Cannabinoids

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.

Do cannabinoids work for therapy-induced nausea and emesis?

Nausea and vomiting are severe and distressing adverse effects of many chemo- and radiotherapeutic treatments. Palliative care patients also complain frequently of nausea that impairs their quality of life.

Nausea and emesis induced by chemotherapy

Systematic reviews

A systematic review is available establishing the efficacy of cannabinoids against chemotherapy-induced nausea and vomiting17. These findings were replicated in another systematic review with meta-analysis18. Thirty randomised-controlled trials were included in this review investigating oral dronabinol, oral nabilone and intramuscular levonantradol in comparison to placebo and antiemetics available in the 1980s (prochlorperazine, metoclopramide, thiethylperazine, haloperidol, domperidone, alizapride). Cannabinoids showed a significantly better control of chemotherapy-induced nausea and vomiting than placebo/control medication, and were preferred for future chemotherapy cycles by two out of three patients in cross-over trials. Benefits seemed to be more pronounced in medium emetogenic chemotherapy than in low or high emetogenic chemotherapy. However, none of the included trials tested cannabinoids against the modern forms of antiemetic prophylaxis (5-HT3-antagonists, NK1-receptor antagonists and drug combinations including glucocorticoids). The authors concluded that in selected patients, cannabinoids may be useful as mood-enhancing adjuvants for the control of chemotherapy-related sickness, but considering the availability of well-investigated modern drug combinations for antiemetic prophylaxis, cannabinoids could not be recommended for solitary or first-line use.

A recent systematic review on antiemetic medication for prevention and treatment of chemotherapy-induced nausea and vomiting in children identified four randomised controlled trials, which were not meta-analysed due to study heterogeneity19. Cochrane authors concluded that cannabinoids “are probably effective, but produce high levels of side effects” (p.14) and no clear route, schedule or dose recommendation could be identified from the included studies.

Controlled trials

As cannabinoids act differently from other antiemetic drugs, they might be effective when administered in combination with modern antiemetics in people whose emesis is not adequately controlled with current treatment options. Plasse reports anecdotal evidence that cannabinoids might help against chemotherapy-induced delayed nausea20. One randomised, placebo-controlled trial investigated the efficacy of dronabinol alone or in combination with ondansetron for the prevention of delayed chemotherapy-induced nausea and vomiting21. Sixty-four participants receiving moderate to high emetogenic chemotherapy were randomised to one of four intervention groups. All participants received dexamethasone plus ondansetron before chemotherapy, the three active intervention groups received additional dronabinol on the day of chemotherapy and either dronabinol, ondansetron or both on the following four days after chemotherapy. Results suggested that dronabinol was equally effective as ondansetron for the prevention of delayed chemotherapy induced nausea and vomiting. Acute chemotherapy induced nausea and vomiting on the first day of chemotherapy was reduced in the three groups receiving additive dronabinol compared to the standard treatment alone (dexamethasone + ondansetron). However, this trial failed to recruit the necessary number of participants for a valid evaluation and findings need to be replicated in a larger study with comparable intervention groups at baseline to further elucidate the potential benefits of additive dronabinol.

Nausea and emesis induced by radiotherapy

One double-blind randomised cross-over trial compared nabilone and metoclopramid for the prevention of radiotherapy-induced nausea in 40 patients22. Findings suggested no difference in the antiemetic effect of 2mg nabilone compared to 30mg metoclopramid, but adverse reactions were more severe in the nabilone group.

Do cannabinoids work for anorexia-cachexia-syndrome?

Clinical studies

Strasser et colleagues conducted a randomised placebo-controlled phase III trial and compared oral THC, oral cannabis extracts and placebo for patients with cancer-related anorexia23. Two hundred and forty-three adults with advanced cancer (54% men) were randomly assigned to THC/cannabidiol (2.5mg/1mg), THC alone (2.5 mg) or placebo orally daily for 6 weeks. The results showed significant unspecific (placebo) effects on symptom control, but no substance-specific benefit of cannabinoids over placebo on appetite or overall quality of life (primary study end points), or mood or nausea (secondary end points). Recruitment for this study was terminated early because of insufficient differences between study arms.

Jatoi24 tested oral dronabinol (2.5mg twice a day + placebo) versus the progesterone derivate megestrol (plus placebo) versus both agents. 469 patients with advanced cancer and weight loss participated in this double-blind randomised trial. Megestrol acetate had better outcomes (appetite, food intake, body weight) than dronabinol, while the combination was not more effective than megestrol alone.

A small placebo-controlled randomised trial investigated THC (2.5 mg/day) in 46 patients with advanced cancer25. Per-protocol analyses of 21 patients found a subjectively increased appetite and taste perception in the THC group, but no differences in total caloric intake between both groups.

Case series / reports

Several findings suggested that oral cannabinoids increased appetite in cancer patients, stopped weight loss or even increased body weight26,27. In an open phase II study, Nelson investigated the effect of 3x2.5 mg oral THC in 19 patients with various malignancies and tumour-associated anorexia28. Thirteen of 18 patients that could be evaluated reported a subjective improvement in appetite. Body weight was measured in six patients and after four weeks was increased in three patients, not changed in two and decreased in one.

