Parkinson’s Disease

Seriousness of medical condition(s)

Parkinson’s Disease (PD) is a progressive, degenerative neurological condition, characterized by the classical motor features of parkinsonism including trembling, muscular rigidity, bradykinesia, postural and gait impairment and loss of fine motor control (Kailia et al, 2015).

An estimated 80,000 Australians currently live with PD with an average age of diagnosis of 65 years, but younger people can also be diagnosed (Parkinson’s Australia). Current treatments fail to slow the neurodegeneration, and symptom management in later stages is difficult (Kailia at al, 2015).

Who could benefit from this treatment?

Patients diagnosed with Parkinson’s with ongoing symptoms not adequately resolved with standard of care medications.

Clinical justification for using Medicinal Cannabis

Treatment is mainly with pharmaceuticals that increase dopamine concentrations or stimulate dopamine receptors (Kailia at al, 2015). However, use of anti-PD medication Levodopa long-term is associated with dyskinesia (Carroll et al, 2014).

 

Research suggests that the modulation of the endocannabinoids signalling system may be useful in treatment of PD (Basavarajappa et al, 2017). Inflammation has been shown to play a significant role in the neurodegenerative process, and since cannabinoids have anti-inflammatory and neuro-protective actions, research suggests that CB2 receptors play a major role in limiting inflammation secondary to glial activation. Preclinical research has found that pharmacological activation of microglial CB2 receptors in a mice PD model by B-caryophyllene led to reduced microglial activation, reduced release of pro-inflammatory cytokines, and prevented the depletion of glutathione (Javed et al, 2016). It is thought that CB2 receptors could represent potential pharmacological targets to treat PD (Palomo-Garo et al, 2016).

 

CBD is known to act at several sites and its neuroprotective actions are based on local anti-inflammatory actions, reductions of oxidative stress, attenuation of glial cell activation and normalisation of glutamate homeostasis (Fernandez-Ruiz et al, 2013). THC has also been found to induce PPAR gamma-dependent mitochondrial biogenesis, a mechanism which may be beneficial in the treatment of PD (Zeissler at al, 2016). The CB2 receptor agonist B-caryophyllene has been shown to be neuroprotectant due to its anti-inflammatory and snit-oxidant properties (Javed et al, 2016).

 

Overall, the benefits indicated in PD patients taking medicinal cannabis may include improvements in falls, pain relief, depression, tremor, muscle stiffness, bradykinesia and sleep and L-dopa induces dyskinesias (Balash et al, 2017).

 

Unknown or expected adverse effects, risks and safety issues & related toxicology:

 

A systematic review by Whiting et al. (2015) stated in their conclusions that “Cannabinoids were associated with an increased risk of short-term adverse effects”.

 

According to the Guidance for the Use of Medicinal Cannabis in Australia: Overview, Therapeutics Good Administration

(2017): Cannabis is not appropriate for patients who:

• Are under the age of 25 (with the exception of intractable epilepsy or severe pain syndrome)

• Have a personal history or strong family history of psychosis

• Have a current or past cannabis use disorder, or active substance use disorder

• Have unstable respiratory or cardiovascular disease (including angina, peripheral vascular disease, cerebrovascular disease, arrhythmias)

• Are pregnant, planning to become pregnant, or

Breastfeeding.

Cannabis should be authorized with caution in patients who:

• Smoke tobacco

• Have risk factors for cardiovascular disease

• Are heavy users of alcohol

• Are taking sedating medications or any other medication metabolized by the CYP450 pathway

• At risk or have liver disease

 

Potential drug interactions

Increasing THC concentration:

Examples of inhibitors:

– Antidepressants (e.g. Fluoxetine, Fluvoxamine)

– Proton Pump Inhibitors (e.g. Omeprazole)

– Cimetidine

– Macrolides (Clarithromycin, Erythromycin)

– Antimycotics (e.g. Itraconazole, Fluconazole, Ketoconazole, Miconazole)

– Calcium Antagonists (e.g. Diltiazem, Verapamil)

– HIV protease inhibitors (e.g. Ritonavir)

– Amiodarone

– Isoniazid

– Grapefruit juice

Increasing CBD concentration:

– Metabolized by CYP 2C19 and CYP 3A4

– Bioavailability could be increased by many of the same substances as for THC

Decreasing THC and CBD concentration:

• CYP 2C9 and 3A4 Inducers accelerate THC and CBD metabolism

• Examples of inducers:

– Rifampicin

– Primidone

– Carbamazepine

– Phenobarbital

– Phenytoin

– Rifabutin

– Saint John’s Wort

 

Significantly changed serum levels of clobazam, rufinamide, topiramate, zonisamide, and eslicarbazepine were seen in the study by Gaston et al (2017) on interactions between cannabidiol (Epidiolex.) and commonly used antiepileptic

drugs. Abnormal liver function test results were noted in participants taking concomitant valproate. This study emphasizes the importance of monitoring serum AED levels and LFTs during treatment with supraphysiological doses of CBD (e.g. 1000mg/kg).

