Routes of administration and cannabis products with therapeutic purposes

The only cannabis medicine approved in Spain covered by the Social Security is Sativex®, a spray for application in the oral mucosa that contains an alcoholic extract of the plant Cannabis sativa, with a 1:1 ratio of its main active compounds [Δ9- tetrahydrocannabiol (THC) and cannabidiol (CBD)]. This medicine can be accessed free of charge, with a doctor's prescription, only by patients who suffer from multiple sclerosis, only to treat the spasticity associated with their pathology, and only if they have not responded to other therapies. The reality of therapeutic use of cannabis in our country is, however, very different. Thousands of patients, with very different pathologies, are using various preparations of these compounds to alleviate their symptoms and improve their quality of life. This article will provide a summary of the products and the most common routes of administration, explaining with scientific rigour the advantages and disadvantages of each, so that the patients using them and those who do so in the future know which options are most appropriate in each case.

Pharmacokinetic considerations

When selecting the optimal product and route of administration to treat a particular symptom or pathology, we must bear in mind its pharmacokinetic characteristics or, in other words, how the active compounds are released once we incorporate the product into our body, how they are absorbed, how they are distributed around the body, how they are inactivated and excreted. Closely related to the pharmacokinetics is the concept of bioavailability, which indicates the percentage of active compound that reaches the bloodstream, which is the system for transporting of nutrients, oxygen, medicines, etc. in our body. All these issues will determine the answers to the three questions that patients should ask themselves when selecting a product and route of administration: how much cannabinoid is going to be incorporated into my body, how long before I feel the effects and how long are they going to last.

Products most commonly used by therapeutic cannabis users.

There is a wide variety of cannabis products used by patients for therapeutic purposes. Among these are the very few medicines approved by North American and European regulatory agencies: Marinol® (dronabinol) and Cesamet® (nabilone): synthetic analogues of THC in the form of capsules; Sativex® (nabiximols), mentioned above; and Epidiolex®: Pure CBD extracted from the plant, presented in the form of syrup. Access to these medicines is extremely limited both on clinical grounds (lack of studies that analyse efficacy in a multitude of pathologies), on economic grounds (the prices are exorbitant in some cases) and on legal grounds (the use of these products is not allowed in the vast majority of countries in the world). Furthermore, these medicines have pharmacological limitations: a very narrow therapeutic window in the case of the pure compounds; a fixed THC:CBD ratio in the case of Sativex; and a slow pharmacokinetics in all of them. For all these reasons, patients are turning to alternative preparations. The most commonly used are dried flowers, extracts, oils and tinctures. More recently, the use of creams, edible products, suppositories and juices is expanding.

More concentrated cannabis products are generically called extracts or resins, and, given the hydrophobic nature of cannabinoids, they are obtained using organic solvents (hexane, butane, acetone, benzene, isopropanol, ethanol, etc.). It is important to note that most solvents of this type are very toxic to the body and that patients should refrain from using products that contain them, even in small amounts. The least toxic solvent for the elaboration of these products is ethyl alcohol (ethanol), food grade certified. Cannabis products obtained by extraction with supercritical fluids have appeared more recently, specifically carbon dioxide (CO₂). This process is more efficient and faster than extraction with organic solvents and leaves no toxic residues in the end products. For the time being, its major drawback is the high cost.

Other cannabis products most used by patients are oils. They are preparations less concentrated than resins or extracts, as they are obtained by means of diluting the latter in vegetable oils or macerating the raw plant in vegetable oils (either cold or hot). The most commonly used oils are olive, sesame, coconut and hemp oil.

When the dilution is made in alcohol, the products are called tinctures. These were widely used throughout the world when the medical use of cannabis was legal, but are not widespread at present due to the harm and discomfort that the consumption of alcohol on a continuous basis represents, as well as due to difficult standardisation as ethanol is a highly volatile solvent.

Cannabis products are produced from both from the resins and the oils whose use is increasing among patients, including foods (sweets, chewing gums, sponges, butters, etc.), topical creams or suppositories.

Routes of administration of cannabis products.

Inhalation. Consumption of cannabis in the form of cigarettes is the most widespread among recreational users and is one of the most popular also among therapeutic users. However, this form of consumption should be avoided because it is associated with adverse effects such as chronic cough, bronchitis, and, above all, inhalation of toxic combustion products (carbon monoxide, tar or ammonia among many others). A very similar way of consuming cannabis, in terms of time of onset, magnitude and duration of effects, is inhalation through use of vaporisers. These instruments heat the cannabis products up to temperatures at which the cannabinoids decarboxylate, but without reaching the point of combustion in which the toxic by-products are generated resulting from pyrolysis. Through this method, cannabinoids reach their maximum concentration in the blood and brain a few minutes after consumption, which represents two important advantages compared to other forms of administration: first, the therapeutic benefit is almost immediate, which is very useful when suffering from acute crises in certain pathologies (peaks of pain, nausea, outbreaks in inflammatory bowel disease, etc.); and on the other hand, the speed of the effect allows avoiding overdose episodes. Last, but not least, bioavailability of the major cannabinoids consumed by this method is very high (around 25%, although with large variations among individuals).

