Written by Natalie Magaya-Kalbermatten and the CAM-Cancer Consortium.
Updated January 19, 2016

Medical cannabis and cannabinoids

What is it?

Description/names

The term medical cannabis is used to denote whole-plant extracts from Cannabis sativa L. (hemp), usually with standardized concentrations of the phytocannabinoids delta-9-tetrahydrocannabinol (THC) and/or cannabidiol. The term cannabinoids covers a heterogeneous group of molecules that demonstrate activity upon cannabinoid receptors and are either endogenous cannabinoids, phytocannabinoids or synthetic cannabinoids.

Ingredients

In C. sativa about 500 different substances have been identified so far, around 70 of which are cannabinoids.1,2  The most important phytocannabinoids are THC, cannabidiol (CBD), cannabigerol and cannabichromen.

Currently available cannabis-based medicines

Various whole-plant cannabis extracts with standardized concentrations of THC (and partially also of cannabidiol) are available for medicinal use. Nabiximols (Sativex®) is the name for a fixed combination of a THC-rich and a CBD-rich whole-plant cannabis extract.

Isolated THC or THC derivatives are currently available as dronabinol (Marinol®), which is half-synthetic THC, and nabilone (Cesamet®), Nabilon®), a synthetic THC derivate.

Another synthetic THC analogue, levonantradol, has been investigated in clinical trials but serious side-effects have limited its use.3

Application and dosage

Cannabis-based medicines are usually taken orally in an oily or alcoholic solution, in capsules or via the application of a sublingual spray; less commonly they are inhaled using a mechanical device.

For clinical use, individual dose titration is usually recommended. Generally, for pain and symptoms associated with cachexia, lower doses than for chemotherapy-induced nausea and vomiting are recommended.

For oral whole-plant extracts and synthetic THC (dronabinol), a typical starting dose is 2–3×2.5 mg THC/day, which is then gradually uptitrated until a recommended maximum daily dose of 50 mg THC/day has been reached.4 For nabiximols (sublingual application containing 2.7 mg THC and 2.5 mg cannabidiol per spray) the recommended starting dose is one spray/day; the number of sprays might be increased to a recommended maximum of 12 sprays/day. The recommended dose increase for all mentioned preparations is typically around 2.5 mg THC every 1–2 days. For the synthetic THC derivate nabilone, a daily dose of 1–4 (–6) mg is usually recommended.  

History

The medical use of cannabis in different regions and medical systems around the world has been a long-established tradition over several thousand years.5 Therapeutic use is documented in traditional Chinese and Indian (Ayurvedic) medicine as well as in mediaeval European healing systems. Modern Western medicine rediscovered the therapeutic potential of cannabis in the 19th century, and by the beginning of the 20th century the use of cannabis products as prescribed medicines was widespread in several Western countries. With the rise in popularity of cannabis as a recreational drug, many countries have instigated prohibitory legislation which has in turn lead to a gradual, but almost complete, elimination of cannabis plant products for medicinal purposes. Debate is still ongoing regarding the potential and therapeutic use of cannabis-based medicines in diseases where available treatment is not satisfactory. Current clinical research and usage is concentrated around multiple sclerosis, AIDS and cancer.

Claims of efficacy and alleged indications

Cannabis-based medicines are claimed to have an antiemetic effect in patients receiving chemo-/radiotherapy and in advanced cancer patients with nausea of various origins. They are also recommended for the stimulation of appetite and food intake, and the consequent stabilisation or weight increase in patients with advanced cancer and weight loss (cancer cachexia).  Furthermore, cannabis-based medicines have been claimed to have an analgesic effect in cancer patients.

Mechanisms of action

Two types of cell-surface receptors for cannabinoids have been identified in human tissue (CB1 and CB2).6–9 Derivates of arachidonic acid, so-called endogenous cannabinoids, work as physiological ligands for both receptor subtypes. The CB1 receptor is predominantly found in tissues of the central, peripheral and autonomous nervous system, with the highest density occurring in the basal ganglia of the brain. The main effect of CB1 receptor stimulation is via 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 leucocytes, bone marrow, spleen, thymus, tonsils, macrophages and mast cells. CB2 receptors mediate the immunomodulative effects of cannabinoids.

