Written by Gabriele Dennert and the CAM-Cancer Consortium.
Updated November 25, 2011

Cannabinoids

What is it?

Names

The term cannabinoids is used for all active substances of plant, animal or endogenous origin that work as agonist ligands at cannabinoid receptors of cells1.

Ingredients

Plant-based cannabinoids are isolated from Cannabis sativa herbs or produced as synthetic cannabinoid analogues. About 500 different substances have been identified in cannabis plants (hemp) so far, almost 70 of which are cannabinoids1,2. The four most important classes of natural C21-compound phytocannabinoids are delta-9-tetrahydrocannabinols (THC), cannabidiols, cannabigerols and cannabichromen cannabinoids.

Delta-9-THC is currently available in natural or synthetic form for medical application: Dronabinol (Marinol (R)) is the (-)-trans-isomer of the natural phytocannabinoid delta-9-THC extracted from cannabis plants that are grown for medical purposes. Nabilone (Cesamet (R), Nabilon (R)) is a synthetic, ketocannabinoid analogue of THC.

In addition, whole-plant cannabis extracts are available for medical use in some countries, either as THC-rich extracts (Tetranabinex (R)), cannabidiol-rich extracts (Nabidiolex (R)) or a combination of both (Sativex (R)).

Another synthetic THC homologue, levonantradol, has been investigated in phase I clinical trials but serious side effects limited its use3.

Application and dosage

Medical cannabinoids are usually taken orally as capsules or oily solution or are applied as sublingual spray; less commonly they are inhaled using a mechanical device. Rectal or transdermal application or parenteral injection remain confined to clinical investigations and are not relevant for clinical practice today.

For clinical use, individual dose finding is necessary beginning with 2x2.5 mg dronabinol/day and a recommended maximum daily dose of 5x10 mg dronabinol4. The dose finding for the sublingual application containing 2.7 mg THC and/or 2.5 mg cannabidiol per spray starts with a maximum of four sprays a day; the number of sprays might be increased to a recommended maximum of 14 sprays per day.

Mechanisms of action

Two types of cell surface receptors for cannabinoids have been identified in human tissue (CB1 and CB2)5-8. Derivates of arachidonic acid, so called endogenous cannabinoids, work as physiologic ligands for both receptor subtypes. The CB1 receptor is predominantly found in tissue of the central, peripheral and autonomous nervous system, with its highest density in the basal ganglia of the brain. The main effect of CB1 receptor stimulation is a decrease in the release of neurotransmitters, such as dopamine, norepinephrine, and serotonin. This receptor subtype mediates the central effects of cannabinoids, such as antiemesis and the alteration of cognitive processes, movement, appetite and pain regulation. The CB2 receptor subtype is mainly expressed in tissue with immunologic function, including peripheral blood leukocytes, bone marrow, spleen, thymus, tonsils, macrophages and mast cells. CB2 receptors mediate the immunomodulative effects of cannabinoids.

In addition to cannabinoid receptors, cannabinoids are probably active by a number of other mechanisms. For example, research suggests that the antiemetic effect might be related to interaction with the 5-HT3A receptor (serotonin receptor)9.

The appetite-stimulating effect of cannabis products has regularly been reported by recreational users of cannabis drugs and could be confirmed in controlled studies with healthy male volunteers using both smoked cannabis and oral THC10. The alteration of appetite and food intake has been attributed to the effects of cannabinoids on the central control of food intake, especially in the hypothalamus5. Evidence has been found that an activation of the CB1 receptor in the central nervous system also inhibits chemically induced vomiting in animals6. A high density of cannabinoids receptors has been found in the nucleus solitary tract, which is important for the control of emesis. The analgesic effects may be produced by both central and peripheral mechanisms. One theory is that cannabinoids inhibit release of transmitters from primary afferents, another is that they activate descending modulatory pathways11.