Despite their usefulness for certain patients or situations, inhalation of cannabis with vaporisers has some associated drawbacks. For example, the amount of cannabinoids incorporated into the body is very variable and depends on parameters such as the amount and type of cannabis product placed in the device, the temperature and duration of the vaporisation, the duration and efficacy of each inhalation, etc. In addition, the effects of cannabinoids are not prolonged in time, as changes in their plasma levels are very fast, both rising (which can be an advantage during acute pain crises, for example) and lowering. Thus, inhalation may be an interesting route of administration to deal with acute episodes that need immediate relief, but it would be the best option for chronic treatments, in which high levels of cannabinoids are looked for during prolonged periods of time and consistency in the dosage.

Oral/oromucosal/sublingual administration.. Many cannabis products used by patients are consumed orally, oromucosally or sublingually (Sativex®, extracts, oils, foods, etc.). In comparison with inhalation, the effects take longer to occur through these routes (0.5-6 hours), last longer and, at an equal dose used, are less intense (as the bioavailability is lower -than 15% approximately - due to the massive degradation suffered by the cannabinoids receptors in the liver before reaching the bloodstream). There are no major differences between the oral, sublingual and oromucosal routes. This form of administration is used by patients with chronic diseases, who need high levels of cannabinoids in their body in a continuous manner.

The effects of edible products are more difficult to control in terms of their intensity and the time they take to appear. This is one of the reasons why this route of administration is associated with more overdose episodes. Absorption is still slower than when resins or pure oils are consumed and lower and more variable bioavailability between individuals (4-12%).

Topical administration.. Although the use of topical creams and ointments is increasingly more extended, no controlled studies have been conducted on the distribution and bioavailability of this route. The little available preclinical research has been conducted with dermal patches and suggests that absorption is slow, long-lasting (maximum peak in plasma at approximately one and a half hours, sustained until 48 hours) and is not too high. Although the potential of this route of administration is yet to be explored, and as different components of cannabis have analgesic, anti-inflammatory, etc. properties, it could be very interesting for the treatment of pain or localised and superficial inflammations, and of skin conditions (acne, psoriasis, wounds, insect bites, etc.).

Rectal administration. No thorough studies or clinical trials or preclinical trials have been conducted to date on the pharmacokinetics of cannabis in this route. However, its use is spreading among patients at an alarming rate. Its justification appears to reside in the testimonies of many of them, who claim to be able to use very high amounts of THC per day (more than 1 g), without feeling any kind of psychotropic effect. However, the lack of psychoactivity is very likely the result of the very low absorption of THC through the rectal mucosa. This tissue does not capture hydrophobic compounds well and cannabinoids, including THC, have this chemical nature. In fact, studies have been conducted to attempt to reduce the hydrophobicity of THC in order to increase its absorption via the rectal route. This way pro-forms of THC have been obtained (primarily bound to hemisuccinate) with greater bioavailability than by oral route. However, it is important to emphasise that these are synthetic forms derived from THC, with unknown biological effects, and not the THC itself, which is what the patients can access. For this reason, potential applications of natural cannabis products through this route of administration are, at least for the time being, very limited. It is worth thinking about their use, for example, for local treatments, in which the last sections of the gastrointestinal tract are affected, or in the case of patients that cannot use the oral or inhalation route.

Quality of cannabis products. It is important to remind patients that the market for cannabis products is a non-regulated market and that the products they consume are not usually subject to the most basic of health controls. Patients should make sure they use products of the highest possible quality and in this case the term quality encompasses two crucial concepts: knowledge of the content in active principles and absence of toxic agents. With respect to the former, it is essential to know at least the amount of THC and CBD present in the products they consume in order to be able to systematically administer and be able to anticipate the effects after taking each dose. In addition, it must be ensured that the products they access are free of both chemical and biological contaminants, and they should choose suppliers that will ensure that these products come from crops developed in lands and environments free of heavy metals, for those that have not used toxic pesticides or fertilizers, which have not been extracted with solvents harmful to health and that are free of moulds, yeasts and bacteria, as well as their possible toxins.

References

1. Canada H, cartographer Cannabis (marihuana, marijuana) and the cannabinoids. Information for Health Care Professionals. Canada2013.

2. Hazekamp A, Pappas G. Self-Medication with Cannabis. In: Pertwee RG, editor. Handbook of Cannabis. Oxford, United Kingdom: Oxford University Press; 2014.

3. Huestis MA, Smith ML. Cannabinoid Pharmacokinetics and Disposition in Alternative Matrices. In: Pertwee RG, editor. Handbook of Cannabis. Oxford, United Kingdom: Oxford University Press; 2014.

4. Biro T, Toth BI, Hasko G, Paus R, Pacher P. The endocannabinoid system of the skin in health and disease: novel perspectives and therapeutic opportunities. Trends Pharmacol Sci. 2009;30(8):411-20.

5. Brenneisen R, Egli A, Elsohly MA, Henn V, Spiess Y. The effect of orally and rectally administered delta 9-tetrahydrocannabinol on spasticity: a pilot study with 2 patients. Int J Clin Pharmacol Ther. 1996;34(10):446-52.