Epilepsy

The anti-epilepsy effects of cannabinoids have been studied since the mid-1970’s (Fried at al, 1973). CBD reliably delivers a range of anticonvulsant effects with few known adverse results and no intoxication (Gloss et al, 2014).

In 2016, the results of a GW trial in Dravet syndrome (Devinsky et al, 2019) showed at a dose of 20mg of CBD per kilogram of patient weight, 43 per cent of CBD patients have a 50 percent reduction in convulsive seizures compared to 27 percent of patients taking placebos. Three of the CBD patients achieved convulsive and total seizure freedom during the entire treatment period. An additional four CBD patients achieved convulsive seizure freedom during maintenance.

In patient observational studies, children with refractory (or intractable) epilepsy who have tried CBD (sometimes with low ratios of THC) have reported significant improvements in seizure frequency (Minchin, 2016). One molecular pathway scientists believe gives CBD its anti-seizure properties is through the suppression of the enzyme fatty acid amide hydroxylase (FAAH). The enzyme breaks down anandamide, a messenger molecule that occurs naturally in our body. Anandamide has a very similar structure to THC and plays a role in bodily activities such as appetite, memory, pain, depression and fertility. Anandamide also has neuroprotective effects against seizures, pain and inflammation (Epilepsy.org).

Acting as an antagonist, CBD has been found to supress the enzyme FAAH, which in turn stops it supressing anandamides anti-seizure properties. Less FAAH means more anandamide is present for longer in the body. By inhibiting the enzyme that metabolises and destroys anandamide, CBD enhances the body’s innate protective endo-cannabinoid response (Minchin, 2016).

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.