To summarise, the most recent and rigorous findings from randomised trials suggested no benefit of treatment with dronabinol/THC alone or in combination with cannabidiol for cancer-related anorexia-cachexia syndrome compared with placebo or megestrol acetate. Recent reviews on the treatment of cancer cachexia support a multimodal approach with different, newer medications29,30.

Do cannabinoids work for pain?

Systematic reviews

A systematic review of randomised clinical trials investigated the efficacy of cannabinoids in the management of pain31. Campbell reviewed five studies with a total of 128 cancer patients comparing oral THC or a THC congener (benzopyranopyridine) to placebo, codeine or a barbiturate. Results were contradictory and cannabinoids were found to be equally or more effective than placebo, and less or equally effective as codeine. Studies were rather small (n=10 to n=37) and dose-limitating adverse effects were a common. Reviewers concluded that there is insufficient evidence to support the introduction of cannabinoids into widespread clinical use as analgesics.

Clinical studies

Two phase II randomised double-blind controlled trials investigated the use of cannabinoids in participants with advanced cancer32,33. Both trials used cannabinoid preparations as oral sprays in comparison to placebo sprays as add-on medication to opioids in participants with intractable cancer pain.

The first trial compared two cannabis extracts (Sativex© and Tetranabinex©) versus placebo for pain control32. A statistically significant improvement of pain (as measured in a pain score) due to cancer unresponsive to opioids was seen for Sativex©, but not for Tetranabinex© compared to placebo (177 participants).

Results of the second trial have so far only been published as a press report: Statistically significant differences from placebo in pain scores were reported for Sativex© at three different doses in this dose-finding study. A phase III trial is under way33.
Maida34 conducted a prospective observational study comparing advanced cancer patients who were treated with or without nabilone in a specialized palliative care center. 112 patients were prescribed or not prescribed nabilone at their physicians’ discretion based on the presence of physical symptoms including pain. Pain and nausea improved in the nabilone group. The uncontrolled study design, however, does not allow to causally attribute these observed findings to nabilone as they might also be related to bias or unspecific effects.

Adverse events

A number of adverse effects have been observed after intake of cannabinoids, some of which may be welcome, such as mood enhancement or sedation. However, serious dose-limitating side effects have also been frequently reported. Most adverse effects appear to be dose-related and more severe in the elderly9.

Central nervous adverse effects comprise alteration of mood (euphoria as well as dysphoria), depression, anxiety and paranoia, sensation of depersonalisation, hallucinations, drowsiness, muddled thinking, loss of coordination/ataxia, blurred vision and dizziness24. These problems are common among patients receiving cannabinoid treatment with an incidence of about 50% for dizziness, 50% for drowsiness/somnolence/sedation, 13% for dysphoria/depression, 6% for hallucinations and 5% for paranoia17.

Cardiovascular adverse effects are also regularly observed, such as hypotension (ca. 25%) and reactive or paroxysmal tachycardia. Cases of cardiac and cerebral ischemia associated with cannabis consumption have been reported35. In addition, patients frequently complain of dry mouth.

Patients with long-term intake of cannabinoids may develop tolerance as well for the psychoactive as for the cardiovascular side effects. Long-term intake of cannabinoids should therefore not be stopped abruptly35.

Cannabinoids can change DNA synthesis and cell reproduction in vitro, but there is no evidence of mutagenic effects or of long-term carcinogenicity of orally administered cannabinoids36.

Interactions

Pharmacokinetic interactions may occur due to interference with metabolism at the cytochrome P450 subsystem in the liver (Cyt P450 3A4) and may theoretically lead to delayed elimination of, for example, fentanyl. Interactions are also possible with known inhibitors (ritanovir, estradiol etc.) or inductors of Cyt P450 3A4 (rifampicin, phenytoin, carbamazepin, St. John´s wort).

There is evidence that cannabinoids pharmacodynamically interact with levodopa and similar anti-Parkinson drugs37. Whether these interactions may be harmful for patients or may help to diminish adverse effects of dopamine agonists is under investigation. Currently, use of levodopa or similar drugs is an absolute contraindication for cannabinoids.

Little is known so far about possible interactions with other centrally active drugs, especially psychiatric medication, or with herbal products.

Contraindications

Due to the possible induction of psychotic episode, a history of psychosis is an absolute contraindication. Relative contraindications are severe ischaemic heart disease and arteriosclerosis of the brain as the effects of cannabinoids on the cardiovascular system cannot be predicted.

THC crosses the placenta barrier and accumulates in breast milk. Findings for cannabinoid effects on male reproduction are being discussed controversially, however, there is evidence that cannabinoids decreases sperm count and motility38. Therefore, pregnant and breast-feeding women, and women and men who wish to have children must not use cannabinoid products.

Some cannabinoid preparations contain additives, e.g. sesame oil, which are contraindicated in people with allergies toward these substances39.

Warnings/precautions

The use of cannabinoids might impair the ability to drive a car and users might be unfit to drive.