PRESCRIBING MEDICINAL CANNABIS

The ideal dosage of medicinal cannabis should be always determined for each patient based on many factors, including the THC content of the medicinal cannabis product, the selected route of administration, and the specific medical condition of the patient. As a general rule, the optimal dose is the lowest dose that can control a patient’s symptoms without side effects. To accomplish this objective, a physician may ask the patient to start with a low dose and to up-titrate according to a proposed titration scheme. This may allow for better tolerability. Different patients may require or tolerate different doses.

For patients who are taking oral forms of medicinal cannabis, the recommendation is to start with a total daily dose of 2.5mg THC (or 1.25mg for frail patients), typically taken in the evening.¹ For patients in need of inhaled medicinal cannabis, there is a greater variability based on the deepness or type of inhalation, so the dosage needs to be highly individualized. However, a general starting point can be between 25mg and 100mg of inhaled dried flower per day.²

The pharmacokinetics (PK) for cannabinoids differs depending on the route of administration.¹ The inhaled bioavailability of THC ranges between 20% and 30% and varies according to depth and duration of inhalation. The bioavailability of inhaled CBD is similar to THC, with an estimated bioavailability ranging from 11% to 45%.³ THC from inhaled medicinal cannabis reaches a peak blood concentration at about 5 to 10 minutes, with about 10% of the peak concentration remaining 1 hour after inhalation.³ Inhalation results in about 33% exposure of the 11-OH-THC metabolite, compared to the oral administration. This is crucial as this metabolite is a more potent agonist at the CB₁ receptor and produces a more pronounced psychoactive effect than THC.

The oral bioavailability of THC ranges normally between 10% and 20% and varies according to the food intake.³ High-fat meals are associated with a higher absorption rate. There is low oral bioavailability due to the high lipid solubility and first-pass hepatic metabolism. The PK parameters of oral CBD are similar to THC, with an estimated oral bioavailability of 6%. THC from oral medicinal cannabis reaches a peak blood concentration at about 3 to 4 hours, with about 30% of the peak concentration remaining 12 hours after ingestion.³

Both THC and CBD are metabolized by the cytochrome P450 (CYP) system. CYP2C9, CYP2C19, and CYP3A4 are the primary enzymes in the metabolism of THC, while CYP2C19 and CYP3A4 are the primary enzymes in the metabolism of CBD. Both cannabinoids are primarily excreted via feces, with some elimination in urine. Like THC, the elimination half-life of CBD is estimated at about 2 to 5 days after oral administration.^3-5

No. In fact, smoking is not recommended.^1,2 There are many ways to inhale or ingest medicinal cannabis. For example, as an alternate to smoking, medicinal cannabis can be inhaled through a vaporizer. A vaporizer is not only safer, since a patient will not inhale a product resulting from the combustion of the dried flower, but also more accurate from a dosing standpoint.

The Foltin Puff Procedure is a good starting point.⁵ It has four key points:

• Recommend vaporization temperature of 190ºC or higher⁵
• When the vaporizer is ready, inhale on the mouthpiece for 5 seconds⁶
• Hold the vapor in the lungs for 10 seconds⁶
• Exhale and wait for 10 to 20 minutes between inhalations

A standardized procedure will guarantee safer administration and will reduce the inter- and intra-variability between patients and administrations.

A vaporizer is a device that heats medicinal cannabis in the form of dried flowers. It uses a lower temperature than an open flame, so a vaporizer allows patients to inhale cannabis in vapor form, rather than smoke. Inhalation allows cannabinoids within the plant to be volatilized with heat, enter the bloodstream, and reach the brain more quickly via inhalation, thereby providing fast-acting relief of symptoms. In addition, vaporization avoids combustion and reduces the presence of potentially harmful irritants that may be contained in cannabis smoke.

Generally, medicinal cannabis that is intended for inhalation acts more quickly and lasts a shorter period, so it is more appropriate for episodic acute symptoms. In contrast, medicinal cannabis intended for oral use usually takes a longer time to act, but then lasts for a longer period, so it is more appropriate for chronic conditions.

There is a potential for some drug-drug interactions with cannabinoids.⁴ A pharmacodynamic interaction may occur with the co-administration of anti-spasticity drugs, as a reduction in muscle tone may occur, leading to a greater risk of falls and injury.
Pharmacodynamic interactions, leading to CNS effects (e.g., dizziness, confusion, sedation, somnolence) may occur when medicinal cannabis is taken concomitantly with drugs that have similar effects on the central nervous system such as CNS depressants.³

Both THC and CBD are metabolized by the cytochrome P450 (CYP) system. CYP2C9 and CYP3A4 are the primary enzymes in the metabolism of THC, while CYP2C19 and CYP3A4 are the primary enzymes in the metabolism of CBD.^3-5 Inhibitors of these enzymes may increase, while inducers may decrease, the systemic exposure of cannabinoids and/or their active metabolite resulting in an increase in adverse reactions or loss of efficacy of the medicinal cannabis.

Physicians should monitor for potentially increased cannabinoid-related adverse reactions when medicinal cannabis is co-administered with inhibitors of CYP2C9 (e.g., amiodarone, fluconazole), CYP2C19 (e.g., ketoconazole, isoniazid), and CYP3A4 (e.g., ketoconazole, itraconazole, clarithromycin, ritonavir, erythromycin).^2,5 Likewise, physicians should monitor for potentially decreased efficacy when medicinal cannabis is co-administered with inducers of CYP2C9, CYP2C19, or CYP3A4 (e.g., rifampicin, rifabutin).^2,5 Finally, physicians should monitor for potentially increased adverse reactions associated with substrates of CYP2C9, CYP2C19, or CYP3A4 (e.g., clarithromycin, erythromycin) when medicinal cannabis is co-administered with them.⁵

There are also potential interactions with highly protein-bound active substances and THC.³

The decision to start or stop a medication is up to the prescribing physician, in dialogue with the patient. That said, there are multiple studies showing that patients who start medicinal cannabis for various pain conditions end up primarily substituting or reducing the dose for opioids

Pre-clinical data show a fair amount of evidence to suggest a functional interaction between the cannabinoid and the opioid systems, although additional research is needed to understand precisely how the two systems communicate with one another. A recent systematic review and meta-analysis of pre-clinical studies examining the strength of the existing evidence for the “opioid-sparing” effect of cannabinoids in the context of analgesia concluded that there was a significant opioid-sparing effect between morphine and THC when co-administered, although there was significant heterogeneity in the data.⁷

Clinical case series and epidemiological data, like surveys of authorized medical cannabis patients, showed that opioids accounted for more than 40% of substituted medications in patients using medicinal cannabis for pain.^8,9 In another study, more than 70% of chronic pain patients who self-reported substituting one or more medications with medicinal cannabis reported substituting opioids.¹⁰