Cancer Treatments in Australia

New therapeutic approaches for Parkinson’s disease

About 1 in 308 Australians are living with Parkinson's disease.

Parkinson’s disease (PD) is a progressive neurodegenerative disorder that affects the control of body movements, such as the loss of ability to move muscles voluntarily, slowness of body movements, tremors, postural instability and difficulty walking, and rigidity or stiffness of the limbs or trunk. Other associated features are a loss of smell, sleep dysfunction, mood disorders, excess salivation, constipation, and excessive periodic limb movements in sleep. As the disease progresses, depression and dementia with significant loss of cognitive function are also common1.

Data from Parkinson’s Australia indicates that about 1 in 308 Australians are living with PD, making it the most common major movement disorder and second highest prevalence neurodegenerative condition, with only dementia exceeding it in the number of deaths. In Australia, the number of people with PD is projected to grow at 3 times the rate of population growth, with about 37 new cases diagnosed each day, 18% of whom are of working age.

What causes Parkinson’s disease?

The disease is characterised by the accumulation of a protein called alpha-synuclein in various parts of the brain, leading to the loss of neurons (nerve cells) that produce dopamine which controls muscle tone and movement[2].

The cause for the accumulation of alpha-synuclein is still largely unclear, but it has been linked to environmental insults, genetic predisposition, or interactions between both. Some research has found an association between PD and the use of pesticides, herbicides, and proximity to industrial plants[3]. Other evidence indicates that oxidative stress is a central factor in the cause of PD[4-6], and yet more evidence points to the breakdown of functional nerve network interactions prior to the accumulation of alpha-synuclein, particularly because the loss of dopamine does not explain the loss of smell and gastrointestinal disturbances that occur years before the first signs of motor symptoms[7]. Thus, PD may be a disease involving multiple organs, not simply a disorder of the central nervous system (CNS)[1].

How is PD treated?

Most of the pharmaceutical options for PD focus on restoring the balance of dopamine and other neurotransmitters. Medications include levodopa which passes into the brain and is converted into dopamine, and dopamine agonists which mimic the action of dopamine in the brain. Levodopa is often combined with carbidopa which decreases side effects and improves CNS bioavailability[1]. Side effects of carbidopa-levodopa may include nausea or light-headedness, and some of the side effects of dopamine agonists can also include hallucinations, sleepiness, and compulsive behaviours.

There are also medications that prevent specific enzymes (MAO B and COMT) from breaking down dopamine.  Side effects may include headaches, nausea or insomnia, and hallucinations if given together with levodopa, or increased risk of involuntary movements, diarrhoea, nausea, and vomiting.

Anticholinergics used for controlling tremor are still available, but rarely used because their effects are modest, and their side effect profile is very high. Amantadine can provide short-term relief of symptoms of mild, early-stage PD, and it may also be given with carbidopa-levodopa during the later stages of the disease to control involuntary movements induced by carbidopa-levodopa. Side effects may include purple mottling of the skin, ankle swelling or hallucinations.

Most medications provide good symptom control for 3 to 6 years. After this period, the disease progresses and is often unresponsive to medications. Therefore, a multidisciplinary approach to manage PD is essential. People with PD do much better when a structured physical therapy program is used to improve balance, gait, and stability, and maintain an active lifestyle[1]

Deep brain stimulation (DBS) is offered to people with advanced PD who have variable levodopa responses. DBS can stabilise medication fluctuations, reduce or halt involuntary movements, reduce tremor, reduce rigidity, and improve slowing of movement. However, surgery involves risks, including infections, strokes, or brain haemorrhage. On the other hand focused ultrasound therapy is non-invasive and can be used for patients whose tremors do not respond to medication.

New therapeutic approaches under investigation

As evidence continues to build supporting the connection between gut health and brain health, a new study has found that PD impacts the gut bacteria’s ability to break down fat, making it more difficult to regulate bile acid production. Thus, disruptions in bile acid production may be a potential early sign of PD, and treatments that target the microbiome and bile acids may help delay disease progression[8]. Supporting the gut-brain connection is a study led by a research team in Taiwan that found that 25 people with PD on standard medication who added the probiotic PS128,  a strain of Lactobacillus plantarum that can modulate dopamine and serotonin neurotransmitter levels, had significant improvements in motor symptoms and in quality of life. A larger clinical trial with 120 patients is currently recruiting.

