Sublingual and Oromucosal Delivery

Oromucosal delivery: the mouth as a delivery system

Forty-three seconds. That's roughly how long the standard instruction says to hold an oromucosal preparation under the tongue before swallowing. It's an easy number to skim past on patient-facing materials. Dig into the underlying pharmacokinetics literature, though, and there's a lot of quietly interesting biology packed into that small window of time, which is why oromucosal delivery deserves a closer look.

Sublingual and oromucosal delivery are often used interchangeably in everyday conversation, but they describe slightly different things. Sublingual means specifically under the tongue (the glossary entry on sublingual covers the term briefly). Oromucosal is the broader category; it covers absorption anywhere across the mucous membranes lining the inside of the mouth, including the gums (gingival), the cheek (buccal), and the floor of the mouth. Both routes are grouped together here because they share the same core rationale: getting compounds into systemic circulation via the oral mucosa rather than through the gastrointestinal tract.

A general reference such as the Wikipedia article on sublingual administration gives a neutral overview of the route. The rest of this piece looks at why the mouth behaves differently from the gut, and what that means when researchers describe cannabinoid absorption.

Why bypass the gut at all?

The short version is first-pass metabolism. When you swallow something, it travels through the gut wall and then straight to the liver via the portal vein before it ever reaches general circulation. The liver is extraordinarily good at breaking things down. For highly lipophilic compounds, and many cannabinoids fit that description, hepatic metabolism can significantly reduce the proportion of the original compound that makes it through intact. This affects bioavailability, which is the fraction of an administered dose that actually reaches systemic circulation in an active form.

The oral mucosa offers a different path. Blood vessels in the sublingual tissue drain primarily into the lingual veins and then the internal jugular vein, feeding into systemic circulation without that first pass through the liver. In principle, this means a higher fraction of an intact compound can reach the bloodstream before hepatic enzymes have a chance to work on it.

In principle. The practical picture is more complicated, and I'll come back to that.

For a fuller walk-through of the liver's role, see first-pass metabolism explained and how the liver metabolises drugs. For the swallowed route that this one is usually compared against, oral oils and capsules is the natural companion read.

The anatomy doing the work

The sublingual mucosa is relatively thin; somewhere in the range of 100–200 micrometres, and it's non-keratinised, which makes it more permeable than, say, the skin. It has a rich capillary network. Buccal mucosa (the cheek lining) is slightly thicker and therefore somewhat less permeable, but it offers a larger surface area and is mechanically more stable if you're designing a mucoadhesive film or wafer.

Permeability matters enormously here. Lipophilic (fat-soluble) molecules generally cross the oral mucosa more readily than hydrophilic (water-soluble) ones, because the mucosal epithelium has lipid-rich cell membranes that small lipophilic molecules can diffuse through passively. Cannabidiol and tetrahydrocannabinol are both highly lipophilic, which is part of the reason the oromucosal route has attracted interest for cannabinoid formulations.

That said, the sublingual mucosa is also covered with saliva, which is an aqueous medium. A compound that doesn't dissolve at all in saliva won't have much contact time with the tissue before it gets washed away. Formulation chemistry has to account for this, hence the use of ethanol, medium-chain triglycerides, and other solubilising vehicles in many oromucosal preparations.

One common misunderstanding is that "thin and well supplied with blood" automatically means "fast and complete". Tissue anatomy sets the ceiling; it doesn't guarantee the result. Contact time, the amount that dissolves, and how much is swallowed all sit between the ceiling and what actually gets absorbed.

Cannabinoids and oromucosal formulations: what the research describes

Regulatory-approved oromucosal cannabinoid formulations do exist. In Australia, the TGA's Australian Register of Therapeutic Goods (ARTG) includes registered medicines in this space, and prescribers working under the Authorised Prescriber framework or the Special Access Scheme may access them. Cannabinoid medicines that contain THC are classified under Schedule 8 of the Poisons Standard as controlled drugs; those that are CBD-only may fall under Schedule 4. This is the regulatory context; prescribers and pharmacists work within it, not consumers buying off a shelf. If the schedules are unfamiliar, Schedule 4 vs Schedule 8 and the Poisons Standard (SUSMP) explained set out how they work.

The pharmacokinetics of sublingually administered cannabinoids have been studied, though the literature has real limitations worth flagging honestly. Sample sizes in many early studies were small, inter-individual variability in absorption is high, and study conditions (fasted versus fed state, vehicle composition, hold time) vary enough to make direct comparisons difficult. A 2020 review published via NCBI (Millar et al.) examined CBD pharmacokinetics across multiple delivery routes and noted that sublingual bioavailability estimates ranged widely, roughly 13–19% in some reported figures, though the authors were careful to note methodological inconsistency across studies.

