and migraines) and can result in increased psychoactive effects of marijuana.

Medical marijuana can be taken in an edible form. Care should be taken with this form, as it takes longer to feel an effect and lasts longer (4-8 hours as opposed to 2-3 hours for smoking or vaporizing). Often, because the effects are slow, people increase their dose, eating more, which can be dangerous. Edibles may also have more toxicity than smoked marijuana, because they are broken down by the liver into more toxic chemicals.

→ Jacqueline Bainbridge, PharmD, FCCP, MSCS, from the University of Colorado, spoke about this topic at the marijuana convening.

The medical marijuana convening brought together a diverse group of experts from academia, clinics, industry, government and the Parkinson's community to establish a consensus on medical marijuana use in PD. The Parkinson’s Foundation will publish its findings on the convening in summer 2020. 

Learn more about Parkinson’s and marijuana at Parkinson.org/Marijuana.

Parkinson’s disease (PD) is largely known for its motor symptoms, slow movement, tremor and stiffness, but other wide-ranging challenges, known as non-motor or non-movement symptoms — can often be most problematic. Treating these non-motor symptoms promotes optimal living.

The following article is part two of a series based on a Parkinson’s Foundation Expert Briefings webinar exploring the latest research and treatments in PD-related non-motor symptoms, by Ronald Pfeiffer, MD, Oregon Health and Sciences University, a Parkinson’s Foundation Center of Excellence. Read part one next.

Gastrointestinal Functions

Gastroparesis is a condition that prevents the stomach from emptying properly. For many with PD, spontaneous stomach muscle movement is impaired, preventing food from easily emptying. This creates a feeling of fullness after a few bites of food, causing reduced appetite. Symptoms include nausea, vomiting, heartburn, bloating and weight loss. Diet and medications, including BOTOX® injections to the pyloric sphincter (a muscle that helps the movement of partially digested food and liquids) are among treatment options. Dopaminergic medication delivery systems may also avoid gastroparesis.

Small Intestinal Bacterial Overgrowth (SIBO): While this recurrent non-motor gastrointestinal issue has not been well-researched in Parkinson’s, one study showed that up to 54 percent of people with PD experience it. Decreased gut motility, which is common with PD, can lead to SIBO, characterized by:

• Increased bacterial density in the small intestine
• Presence of colonic-type bacterial species in the small intestine

SIBO can result in malabsorption (condition that makes it difficult to digest and absorb nutrients from food) and might explain weight loss in PD. When experiencing SIBO, levodopa and medications may take longer to work, wear off more quickly or not work at all, because they must travel to, and through, the stomach to be effective. Antibiotics may help.

Constipation: This can be chronic in PD. It can be caused by physical changes due to the disease and/or PD medications. Increasing dietary fiber, through food and supplements, increasing fluids and exercise, and minimizing starchy foods can all be beneficial. More than 60 percent of people with PD experience increased straining, pain and incomplete evacuation of their bowels. Dopaminergic medications, including apomorphine injects, BOTOX® injections or biofeedback techniques may offer relief.

Cardiovascular Functions

Orthostatic hypotension: More than half of people living with PD experience a significant blood pressure drop upon standing; certain medications can worsen this. This drop can cause lightheadedness or fainting, fuzzy vision, foggy thinking, headache, lower back ache, lethargy or fatigue. Increase blood pressure or reduce lightheadedness by:

• Drinking 12-16 ounces of cold water before standing
• Crossing legs or flexing calf muscles can
• Eating small, frequent meals and increasing fluids and salt
• Making slow position changes
• Wearing abdominal binders or pressure stockings that reach the waist, like pantyhose
• Talking to your doctor about blood pressure medications

Postprandial hypotension: Occurs when a person’s blood pressure drops after eating. Meals heavy in carbohydrates can worsen the condition, which develops within 15 minutes of eating and may persist up to three hours after. Ease symptoms by consuming less carbohydrates at meals or napping after eating.

For others with PD, blood pressure can rise too high when lying down; blood pressure can also rise drastically at night. Discuss prescription treatments with your doctor.

Bladder Functions

Overactive bladder can occur in more than 80 percent of people with PD, causing frequent or nighttime urination, urination in small amounts, the sudden need to urinate and involuntary leakage. Newer anticholinergic (treat multiple urinary conditions, including incontinence and overactive bladder) drugs (including trospium (Sanctura®), darifenacin (Enables®) and solifenacin (VESIcare®), can treat incontinence and overactive bladder, as can mirabegron (Moretti®), which fosters bladder relaxation and increases bladder capacity. Detrusor muscle BOTOX ® injections can also improve urinary dysfunction.

Obstructive urinary symptoms: These issues account for less than 40 percent of PD-related urinary problems and are often characterized by urinary hesitancy or a weak stream. These features may lead to overflow incontinence, which can cause unexpected urine leakage due to an overfull bladder. Medications, including alpha blockers (terazosin, doxazosin, or tamsulosin), 5-alpha-reductase inhibitors (dutasteride or finasteride) or a parasympathomimetic agent, such as bethanecol, as well as intermittent catheterization, may improve obstructive urinary symptoms. Talk to your doctor about symptoms and treatment.

Sexual Functions

Sexual dysfunction in PD affects women and men. Women may undergo reduced vaginal sensitivity or reduced desire. Men may experience erectile dysfunction or decreased desire or orgasm. Testosterone therapy can improve decreased libido in men, while water-soluble lubricants can improve lubrication. Discuss treatment options with your doctor.

Prescription treatment of erectile dysfunction may include PDE5-inhibitors, including sildenafil (Viagra®), tadalafil (Cialis®) and vardenafil (Levitra®); sublingual apomorphine; or intrapenile injections of a vasoactive drug, such as alprostadil (Caverject®) or papaverine.

Thermoregulatory Functions

This inability to regulate body temperature can manifest as excessive sweating, or a drastic rise or drop in body temperature. Excessive sweating (hyperhidrosis), experienced by more than 50 percent of people with PD, consists of sudden, drenching sweats of the head and neck. Though it may occur in people taking no PD medications, it often occurs as prescriptions wear off or during episodes of dyskinesia. Adjusting dopaminergic therapy can help. One study suggests subthalamic deep brain stimulation (DBS) may also help. BOTOX ® injections can be used if sweating is localized to armpits.

Fatigue

Present in almost 60 percent of people with PD, fatigue is an understudied non-motor symptom. It is often ranked by people with PD as one of their most disabling symptoms. It’s still unclear whether fatigue in PD is a brain or muscular problem; currently there are no well-formulated treatments. While medications have been tried with inconsistent results, some studies suggest exercise helps.

Breathing Difficulties

Some people with Parkinson’s experience shortness of breath; this is due to chest wall muscle rigidity preventing full chest expansion. Adjusting medications to reduce “off” times and dyskinesia can help. Treating anxiety or obstructive sleep apnea, if present, can also help, as can inspiratory and expiratory muscle strength training.

Recognizing and Addressing Symptoms

Non-motor PD features may also include sleep disorders, cognitive changes, hallucinations and delusions or weight changes. It’s important to stay abreast of all symptoms, and to discuss treatments with your doctor.

Read the first article in series now: Non-motor Symptoms: What’s New? Part 1.

View free resources on non-motor symptoms