In the existing medicinal cannabis market, there are a wide array of products available which can be consumed with various means of administration. The route of administration is defined as “the path by which a substance is taken into the body (i.e., by mouth, injection, inhalation, rectum, or by application).” The route of administration of any therapeutic compound (in this case CBD) is extremely important as it can govern the uptake, distribution and elimination of the therapeutic. Consequently it can govern how effective the therapeutic will be.
Cannabinoids can be delivered in many ways based on the requirements and preferences of the user. In the medical practice, the preference of the user (how comfortable they are with the administration) can be a very important factor and it often plays a large role in the ‘modus operandi’ of prescribing practices. However, comfort should not be prioritized over effectiveness, as the route of administration can tailor the treatment to a particular site of action. This can have a more pronounced effect in treating the disease or symptom.
The absorption of a drug or a supplement is its transfer from the site of administration to the bloodstream. The medical term for this absorption is called the bioavailability. It is defined as “the degree and rate at which a substance (such as a drug) is absorbed into a living system or is made available at the site of physiological activity”. A substance delivered intravenously is assumed to have 100% bioavailability, and other routes of administration are compared to the intravenous route as a ratio for the percentage bioavailability. The table below summarizes the estimated bioavailability of CBD across the four routes of administration.
The major forms of administration of cannabidiol (CBD), as well as any relevant bioavailability data, are discussed below.
The most common route of administration of medicinal cannabis products is via the oral route. This is the easiest way in which consumers can have the product, particularly because cannabinoids can be incorporated into many food products or can ingested easily via capsules or oils. Participants of one study consumed chocolate cookies to get a dose of 40 mg of CBD and the bioavailability was reported to be 6% (compared to the intravenous route). A pharmacokinetic study performed with CBD in dogs estimated a higher oral bioavailability of between 13 to 19%, however it is important to note that animal and human oral bioavailabilities do not always correlate.
In a clinical trial conducted on patients with Huntington’s disease, where CBD was administered orally, it also showed very low bioavailability levels. CBD levels were present in low concentrations in the blood plasma and within a relatively narrow range. Mean levels (of 14 patients) ranged from a low of 5.9 ng/ml to a high of 11.2 ng/ml.
First pass metabolism is the main reason for the low oral bioavailability of CBD. First pass metabolism is caused by the actions of enzymes of the gastrointestinal lumen, gut wall enzymes, bacterial enzymes, and hepatic enzymes-before CBD reaches the circulatory system. CBD is acted on by enzymes in the liver called CYP450 mixed function oxidases, to yield more than 100 different metabolites.
There are a number of ways in the oral bioavailability can be enhanced. Once such way is by co-administration of CBD with long-chain triglycerides (fatty acids). A recent study suggested that co-administration of CBD with long-chain triglycerides can bypass hepatic first pass metabolism. The proposed mechanism for this is via the intestinal lymphatic system, consequently getting access to the bloodstream via the left internal jugular and left subclavian veins and bypassing the liver in the process.
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More attributed to recreational users of the cannabis, this route of administration does have benefits in terms of attaining higher bioavailability. Therefore users feel the psychoactive effects of THC faster when inhaled as compared to taking it orally, and this was observed in a clinical study. In this study, bioavailability of THC after inhalation was estimated to be 18% whereas oral THC in a chocolate cookie provided systemic availability of 6%. Given the similarity in the lipophilicity of THC and CBD, bioavailability data correlates between the two.
A key observation from this study was that the clinical effects had a slower onset but lasted for a longer period of time. Henceforth the slower absorption of the oral route allows for less rapid elimination as compared to the inhaled route, and can therefore have a longer lasting effect.
This clinical observation can be highly relevant for medical applications (even CBD products), especially due to the dramatic increase in the bioavailability seen through the inhaled route. CBD bioavailability after inhalation was found to have a mean value of 31%, which is significantly higher than the oral route of administration.
The high bioavailability seen with this route of administration is due to the fact that the lungs have high permeability, a large absorptive surface area and a good blood supply for CBD to enter the systemic circulation. Henceforth it is another means for bypassing first pass metabolism.
The sublingual route of administration is probably on par with the oral route with regards to comfortness. Common methods of sublingual administration include sublingual tablets, sublingual strips, lozenges and sprays.
A study performed with rabbits compared the bioavailability of oral and sublingual CBD solutions. The results of this study showed that the CBD delivered sublingually showed significantly higher bioavailability than the CBD delivered orally.
The sublingual route of administration also bypasses first-pass metabolism, as the high abundance of capillaries below the tongue allow CBD to enter the bloodstream through this route.
The rectal route of administration is generally favoured in situations where the oral route is not possible, such as in scenarios where patients have trouble swallowing or suffer from nausea and vomiting (a side effect of their diseases).
Currently, there is a lack of data specifically calculating the bioavailability of CBD rectally. Bioavailability data from pharmacokinetic studies assessing THC showed that the rectal route of administration had approximately double the bioavailability as compared to the oral route. Another study found the bioavailability of THC from a rectal formulation to be 13.5%. Out of the three veins in the venous drainage of the rectum, only one of them (the superior rectal vein) flows into the liver. Henceforth there is only a partial first pass metabolism effect from this route of administration, and consequently higher bioavailability is reported (as more CBD end up in the blood circulation). As a result, suppositories have a faster onset of action of CBD as compared to oral means of administration (oils, capsules).
One highly relevant study compared the effects of CBD delivered orally and rectally in mice induced with colonic inflammation. The results from this study showed that CBD delivered rectally significantly reduced inflammation in the rectum, whereas CBD delivered orally had no effect. The authors of this study suggested that CBD could protect against colitis locally through the rectal route, but this remains to be explored further.
Inhalation vs Oral: what is more effective?
In a study by Hollister et al. comparing three routes of administration of cannabinoids (oral, inhaled and intravenous), it was found that the oral route provided the longest period of “clinical effects”. This is contrary to the fact that the oral route produced the lowest plasma concentration out of the three. The two graphs below show the pharmacokinetics of THC relative to time (taken from Hollister et al.)
Although the inhaled route can provide a more rapid onset, it also has a shorter clinical effect (approximately 1-3 hours) as it is cleared rapidly. This is because the plasma concentrations peak extremely fast and CBD is eliminated from the bloodstream following first order elimination kinetics (rate of elimination is proportional to the amount of drug in the body).
On the other hand, the oral route of administration is slowly released into the bloodstream. It maintains low concentrations in the blood over a longer period of time, and is therefore eliminated at a slower rate (slower elimination). Therefore it has a longer lasting effect (approximately 7 hours).
What is the best route of administration?
In terms of bioavailability, the sublingual and inhalation routes are the most efficient in delivering CBD to the bloodstream. This can be important for symptoms that require fast amelioration, and high levels of CBD in the bloodstream.
However there isn’t a ‘one size fits all’ solution where one form trumps the others.
Oral administration may be effective in terms of comfort and ease, and to treat those symptoms which only require a small concentration of CBD in the systemic circulation for a longer period of time. However the rectal route of administration can provide local anti-inflammatory effects, which could be pivotal in treating various colonic diseases, as well as increased bioavailability to provide a higher concentration of CBD to the target area in the body.
By Abdul Rehman Mohammad, BSc