Parkinson’s Disease

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.