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Innovative Medicines & Omics A perspective on medicinal cannabis delivery systems

Cannabinoids are the most abundant and exclusive anti-inflammatory, antineoplastic, and analgesic activities,
metabolites of these species and the most important whereas some lignanamides have shown cytotoxic activity. 3
because they are capable of interacting with an entire
system of endogenous receptors (endogenous cannabinoid 2. Medicinal cannabis delivery systems
system). In addition, they are terpenophenolic in nature Given the low bioavailability of cannabinoids, their clinical
and are generally concentrated in the resin produced in the use is limited. In this sense, the pharmaceutical industry is
plant’s trichomes, especially in the female inflorescences. focused on improving this point to optimize the different
There are around 70 known terpenophenolics, of which formulations. At present, a wide variety of cannabis
tetrahydrocannabinol (THC) is the most studied. products are commercially available to be administered in
3
Cannabinoids are synthesized and accumulated as several routes, namely oral, transdermal, pulmonary, and
cannabinoid acids, and it is not until the drying and transmucosal administration. Various release systems have
storage process that the acids are gradually decarboxylated been proposed for each administration route to increase
until they reach their final form, such as THC or their efficacy. Table 1 shows the main advantages and
cannabidiol (CBD). Around 120 terpenes have also been disadvantages of each route of administration.
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identified in these plant species. These metabolites are
3,7
responsible for the flavor of the different varieties. Some 2.1. Oral administration
of these terpenes are pharmacologically active and could Although oral administration of cannabinoids has been
produce synergistic effects with cannabinoids. Flavonoids shown to have poor bioavailability, mainly due to poor
8
are aromatic compounds and can be found in free form absorption and degradation in the stomach or pre-
or conjugated with a glucoside. More than 20 of these systemic metabolism in the liver, various formulations
metabolites are produced, mainly found in the plant have been proposed to counteract this disadvantage.
3,7
leaves, and some studies suggest that they modulate the For example, several encapsulation systems have been
action of cannabinoids. Other chemical components also proposed to protect cannabinoids, such as micelles, soft
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present in the plant are alkaloids, although they are found capsules, and tablets. 9-11 Another alternative to improve
in lower proportions. These are nitrogenous compounds oral bioavailability is the combination with lipids, which
that usually present biological activity at low doses and can has been shown to increase the cannabinoid absorption
be derived from amino acids. Due to the low concentration rate. In the case of long-chain triglycerides, it has also been
of alkaloids present in these species, their pharmacological shown that this combination can cross the liver, reducing
evaluation is difficult. Finally, it also contains stilbenoids, the possibility of pre-systemic metabolism. Cyclodextrins
12
lignanamides, and phenolic amides. Stilbenoids are or their derivatives have also been proposed to form
phenolic compounds which are presumed to have certain inclusion complexes that significantly increase cannabinoid
pharmacological activities, such as antibacterial, antifungal, solubility. Another approach to improve cannabinoid
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anti-inflammatory, antineoplastic, neuroprotective, solubility is their derivatization, known as prodrugs. An
cardio- and vasculo-protective, and antioxidant effects. example is the CBD/naproxen combination developed
Phenolic amides have also been reported to have cytotoxic, by Claritas Pharmaceuticals (USA), which is being tested

Table 1. Main advantages and disadvantages of oral, transdermal, pulmonary, and transmucosal administration of cannabis
products

Route of Advantages Disadvantages
administration
Oral Patients prefer oral administration for its simplicity. This route causes slow and erratic absorption and degradation
by stomach acids. Bioavailability is reduced by the pre-systemic
metabolism in the liver.
Transdermal Transdermal delivery bypasses the first-pass metabolism effect, Local irritation and limited skin penetration of drugs.
resulting in increased drug bioavailability. Besides, it can
provide continuous drug release. Topical application is suitable
for localized pathologies.
Pulmonary Highly effective, rapid distribution to the central nervous Inhaling harmful combustion products can cause bronchitis
system, and higher systemic bioavailability. and chronic coughing. Vaporization systems and nebulization
formulations lack practicality.
Transmucosal Transmucosal delivery bypasses the first-pass metabolism effect, The use of transmucosal excipients may cause mouth ulcers. The
resulting in increased drug bioavailability. bioavailability of intranasal delivery systems could be improved.

Volume 2 Issue 1 (2025) 51 doi: 10.36922/imo.4448