Insomnia

1. The medicinal cannabis’s suitability for the intended indication and
2. the medicinal cannabis’s efficacy and expected benefits

Given how important quality sleep is for optimizing mental and physical wellbeing, it is alarming how pervasive sleep disturbances are throughout society (Ellis et al, 2012) The limited effectiveness and risk of undesirable and potentially dangerous side effects of conventional pharmaceutical sleep aids (Morin et al, 2012) result in nearly 50% dissatisfaction rates (Chung et al, 2016)

Evidence indicates that following cannabis use there may be a decrease in slow wave sleep (SWS) times and a corresponding increase in time spent in stage 2 sleep. Among those with a medical condition that impacts upon sleep, reductions in sleep disturbance (not necessarily causing early awakening) appear to improve quality of sleep (Gates et al, 2014)

In one study, 74% of the 1,000 interviewees said they used cannabis to help them sleep — 84% of whom said the cannabis had helped them, and over 83% said that they had since reduced or stopped taking over-the-counter or prescription sleep aids. The study suggests that cannabis could lower opioid use. However, the researchers caution that more needs to be done to understand the potential therapeutic benefits of cannabis. (Taylor & Francis Group, 2019)

CBD has demonstrated preliminary efficacy for a range of physical and mental health care problems. In the decade before 2012, there were only 9 published studies on the use of canna­binoids for medicinal treatment of pain; since then, 30 articles have been published on this topic, according to a PubMed search conducted in December 2017. Most notable was a study con­ducted at the University of California, San Diego’s Centre for Medicinal Cannabis Research that showed cannabis cigarettes reduced pain by 34% to 40% compared with placebo (17% to 20% decrease in pain) (Abrams et al, 2007). In particular, CBD appears to hold benefits for a wide range of neurologic disorders, including decreasing major seizures. A recent large, well-controlled study of paediatric epilepsy documented a beneficial effect of CBD in reducing seizure frequency by more than 50% (Devinsky et al, 2017). In addition to endorphin release, the “runner’s high” experience after exercise has been shown to be induced in part by anandamide acting on CB1 receptors, eliciting anxiolytic effects on the body. (Fuss et al, 2015)

A crossover study comparing CBD with nitrazepam found that high-dose CBD at 160 mg increased the duration of sleep. The higher doses of CBD that studies suggest are therapeutic for anxiety, insomnia, and epilepsy may also increase mental sedation (Shannon et al, 2012).

1. any unknown or expected adverse effects, risks and safety issues & d. 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

Drug Interactions – CYP P450 Enzyme System

THC and CBD are metabolized by Cytochrome P450 enzyme system, including CYP1A2, CYP2C9, CYP2D6, CYP2C19 and CYP3A4. Based on in vitro and animal studies with cannabis, there is a potential for interactions with the medications metabolized by the P450 enzymes (2C9, 2C19, 3A4). It’s notable, however, that the inhibitory effects in vitro and in animal models were only seen at exposures significantly higher than the maximum observed in clinical trials. For instance, in clinical trials were Sativex® has been taken concomitantly with other drugs metabolized by the Cytochrome P450 enzyme system, no clinically apparent drug-drug interactions have been seen in these trials at clinical doses. In an in vitro study with 1:1% (v/v) THC botanical drug substance (BDS) and CBD BDS, no relevant induction of the Cytochrome P450 enzymes was seen for human CYP1A2, CYP2C9, CYP2C19 and CYP3A4 in human hepatocytes at doses of up to 1µM (314ng/mL) (Stout and Cimino, 2014).

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.