Dosing and administration
Information to consider before prescribing.
When authorizing cannabinoids for patient use, it is important to consider:
- the route of administration
- concomitant medications
Given the lack of clear information on the pharmacokinetics and pharmacodynamics of cannabis, it’s best to begin cannabis therapy using a “start low and go slow” approach, while monitoring patients for desired and adverse effects.
Routes of administration
There are various ways of administering medical cannabis:
- inhalation (smoking, vaporization)
- oral ingestion (oils, capsules, edibles)
- topical application (ointments, lotions, patches)
Smoking is not recommended by Health Canada, as cannabis smoke contains harmful combustion products, including carcinogens and carbon monoxide.1
Cannabis routes of administration:2
- Most common route of administration, but not recommended (joints, bongs, pipes, etc.)
- Combustion at 600-900 oC producing toxic biproducts: tar, PAH (polycyclic aromatic hydrocarbons), carbon monoxide (CO), ammonia (NH3).
- Chronic use associated with respiratory symptoms (bronchitis, cough, phlegm), but not lung cancer nor COPD (if cannabis only).
- Patients may mix with tobacco increasing respiratory/cancer risk.
- 30-50% of cannabis is lost to ‘side-stream’ smoke.
- Heats cannabis at 160-230oC. Reduced CO, but not complete elimination of PAH demonstrated to date.
- Vaporisation produces significantly less harmful biproducts vs. smoking.
- Decreased pulmonary symptoms reported compared to smoking.
- Oils, capsules and other po routes increasingly popular due to convenience and accuracy of dosing.
- Edibles (brownies/cookies) may be more difficult to dose.
- Juicing and cannabis teas do not allow for adequate decarboxylation of raw plant.
- Nabiximols oromucosal spray is currently the only cannabis-based prescription that delivers standardised dosage of CBD/THC in a 1:1 ratio with extensive research.
- Tinctures and lozenges intermediate onset with limited research.
(Adapted from MacCallum CA, Russo EB, 2018)
The onset and the duration of action of each administration form is dependent on absorption, distribution, and metabolism of cannabinoids.2 Absorption is the most variable of all parameters; for example, bioavailability of Δ9-THC through the smoking route is 2-56%.1
Absorption is greatly affected by product lipophilicity and organ tissue differences.1,2 Δ9-THC is taken up primarily by fatty tissues and highly perfused organs such as the brain, heart, lung, and liver.1 The highest concentrations of Δ9-THC with the levels up to 1000 times that of plasma can be found in the heart and in adipose tissue.1 The other factors that can affect absorption include amount of food ingested in a recent meals, depth of inhalation, duration of breath holding, and temperature of vaporizer.2
Table 2: Onset, peak, and duration of cannabinoid effects3
|Route of administration||Onset of the effect||Peak of the effects||Duration of the acute effect||Maximum duration of the effect|
|Inhalation (smoking, vaporization)||within a few minutes||30 minutes||2-4 hours||~24 hours|
|Oral (oils, capsules)||30 min – up to3-4 hours||3-4 hours||up to 8 hours||12-24 hours|
With topical application, it is not known how long it takes for potential therapeutic effects to appear, nor how long they last.
Metabolism and drug-drug interactions
Most cannabinoid metabolism occurs in the liver, and different metabolites predominate depending on the route of administration.
Metabolism of THC is predominantly hepatic, via cytochrome P450 (CYP 450) isozymes CYP2C9, CYP2C19 and CYP3A4.4
Substances that inhibit CYP isoenzymes leading to the increase in the bioavailability of Δ9-THC as well as the chance of experiencing THC-related side effects:1
- anti-depressants (e.g., fluoxetine, fluvoxamine, and nefazodone)
- proton pump inhibitors (e.g., cimetidine and omeprazole)
- macrolides (e.g., clarithromycin and erythromycin)
- anti-mycotics (e.g., itraconazole, fluconazole, ketoconazole, miconazole)
- calcium antagonists (e.g., diltiazem, verapamil)
- HIV protease inhibitors (e.g., ritonavir)
Substances that accelerate Δ9-THC metabolism via 2C9 and 3A4 isozymes leading to the decrease in the bioavailability of THC and its effectiveness if used in a therapeutic context:1
- Saint John's Wort
CBD (cannabidiol) is also hepatically metabolised, primarily by isozymes CYP2C19 and CYP3A4 and additionally, CYP1A1, CYP1A2, CYP2C9, and CYP2D6.4 CBD is known to inhibit CYP isozymes such as CYP1A1, 1A2, and 1B1. Cannabis may therefore increase the bioavailability of drugs metabolized by these enzymes, e.g. amitryptiline, phenacetin, theophylline, granisetron, dacarbazine, and flutamide.1
Both THC and CBD can stimulate, and in some cases even inhibit, the activity of the drug transporter P-glycoprotein in vitro.1
Considering the effects of cannabinoids on the therapeutic drug efficacy and toxicity of co-administered drugs, it is important to be aware of other medications that the patient is taking and carefully monitor patients using other drugs along with cannabis or cannabinoids.
Elimination half-life of THC can vary: a population pharmacokinetic model has described a fast, initial half-life and long, terminal half-life (22 hours). In heavy users, THC concentrations > 1 μg/L may be measurable in the blood > 24 hours post last cannabis use. THC metabolites are excreted in faeces and urine. THC is able to cross the placenta and is excreted in lipophilic human breast milk.
