Module 2: Routes of Administration

Routes of Administration.

The route of administration and the drug formulation of cannabis are important factors that determine the rate of absorption. Depending on the route, (smoked, vaporised, oral, oro-mucosal, rectal or topical), the onset and duration of effects of medicinal cannabis can vary.


Smoking cannabis is more commonly associated with recreational use and although it is an effective means for rapid drug delivery, it is not an advised route of administration. Smoking results in a more rapid onset of action, (usually within minutes) and a shorter duration of pharmacodynamics effects, when compared to oral ingestion (1). The dose of THC delivered and the level of absorption is also highly variable and can depend on the depth and duration of inhalation, as well as length of breathhold. As such, the bioavailability of smoked cannabis has been reported to range between 2 and 56% (2,3). In addition to the difficulty in controlling dose, smoked cannabis is also not recommended for medicinal purposes as toxic by-products such as carbon monoxide, polycyclic aromatic hydrocarbons and tar may cause irritation to the lungs.


Vaporization has a similar PK/PD profile as smoking cannabis- rapid onset of action and shorter duration, but unlike smoking, vaporizing or “vaping” does not generate toxic by-products. This route of administration may be beneficial for conditions where rapid relief is required. However, a number of variables can affect the doses received (such as amount of cannabis placed in vaporizer, temperature, duration of vaporization, balloon volume) and this can make it difficult to achieve consistent dosing.


Oral administration results in a slower onset of action (~1-4 hours) with a more delayed peak THC concentration ultimately resulting in a longer duration of effect when compared to smoking (1). Oral bioavailability has been estimated to be as low as 4 – 20% (compared to intravenous administration) due to a number of factors including, degradation in the stomach and significant first pass metabolism (4). Vehicle such as the carrier oil or capsule can also have an effect on the final plasma concentration of ingested cannabis. THC is converted in the liver to its equipotent and longer-acting active metabolite 11-OH-THC. After oral ingestion, THC and 11-OH-THC are reported to be present in the plasma at approximately equal concentrations (5,6). Despite the low bioavailability, oral ingestion is a relatively reliable delivery system for medicinal cannabis and is amenable to self-titration.


The oral mucosa is well vascularized and relatively permeable allowing systemic absorption of cannabis (Sativex; THC:CBD buccal spray) while somewhat evading first pass metabolism. Some portion of Sativex is swallowed and hence levels of the active metabolite 11-OH-THC can be found post dosing (7). Oro-mucosal administration of Sativex results in similar cannabinoid blood levels when compared to ingestion and lower cannabinoid blood levels in comparison to inhalation (7,8). Inter-individual variation was also apparent with regards to peak plasma concentration with the mean peak plasma concentration occurring between 2 – 4 hours (8). Like oral ingestion, oro-mucosal administration is amenable to self-titration however, due to the high alcohol content in the spray, chronic use of Sativex can cause stinging and white lesions in the mouth (9).


Suppository preparations of medicinal cannabis such as the pro-drug THC-hemisuccinate are available and have far better bioavailability than the oral route (52 – 61%) due to higher absorption and lower first pass metabolism (10 – 12). Rectal administration is an important avenue for patients who are unable, or have difficulty taking medication orally.


Transcutaneous administration is another route of cannabinoid delivery that avoids first pass metabolism. Due to the highly hydrophobic properties of cannabinoids, traversing the aqueous layer of the skin represents the rate limiting step in the topical diffusion process (1). Of note, CBD and CBN are reported to permeate the skin 10-fold more than THC (13). Recently, Zynerba Pharmaceuticals investigated the efficacy of transdermal CBD gel (ZYN002) in phase 2 trials for partial onset seizures and knee pain due to osteoarthritis (trial IDs: ACTRN12616000510448 and ACTRN12616001104448). Although neither study reached its primary outcome, ZYN002 was found to be well tolerated and have a favorable safety profile. Further research is needed to establish the clinical uses of topical cannabinoids.

Route of Administration Onset Duration Bioavailability Note
Smoking ~30 sec 30 min – 2 hours High Rapid relief. Short duration.

May cause respiratory irritation.

Vaping ~30 sec 30 min – 2 hours High Rapid relief. Short duration.
Oral 30 min – 2 hours 3 – 6 hours Low Sustained mild dose. Significant first pass metabolism.
Oro-mucosal 30 min – 1 hour 1 – 6 hours Low-Medium May cause sores/lesions in mouth with prolonged use.
Rectal (THC-hemisuccinate) 10 min- 1 hour 2-4 hours Medium-High Largely avoids first pass metabolism
Transdermal 1 min – 2 hours 4 – 8 hours Medium-High Localised relief, avoids first pass metabolism. CBD more permeable than THC

*All times are approximate and can vary greatly from person to person.


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