Pharmacology

Pharmacokinetics3,12 have been intensively investigated. Absorption in the GI-tract is high (90-95%), but due to hepatic first-pass metabolism oral bioavailability ranges only between 5 to 20%. Systemic bioavailability is slightly higher after inhalation, with a considerable interindividual variation (~20% +/-10%). Peak plasma concentrations are seen within minutes after intravenous or inhalative administration and between 2 to 4 hours after oral intake. THC in the plasma is bound to plasma lipoproteins (95 to 99%), less to albumin. As a lipophilic compound, THC is rapidly eliminated from plasma through distribution to highly vascularised tissue and is able to cross the blood-brain-barrier. Subsequently, redistribution to, and accumulation in, body fat can be observed. Peak effects are seen with a lag of 15 to 60 minutes after peak plasma concentration; pharmacologic effects are not correlated with maximum plasma levels3,12. Plasma half-life ranges between 28 to 57 hours due to interindividual differences in redistribution from fat tissue. Cannabinoids are metabolised by cytochrome P450 subsystems in the liver and metabolites are excreted in bile and urine over several days with an extensive enterohepatic recirculation.

History

Medical use of cannabis has a long tradition in different regions and medical systems around the world for several thousand years13. Their therapeutic use is documented in traditional Chinese and Indian (Ayurvedic) medicine as well as in the traditional mediaeval European healing system. Modern Western medicine rediscovered the therapeutic potential of cannabis in the 19th century, and by the beginning of the 20th century, cannabis products were in widespread use as prescription medicine in several Western countries. Due to the increasing use of cannabis as a recreational drug, many countries all over the world put prohibitory legislation into effect, gradually leading to the almost complete elimination of cannabis plant products from medical use. In Europe, the debate about the therapeutic use and potential of cannabinoids in diseases where available treatment is not satisfactory is still ongoing. Current clinical research and usage is concentrated around multiple sclerosis, AIDS and cancer.

Claims of efficacy and alleged indications

Medical cannabinoids are claimed to stimulate appetite and food intake and consequently stabilise or increase body weight of patients with advanced cancer and weight loss (anorexia-cachexia-syndrome). An antiemetic effect has also been attributed to cannabinoids in patients receiving chemo-/radiotherapy and in palliative care patients. Furthermore, cannabinoids have been claimed to have an analgesic effect in cancer patients.

Prevalence of use

Data on the prevalence of medical use of cannabinoids is not available for Europe. However, several surveys with convenience samples of self-selected users of cannabinoids and cannabis products for medical purposes have been conducted. Survey participants in different European countries have most commonly reported the use of cannabinoids/cannabis for neurological diseases, for example, multiple sclerosis and chronic pain. In a UK survey, less than 1% used cannabis for cancer 14, while in a Dutch survey 14% reported a malignant disease15.

Legal issues and providers

Trade with cannabinoids is internationally restricted and legal regulations for the medical use of cannabinoids differ between countries. Special legal requirements have to be met to substantiate an import claim16.

Dronabinol is licensed as antiemetic in the US for the treatment of chemotherapy-induced nausea and stimulation of appetite in AIDS patients. It is also marketed by a German pharmaceutical company. Nabilone is manufactured in the UK. The THC/cannabidiol spray has been licensed in Europe for the use against spasticity associated with multiple sclerosis. All products may be imported via an international pharmacy.

Whole-plant extracts for sublingual application are licensed in Canada as adjunctive pain medication. The legal situation concerning whole-plant cannabis extracts and consequently their availability differs between European countries. They are marketed by two companies in Spain and the UK.

Cost(s) and expenditures

Costs for medical cannabinoids range between 1 to 5 Euros per milligram depending on the provider. In general, domestic products are cheaper than imported drugs, but are not available in all countries. Monthly expenses for the minimum daily dose add up to 150 to 750 Euros for the patient. Some health insurances reimburse the costs, but regulation and practice differ in European countries and between health insurances companies.

Citation

Gabriele Dennert, CAM-Cancer Consortium. Cannabinoids [online document]. http://www.cam-cancer.org/CAM-Summaries/Herbal-products/Cannabinoids. November 25, 2011.

Document history

Last updated in November 2011 by Gabriele Dennert.
Fully updated and revised in November 2009 by Gabriele Dennert.
Summary first published in November 2005, authored by Gabriele Dennert.

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The present documentation has been compiled by the CAM-CANCER Project with all due care and expert knowledge. However, the CAM-CANCER Project provides no assurance, guarantee or promise with regard to the correctness, accuracy, up-to-date status or completeness of the information it contains. This information is designed for health professionals. Readers are strongly advised to discuss the information with their physician. Accordingly, the CAM-CANCER Project shall not be liable for damage or loss caused because anyone relies on the information.