CBD also has a long terminal elimination half-life, with the average half-life observed post inhalation to be 31 ± 4 hours. An investigation of repeated daily oral administration of CBD elicited an elimination half-life ranging from 2 to 5 days. CBD metabolites are excreted in faeces and, to a lesser extent, in urine.4
Since cannabis has many variables (e.g., complex pharmacology of cannabinoids, genetic differences in cannabinoid receptor structure and function and cannabinoid metabolism, etc.) that do not fit well with the typical medical model for drug prescribing, and different routes of administration, it is difficult to establish uniform dosing schedules for cannabinoids.1
While precise dosages have not been established, some "rough" dosing guidelines are available.
General considerations to cannabis therapy initiation:2
- “Start low, go slow, and stay low”.
- For cannabis inhalation, patients should start with 1 inhalation and wait 15 min. Then, they may increase by 1 inhalation every 15–30 min until desired symptom control has been achieved.
- Attainment of euphoric effects is not required to attain symptom control. For chronic conditions and symptoms, long acting oral preparations are the mainstay of treatment.
- Limited clinical studies of cannabis for medical purposes indicate the daily doses of smoked or vapourized dried cannabis could range from as little as 75 mg of dried cannabis (9.4% THC by weight; i.e. 7 mg THC/day) to a maximum of 3.2 grams of dried cannabis (1–8% THC by weight; i.e. 32 to 256 mg THC).
- Doses of THC as low as 2.5–3 mg (and even lower) are associated with a therapeutic benefit and minimal psychoactivity.
- Majority of people using smoked or orally ingested cannabis for medical purposes reported using between 10–20 grams of cannabis per week, or approximately 1–3 grams of dried cannabis per day.
Cannabis dosing remains highly individualized and relies to a great extent on titration. Patients with no prior experience with cannabis and initiating cannabis therapy for the first time should be cautioned to begin at a very low dose and to stop therapy if unacceptable or undesirable side effects occur.
Table 3: Approximate Conversion Factors Smoked/Oral Δ9-THC1
|From smoked dose* to oral dose†||From oral dose† to smoked dose*|
|Multiply the dose of Δ⁹-THC (in mg) in the dried plant material to be smoked by a factor of 2.5 to obtain the estimated dose of Δ⁹-THC (in mg) to be ingested orally.(Smoked dose in mg X 2.5 = Oral dose in mg)||Divide the dose of Δ⁹-THC (in mg) to be ingested orally by a factor of 2.5 to obtain the estimated dose of Δ⁹-THC (in mg) to be smoked.(Oral dose in mg ÷ 2.5 = Smoked dose in mg)|
- * A "smoked dose" can be defined as the total available amount of Δ⁹-THC in a cannabis cigarette (calculated by multiplying the percentage of Δ⁹-THC by the total gram amount of cannabis in the cigarette).
- † An oral dose is defined as the total amount of Δ⁹-THC that is ingested orally.
Table 4: Quick reference of smoked to estimated oral doses of Δ9-THC1
|"Smoked Dose"* % THC in a 750 mg cannabis cigarette (total available mg Δ⁹-THC)||Estimated Oral Dose (mg Δ⁹-THC)†|
|1 % THC (7.5 mg)||18.8 mg|
|2 % THC (15 mg)||37.5 mg|
|2.5 % THC (18.8 mg)||46.8 mg|
|3 % THC (22.5 mg)||56.3 mg|
|5 % THC (37.5 mg)||93.8 mg|
|7.5 % THC (56.3 mg)||140.6 mg|
|10 % THC (75 mg)||187.5 mg|
|12.5% THC (93.8 mg)||234.4 mg|
|15 % THC (112.5 mg)||281.3 mg|
|20 % THC (150 mg)||375 mg|
- *A "smoked dose" is defined as the total available amount (in mg) of Δ9-THC in a standard cannabis cigarette (750 mg joint)
- †An oral dose is defined as the total amount (in mg) of orally ingested Δ9-THC
- Numbers in the table are rounded to the nearest decimal place
Table 5: Quick reference of oral to estimated smoked doses of Δ9-THC1
|Oral Dose (mg Δ⁹-THC)*||Estimated "Smoked Dose" (Total available mg Δ⁹-THC in the dried plant material in the cigarette)†|
- *An oral dose is defined as the total amount (in mg) of orally ingested Δ⁹-THC
- †A "smoked dose" is defined as the total available amount (in mg) of Δ⁹-THC in a standard cannabis cigarette (750 mg joint)
- Numbers in the table are rounded to the nearest decimal place
1. Health Canada. Information for Health Care Professionals: Cannabis (marihuana, marijuana) and the cannabinoids. 2013. https://www.canada.ca/en/health-canada/services/drugs-medication/cannabis/information-medical-practitioners/information-health-care-professionals-cannabis-cannabinoids.html. Accessed August 28, 2018.
2. MacCallum CA, Russo EB.. Practical considerations in medical cannabis administration and dosing. Eur J Intern Med. 2018;49:12-19. Doi: 10.1016/j.ejim.2018.01.004. Epub 2018 Jan 4.
3. Health Canada. Marihuana for Medical Purposes Regulations Daily Amount Fact Sheet (Dosage). April 2016.
4. Lucas CJ, Galettis P, Scheider J. The pharmacokinetics and the pharmacodynamics of cannabinoids [published online ahead of print Jul 12, 2018]. Br J Clin Pharmacol. doi: 10.1111/bcp.13710.