• Caution with blood thinners like Warfarin, Heparin,

Clopidogrel (Plavix)

• Additionally, pharmacodynamic interactions should be expected between cannabis and drugs with sympathomimetic activity (tachycardia,

hypertension), central nervous system depressants (drowsiness, ataxia), and drugs with anticholinergic effects (tachycardia, drowsiness).

 

Many of these drug interactions can be mitigated in complex patients with polypharmacy by slowly titrating cannabis.

Approved treatments for this medical condition

Levodopa is the drug available for treating the motor symptoms of idiopathic Parkinson’s disease. It is usually combined with a peripheral dopa decarboxylase inhibitor. Early treatment with dopamine agonists can reduce the risk of developing dyskinesia.

Why is medicinal cannabis appropriate for use?

Medicinal cannabis products will be considered for treatment when:

  • standard of care medications have been trialed to maximally tolerated dose without acceptable symptom relief or functional improvements.
  • Patient is unable to tolerate standard of care medications
  • Standard of care medications are contraindicated.

The medicinal cannabis will not be used as sole treatment of condition. Parkinson’s may require polypharmacy and other therapies to manage. In this way, the medicinal cannabis will act as an adjuvant. Tolerability and efficacy of adjuvants must be trialled in individual patients.

References

  • Balash, Y., Bar-Lev Schleider, L., Korczyn, A. D., Shabtai, H., Knaani, J., Rosenberg, A., Baruch, Y., Djaldetti, R., Giladi, N., & Gurevich, T. (2017). Medical Cannabis in Parkinson Disease: Real-Life Patients’ Experience. Clinical neuropharmacology40(6), 268–272. https://doi.org/10.1097/WNF.0000000000000246Whiting PF, Wolff RF, Deshpande S, Di Nisio M, Duffy S, Hernandez AV, et al. Cannabinoids for medical use: a systematic review and meta-analysis. JAMA 2015;313(24):2456-73. Errata in: JAMA 2016;315(14):1522, JAMA 2015;314(21):2308, JAMA 2015;314(5):520, JAMA 2015;314(8):837.
  • Basavarajappa BS, Shivakumar M, Joshi V, Subbana S. Endocannabinoid system in neurodegenerative disorders. J Neurochemistry 2017; 142: 624-648.
  • Carroll CB, Bain PG, Teare LBM et al. Cannabis for dyskinesia in Parkinson’s Disease: A randomized double-blinded crossover study. Neurology 2014; 63 (7): 1245-1250
  • Fernández-Ruiz, J., Sagredo, O., Pazos, M. R., García, C., Pertwee, R., Mechoulam, R., & Martínez-Orgado, J. (2013). Cannabidiol for neurodegenerative disorders: important new clinical applications for this phytocannabinoid?. British journal of clinical pharmacology75(2), 323–333. https://doi.org/10.1111/j.1365-2125.2012.04341.x
  • https://www.tga.gov.au/medicinal-cannabis-guidance-documents
  • Javed, H., Azimullah, S., Haque, M. E., & Ojha, S. K. (2016). Cannabinoid Type 2 (CB2) Receptors Activation Protects against Oxidative Stress and Neuroinflammation Associated Dopaminergic Neurodegeneration in Rotenone Model of Parkinson’s Disease. Frontiers in neuroscience10, 321. https://doi.org/10.3389/fnins.2016.00321 
  • Kailia LV, Lang AE. Parkinson’s Disease. Lancet 2015; 386 (9996): 896-912
  • Palomo-Garo, C., Gómez-Gálvez, Y., García, C., & Fernández-Ruiz, J. (2016). Targeting the cannabinoid CB2 receptor to attenuate the progression of motor deficits in LRRK2-transgenic mice. Pharmacological research110, 181–192. https://doi.org/10.1016/j.phrs.2016.04.004 
  • Parkinson’s Australia. About Parkinson’s. https://www.parkinsons.org.au/statistics 
  • Zeissler, M. L., Eastwood, J., McCorry, K., Hanemann, C. O., Zajicek, J. P., & Carroll, C. B. (2016). Delta-9-tetrahydrocannabinol protects against MPP+ toxicity in SH-SY5Y cells by restoring proteins involved in mitochondrial biogenesis. Oncotarget7(29), 46603–46614. https://doi.org/10.18632/oncotarget.10314