Another interesting study has shown that a drug commonly used to treat an enlarged prostate is associated with a lower risk of developing PD. Men who took terazosin were between 12% and 37% less likely to develop PD than men taking another drug for enlarged prostate. The drug’s ability to protect against PD may be related to its ability to regulate cellular energy production. However, clinical trials will be needed to determine whether the association is real. The downside is that terazosin can worsen low blood pressure in people with PD[9].

Around the world more than 650 clinical trials are listed for Parkinson’s disease, all testing new combinations of existing treatments or new methods of delivery, or novel therapeutic options such as  new and repurposed drugs like a c-Abl inhibitor, zosinamide, exenatide, yohimbine, insulin, ceftriaxone, immunosuppressants (prednisone, sirolimus), tavapadon, alpha-synuclein inhibitors, and many others.  Other studies are examining the effectiveness of transcranial magnetic stimulation (TMS), transcranial pulsed count stimulation (tPCS), neurofeedback, or photobiomodulation. Dietary supplementation is also being investigated with medicinal mushroom species, niacin, niacinamide, nicotinamide riboside, and an SQJC Chinese herbal mixture. Other studies are targeting the microbiome,  or exploring gene transfer, or using stem cell transplantation. A large number of devices and exercise/rehabilitation programs are also under trial.

What about medicinal cannabis?

The neuroprotective potential of cannabinoids, due to their anti-inflammatory and anti-oxidant properties, is of particular interest and is presently under intense preclinical research in numerous neurodegenerative disorders, including PD[10].  Preclinical (animal) models of Parkinson’s disease have shown that tetrahydrocannabinol (THC), cannabidiol (CBD) and tetrahydrocannabivarin (THCV) exert a neuroprotective effect as antioxidant compounds[10-14].

The endocannabinoid system (ECS) regulates cell, tissue, organ and organism homeostasis (balance), brain development, and neurotransmitter release, and hence is implicated in multiple neurological disorders[15].  In Parkinson’s disease, ECS signalling is altered and enhancers or inhibitors of ECS signalling have been shown to bind to cannabinoid 1 (CB1) or 2 (CB2) receptors and to have therapeutic effects in animal models of PD[15, 16].

In people with PD, PET and MRI scans have shown that CB1 levels are increased[17, 18], and similar imaging in both rodents and patients has also revealed CB2 upregulation[18, 19].  In addition, abnormal endocannabinoid (cannabinoids produced naturally by the body) levels in the cerebrospinal fluid (CSF) of untreated patients with PD and in an animal model of PD have been reversed by levodopa treatment[20-24], suggesting that ECS alterations are related to disease symptoms. Moreover, endocannabinoid levels also vary in the CSF and blood of people with and without levodopa-induced uncontrolled movements[25].

In an exploratory, double-blind trial of CBD in patients with PD, the highest dose tested (300 mg daily) improved quality of life[26].  In another pilot study, THC reduced levodopa-induced involuntary movements in PD[27].  On the other hand, previous studies found no improvement in psychosis or involuntary movements after treatment with either THC, CBD, or a combination of both[28, 29].

Recently, a study published in February 2021 in the Journal of Parkinson’s Disease, reported that in Germany, more than 8% of the people with PD surveyed were using cannabis products to alleviate symptoms, and more than half of those experienced beneficial clinical effects[30].  Results of a similar survey published in March 2021 in NPJ Parkinson’s Disease, found that almost 25% of people with PD in the US had used cannabis products in the six months prior to the survey. Cannabis was most often used to treat nonmotor symptoms of anxiety, pain, and sleep disorders. However, nearly a quarter of users also reported they had stopped cannabis use in the previous six months, primarily due to a lack of symptom improvement. Three quarters of respondents did not use cannabis, primarily because there was a lack of scientific evidence supporting efficacy[31].

It is clear that although cannabinoids for PD show some promise, research is still in its infancy and more clinical trials will be needed to determine its safety and efficacy. In Canada, the University Health Network in Toronto is conducting a randomised, double-blind study to evaluate the tolerability, safety and dose-finding of THC/CBD oils for pain in Parkinson’s disease (NCT03639064). In Australia, an observational study is evaluating the safety and efficacy of a pharmaceutical grade CBD medicine in patients undergoing medicinal cannabis therapy for a number of conditions including PD. To find more information about the trial, visit ANZCTR.