A high density of cannabinoid receptors has been found in the nucleus solitary tract, which is important for the control of emesis. Evidence has been found that an activation of the CB1 receptor in the central nervous system also inhibits chemically induced vomiting in animals.7 The appetite-stimulating effect of cannabis products has regularly been reported by recreational users of cannabis drugs and has been confirmed in controlled studies in which healthy male volunteers used both smoked cannabis and oral THC.10 The alteration of appetite and food intake has been attributed to the effects cannabinoids have on the central control of food intake, especially in the hypothalamus.6 The analgesic effects may be produced by both central and peripheral mechanisms including modulation of central neuronal activity, anti-nociceptive effects in descending pain pathways, and anti-inflammatory properties by acting through prostaglandin synthesis inhibition.11

The action of THC on cannabinoid receptors is responsible for a substantial part of the therapeutic, but also of the typical psychotropic effects of cannabis-based medicines. However, cannabinoids are probably activated by a number of other mechanisms. The major non-psychotropic cannabinoid, cannabidiol, has no direct affinity to CB receptors,11 but does have anti-psychotic, anxiolytic, anti-inflammatory and immune-modulatory effects, partially, but not exclusively, via modulation of the endocannabinoid system.1,12,13 Cannabidiol and other cannabinoids modulate effects of THC through a variety of mechanisms, as has been shown in a number of experimental and clinical studies.12,14,15 This is the so-called ‘entourage effect’ and has been shown to contribute to therapeutic effects as well as to the reduction of side-effects.

Pharmacology

Pharmacokinetics have been intensively investigated.3,16 Absorption in the gastrointestinal tract is high (90–95%) but, because of hepatic first-pass metabolism, the range of oral bioavailability is only 5–20%.1 Systemic bioavailability is slightly higher after inhalation, with considerable inter-individual variation (~20% ±10%). Peak plasma concentrations are seen within minutes if administered either intravenously or via inhalation, and 2–4 hours after oral intake. In plasma, THC is strongly bound to plasma lipoproteins (95–99%) and less so to albumin. As a lipophilic compound THC is rapidly eliminated from plasma via distribution to highly vascularised tissue and is also 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 15–60 minutes after peak plasma concentration; pharmacologic effects are not correlated with maximum plasma levels.3,16 Plasma half-life ranges from 28–57 hours owing to inter-individual 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 extensive enterohepatic circulation.

Prevalence of use

Data on the prevalence of cannabis-based substances for medical use are not available for countries in Europe. However, several surveys have been conducted, with convenience samples, of self-selected users of cannabinoids and cannabis products for medical purposes. Survey participants in different European countries have most commonly reported the use of cannabis-based medicines for neurological diseases such as multiple sclerosis and chronic pain. In a UK survey, less than 1% used cannabis for cancer,17 while in a Dutch survey 14% reported use for a malignant disease.18

Legal issues and providers

Trading cannabis-based medicines is internationally restricted and there are differing legal regulations between countries for the medical use of cannabis. Special legal requirements have to be met in order to substantiate an import claim.19

The legal situation concerning non-licensed whole-plant cannabis extracts (e.g. produced by individual pharmacies), and consequently their availability, differs between countries. Nabiximols has been licensed in Europe for use against the spasticity associated with multiple sclerosis. Dronabinol is licensed as an antiemetic in the USA 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 and licensed for chemotherapy induced nausea and vomiting. All products may be imported via an international pharmacy.

Cost and expenditures

The cost of cannabis-based medicines ranges from €1–5/mg depending on the provider. Whole-plant extracts are generally cheaper than synthetic cannabinoids. A patient’s monthly expenses for the minimum daily dose can add up to anything between €150 and €750. Some health insurance companies reimburse these expenses, but regulations and practices vary between European countries and also between health insurance companies.

Citation

Natalie Magaya-Kalbermatten, CAM-Cancer Consortium. Cannabis and cannabinoids [online document]. http://cam-cancer.org/The-Summaries/Herbal-products/Cannabis-and-cannabinoids. January 19, 2016.

Document history

Fully revised and updated by Natalie Magaya-Kalbermatten in December 2015.

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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