What the research does consistently show is that the time-to-peak plasma concentration (Tmax) for oromucosal cannabinoid delivery tends to be faster than for oral ingestion, and slower than inhalation. The pharmacokinetics profile therefore sits between those two routes in terms of onset and duration; not as fast as inhaled, not as prolonged in its absorption phase as an oral capsule or edible. More on how these figures are built and compared is in bioavailability of cannabinoids.

Formulation variables that change the picture

This is the part that, honestly, I think gets underdiscussed in popular writing on the topic. The vehicle, the liquid or semi-solid the active compound is dissolved or suspended in, has a substantial effect on how well anything crosses the oral mucosa.

Ethanol increases mucosal permeability and also acts as a solubiliser for lipophilic cannabinoids. Medium-chain triglycerides (MCTs) are a common oil vehicle; they assist solubility but may also mean some portion of the dose ends up swallowed rather than absorbed transmucosally, which reintroduces first-pass metabolism into the equation. Propylene glycol has been used in some formulations for similar solubilising reasons. Mucoadhesive polymers, materials that stick to mucosal tissue, can extend contact time and improve absorption, which is why some oromucosal formulations come as films or wafers rather than liquids.

The hold time matters too. If a preparation is swallowed quickly, a large fraction of it goes to the GI tract regardless of how it was designed. This is partly why instructions specify a hold time, and why the actual absorbed fraction in real-world use probably differs from what controlled studies report.

For formulations containing a full-spectrum extract, meaning the full range of cannabinoids, terpenes, and other phytochemical constituents are present, the vehicle chemistry becomes even more complex. Terpenes themselves are volatile and lipophilic, and whether they survive the formulation process and contribute meaningfully to mucosal absorption is an open question. The entourage effect hypothesis, which proposes that these constituents interact, is still being characterised in the research literature; it's harder to study in an oromucosal context than in inhalation.

Other delivery technologies, such as liposomal delivery systems, tackle the same underlying problem from a different angle: how to keep a poorly water-soluble compound in contact with absorbing tissue long enough to matter.

Individual variation, the part nobody loves talking about

Salivary flow rate and mucosal absorption make for a surprisingly deep rabbit hole in the reference literature. Salivary volume, salivary pH, and the composition of the mucosal epithelium all vary meaningfully between individuals, and within the same individual depending on hydration, medications, and time of day. Anticholinergic medications, for instance, reduce salivary flow and can affect how a sublingual preparation dissolves and spreads across the tissue.

Age changes mucosal thickness and vascularity. Smoking history affects the epithelium. None of this is unusual in pharmacology; inter-individual variability is everywhere, but it's worth holding in mind when reading any average bioavailability figure from the literature. Averages flatten a lot of real-world spread, and a single published percentage describes a group in particular study conditions, not any one person.

My measured view: I reckon the popular coverage of sublingual delivery tends to overstate the precision of absorption estimates and understate how much the formulation itself drives outcomes. A cannabinoid dissolved in a well-designed mucoadhesive vehicle, held correctly, will behave very differently from the same cannabinoid dropped into a carrier oil and swallowed more or less immediately. The number on the bottle doesn't tell you which situation you're in.

This is also why evidence quality matters when reading about any delivery route. Small studies, mixed conditions and differing vehicles can all produce figures that look comparable on paper but aren't. Readers wanting the wider frame can look at bioavailability and the first-pass effect.

Regulatory and quality considerations

For oromucosal medicines on the ARTG, Good Manufacturing Practice (GMP) standards apply to manufacture, which includes requirements around dissolution, content uniformity, and microbiological quality. GMP-manufactured products have been through a level of quality control that unregistered preparations have not, and in Australia, supplying unapproved therapeutic goods without TGA approval carries serious regulatory consequences under the Therapeutic Goods Act 1989.

This matters because the oromucosal route is sensitive to formulation quality in ways that oral capsules are sometimes not. A poorly manufactured sublingual drop with inconsistent cannabinoid concentration across the bottle will produce inconsistent absorption. Quality control in manufacture is therefore directly relevant to the pharmacokinetics; they're not separable.

Content uniformity is the plain-language version of this point: every measured portion from a container should contain about the same amount of active compound. Dissolution testing, similarly, checks that a preparation releases its contents in the way the design assumes. Neither can be judged by looking at a bottle, which is one reason published quality standards, rather than marketing claims, are the thing to read.

The TGA's pages on medicinal cannabis and on scheduling are the authoritative starting points for how these rules apply in Australia, and they're listed below.

Sources

• Millar et al. (2020), "A Systematic Review on the Pharmacokinetics of Cannabidiol in Humans", NCBI/PMC
• Guidance on the use of medicinal cannabis in Australia, TGA
• Rathbone MJ, Drummond BK, Tucker IG, "The oral cavity as a site for systemic drug delivery"; NCBI Bookshelf
• Scheduling of Medicines and Poisons, TGA (Poisons Standard)

Tom Whitfield, Health librarian, references & fact-checking