If you would like to discuss your condition and possible treatment options for Parkinson’s disease, please book an appointment with a Tetra Health doctor.

[1] Zafar S, Yaddanapudi SS. Parkinson Disease.  StatPearls. Treasure Island (FL): StatPearls Publishing. Copyright © 2021, StatPearls Publishing LLC.; 2021.

[2] Chung SJ, Yoo HS, Lee HS, Oh JS, Kim JS, Sohn YH, et al. The Pattern of Striatal Dopamine Depletion as a Prognostic Marker in De Novo Parkinson Disease. Clin Nucl Med. 2018;43(11):787-92.

[3] McKnight S, Hack N. Toxin-Induced Parkinsonism. Neurol Clin. 2020;38(4):853-65.

[4] Hirsch E, Graybiel AM, Agid YA. Melanized dopaminergic neurons are differentially susceptible to degeneration in Parkinson’s disease. Nature. 1988;334(6180):345-8.

[5] Branchi I, D’Andrea I, Armida M, Carnevale D, Ajmone-Cat MA, Pèzzola A, et al. Striatal 6-OHDA lesion in mice: Investigating early neurochemical changes underlying Parkinson’s disease. Behav Brain Res. 2010;208(1):137-43.

[6] Aureli C, Cassano T, Masci A, Francioso A, Martire S, Cocciolo A, et al. 5-S-cysteinyldopamine neurotoxicity: Influence on the expression of α-synuclein and ERp57 in cellular and animal models of Parkinson’s disease. J Neurosci Res. 2014;92(3):347-58.

[7] Gratton C, Koller JM, Shannon W, Greene DJ, Maiti B, Snyder AZ, et al. Emergent Functional Network Effects in Parkinson Disease. Cereb Cortex. 2019;29(6):2509-23.

[8] Li P, Killinger BA, Ensink E, Beddows I, Yilmaz A, Lubben N, et al. Gut Microbiota Dysbiosis Is Associated with Elevated Bile Acids in Parkinson’s Disease. Metabolites. 2021;11(1).

[9] Simmering JE, Welsh MJ, Liu L, Narayanan NS, Pottegård A. Association of Glycolysis-Enhancing α-1 Blockers With Risk of Developing Parkinson Disease. JAMA Neurol. 2021.

[10] Fernández-Ruiz J, Sagredo O, Pazos MR, García C, Pertwee R, Mechoulam R, et al. Cannabidiol for neurodegenerative disorders: important new clinical applications for this phytocannabinoid? Br J Clin Pharmacol. 2013;75(2):323-33.

[11] García-Arencibia M, González S, de Lago E, Ramos JA, Mechoulam R, Fernández-Ruiz J. Evaluation of the neuroprotective effect of cannabinoids in a rat model of Parkinson’s disease: importance of antioxidant and cannabinoid receptor-independent properties. Brain Res. 2007;1134(1):162-70.

[12] Lastres-Becker I, Molina-Holgado F, Ramos JA, Mechoulam R, Fernández-Ruiz J. Cannabinoids provide neuroprotection against 6-hydroxydopamine toxicity in vivo and in vitro: relevance to Parkinson’s disease. Neurobiol Dis. 2005;19(1-2):96-107.

[13] García C, Palomo-Garo C, García-Arencibia M, Ramos J, Pertwee R, Fernández-Ruiz J. Symptom-relieving and neuroprotective effects of the phytocannabinoid Δ⁹-THCV in animal models of Parkinson’s disease. Br J Pharmacol. 2011;163(7):1495-506.

[14] Mohanty D, Lippmann S. Marijuana for Parkinson’s Disease? Innov Clin Neurosci. 2019;16(1-2):33-4.

[15] Cristino L, Bisogno T, Di Marzo V. Cannabinoids and the expanded endocannabinoid system in neurological disorders. Nat Rev Neurol. 2020;16(1):9-29.

[16] Patricio F, Morales-Andrade AA, Patricio-Martínez A, Limón ID. Cannabidiol as a Therapeutic Target: Evidence of its Neuroprotective and Neuromodulatory Function in Parkinson’s Disease. Front Pharmacol. 2020;11:595635.

[17] Rojo-Bustamante E, Abellanas MA, Clavero P, Thiolat ML, Li Q, Luquin MR, et al. The expression of cannabinoid type 1 receptor and 2-arachidonoyl glycerol synthesizing/degrading enzymes is altered in basal ganglia during the active phase of levodopa-induced dyskinesia. Neurobiol Dis. 2018;118:64-75.

[18] Navarrete F, García-Gutiérrez MS, Aracil-Fernández A, Lanciego JL, Manzanares J. Cannabinoid CB1 and CB2 Receptors, and Monoacylglycerol Lipase Gene Expression Alterations in the Basal Ganglia of Patients with Parkinson’s Disease. Neurotherapeutics. 2018;15(2):459-69.

[19] Gómez-Gálvez Y, Palomo-Garo C, Fernández-Ruiz J, García C. Potential of the cannabinoid CB(2) receptor as a pharmacological target against inflammation in Parkinson’s disease. Prog Neuropsychopharmacol Biol Psychiatry. 2016;64:200-8.

[20] van der Stelt M, Fox SH, Hill M, Crossman AR, Petrosino S, Di Marzo V, et al. A role for endocannabinoids in the generation of parkinsonism and levodopa-induced dyskinesia in MPTP-lesioned non-human primate models of Parkinson’s disease. Faseb j. 2005;19(9):1140-2.

[21] Pisani A, Fezza F, Galati S, Battista N, Napolitano S, Finazzi-Agro A, et al. High endogenous cannabinoid levels in the cerebrospinal fluid of untreated Parkinson’s disease patients. Ann Neurol. 2005;57(5):777-9.

[22] Gubellini P, Picconi B, Bari M, Battista N, Calabresi P, Centonze D, et al. Experimental parkinsonism alters endocannabinoid degradation: implications for striatal glutamatergic transmission. J Neurosci. 2002;22(16):6900-7.

[23] Di Marzo V, Hill MP, Bisogno T, Crossman AR, Brotchie JM. Enhanced levels of endogenous cannabinoids in the globus pallidus are associated with a reduction in movement in an animal model of Parkinson’s disease. Faseb j. 2000;14(10):1432-8.

[24] Pisani V, Moschella V, Bari M, Fezza F, Galati S, Bernardi G, et al. Dynamic changes of anandamide in the cerebrospinal fluid of Parkinson’s disease patients. Mov Disord. 2010;25(7):920-4.

[25] Marchioni C, Santos-Lobato BL, Queiroz MEC, Crippa JAS, Tumas V. Endocannabinoid levels in patients with Parkinson’s disease with and without levodopa-induced dyskinesias. J Neural Transm (Vienna). 2020.

[26] Chagas MH, Zuardi AW, Tumas V, Pena-Pereira MA, Sobreira ET, Bergamaschi MM, et al. Effects of cannabidiol in the treatment of patients with Parkinson’s disease: an exploratory double-blind trial. J Psychopharmacol. 2014;28(11):1088-98.

[27] Sieradzan KA, Fox SH, Hill M, Dick JP, Crossman AR, Brotchie JM. Cannabinoids reduce levodopa-induced dyskinesia in Parkinson’s disease: a pilot study. Neurology. 2001;57(11):2108-11.

[28] Zuardi AW, Crippa JA, Hallak JE, Pinto JP, Chagas MH, Rodrigues GG, et al. Cannabidiol for the treatment of psychosis in Parkinson’s disease. J Psychopharmacol. 2009;23(8):979-83.

[29] Carroll CB, Bain PG, Teare L, Liu X, Joint C, Wroath C, et al. Cannabis for dyskinesia in Parkinson disease: a randomized double-blind crossover study. Neurology. 2004;63(7):1245-50.

[30] Yenilmez F, Fründt O, Hidding U, Buhmann C. Cannabis in Parkinson’s Disease: The Patients’ View. J Parkinsons Dis. 2021;11(1):309-21.

[31] Feeney MP, Bega D, Kluger BM, Stoessl AJ, Evers CM, De Leon R, et al. Weeding through the haze: a survey on cannabis use among people living with Parkinson’s disease in the US. NPJ Parkinsons Dis. 2021;7(1):21.

Stay up to date

Sign up to the Tetra Health Newsletter