Description
Medical cannabis refers to preparations from the ingredients of the hemp plant Cannabis sativa L. used for medical purposes. The ingredients characteristic of the hemp family are cannabinoids, which are responsible for the pharmacological effects. Common uses of medical cannabis include neurogenic spasticity, chemotherapy-induced nausea and vomiting, anorexia, and chronic pain.
Efficacy
The findings from randomized controlled trials of medical cannabis and cannabinoids in symptom-related therapy indicate:
Nausea and vomiting: slight enhancement of the effects of standard antiemetic therapeutic agents on chemotherapy-induced (n=2) but not radiation-induced (n=2) nausea and vomiting
Anorexia: no (n=2) to slight appetite-increasing (n=2) effect
Taste disorders: preliminary evidence (n=1) for potential improvement of taste disorders
Pain: No effect on cancer pain (n=1) but slight improvement of neuropathic pain in non-cancer patients (1 systematic review of n=16)
Safety
Effects on the central nervous system are common with medical cannabis and cannabinoids. Effects are dose dependent and include changes in mood (euphoria and dysphoria), memory disorders, blurred vision and dizziness as well as dry mouth. The risk of drug interactions with the various medical cannabis and cannabinoid preparations is low.
Citation
Horneber M, Landwehr C, Kalbermatten Magaya N, Ritter C, Ziemann C, CAM Cancer Collaboration. Medical cannabis and cannabinoids [online document], Oct 30, 2020
Document history
Latest update: October 2020
Next update due: October 2023
Description, background and characterisation of the medicinal plant
The term medical cannabis refers to the flowers or their extract as well as preparations made from the ingredients of the female cannabis plant Cannabis sativa L. (hemp), which are intended for medical use. This plant species from the hemp family (Cannabaceae) is internationally known mainly for its long-stemmed, finger-shaped split leaves, which are also used as intoxicants. So far, it has been disputed whether Cannabis indica and Cannabis ruderalis are subspecies of Cannabis sativa or separate species (1, 2).
As a plant cultivated for fibre production, cannabis spread increasingly from Central Asia throughout the world (3). However, hemp as a crop is characterised by a low content of psychoactive substances compared to hemp for medical purposes, the cultivation of which is regulated differently from country to country (4). In the vernacular, cannabis is also a collective term for the narcotic drugs produced from hemp. While marijuana (also called Mary Jane, grass or weed) is made from the dried leaves and flowers, hashish (also called dope or shit) is based on the resin of the inflorescences (5).
Ingredients and quality requirements
So far, approx. 560 different substances have been identified in Cannabis sativa (6). Of these, around 120 are cannabinoids which are characteristic for this plant genus and responsible for its pharmacological effect (6). Cannabinoids are a non-uniform group of substances. They include the phytocannabinoids and synthetic cannabinoids found in the plant as well as endocannabinoids, the messenger substances produced naturally in the body. The most important phytocannabinoids are delta-9-tetrahydrocannabinol (THC), cannabidiol (CBD) and their inactive precursors, delta-9-tetrahydrocannabinolic acid (THC-A) and cannabidiolic acid (CBD-A) (6). The concentration of the cannabinoids depends on the plant drug (flowers or leaves) and the preparation method. The highest quantity is found in the essential oil, which is obtained by distilling the flowers or resin (3). This essential oil should not be confused with hemp oil obtained from cannabis seeds, which, as an edible oil, does not contain significant amounts of cannabinoids.
At European level, there are as yet no uniform quality standards for cannabis and its medicinal preparations. The German Pharmacopoeia contains monographs on cannabis flowers, cannabis oil resin and the substances dronabinol (THC) and cannabidiol. Corresponding regulations for the cannabis extract are currently being developed.
The cannabis flowers drug is composed of the flowering, dried shoot tips of the female Cannabis sativa L plant. The content should correspond to between 90 and 110% of the declared amount of cannabinoids (e.g. THC and CBD) and cannabinoid carboxylic acids (including THC-A and CBD-A), calculated as THC and CBD respectively.
Nabilone is a synthetic derivative of THC with comparable pharmacological effects.
Alleged indications
Results from intervention studies justify the use of medical cannabis in the treatment of spasticity, cytostatic-induced nausea and vomiting, anorexia in HIV/AIDS and chronic pain. Other potential areas of application include gastrointestinal, neuroinflammatory, neurological and psychological diseases (7).
Cannabidiol (CBD) is used as a single substance in epilepsy (8-10) and, due to its antipsychotic effects, in schizophrenia and schizophreniform psychosis (11-13).
Application and dosage
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. 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. Nabilone is manufactured in the UK and licensed for chemotherapy induced nausea and vomiting. All products may be imported via an international pharmacy.
In Germany, for example, cannabis can be prescribed for medical use, as a prescription drug (cannabis flowers and extract, dronabinol/cannabidiol preparations), as an approved proprietary medicinal product (Canemes® and Sativex®) or as a proprietary medicinal product without approval in Germany (Marinol® as import) (14). These drugs are administered orally in the form of an oily or alcoholic solution, capsule, tea or as a spray for use in the oral cavity. However, if the patient so desires and depending on the disease, inhalation therapy may also be useful.
Vaporisation by means of a mechanical atomiser (vaporiser) is preferable to smoking in order to prevent the inhalation of potential pollutants (15, 16).
Since the required dose can vary individually, it should be adapted to the patient according to the mode of intake, indication and duration of effect.
Both medical cannabis and cannabinoid preparations should be given in a low initial dose and gradually increased to prevent acute adverse drug reactions. The following table gives an overview of the dosages of cannabis flowers, extract and cannabinoids.
Tab. 1. Dosage of cannabis flowers, cannabinoids and cannabis extract for oral use and for use in the oral cavity (source: Kiefer A et al. Cannabis for medical purposes and its prescription. Bundesgesundheitsbl 2019; 62:811–7).
| Drug | Initial dosage/day | Daily doses |
| Cannabis flowers | 0.05 to 0.1g | up to 3g |
| THC | 1.7 to 2.5mg | up to 30mg |
| Nabilone (Canemes®) | 1mg | up to 6mg |
| Cannabis extract (Sativex®) | 1 spray (= 2.7mg THC and 2.5mg CBD) | up to 12 sprays |
The individual dose variations are sometimes due to pharmacokinetic properties such as the low water solubility of cannabinoids, which cause an oral bioavailability of only 5-20% (17). Inhalation can comparatively significantly increase the proportion and accelerate the onset of action. Thus with inhalation, the maximum plasma concentration is already reached after about 20 minutes, while with oral intake only after 2-4 hours (see Table 2). The pharmacological effects do not correlate with the maximum plasma concentrations (18). Due to the long plasma half-life of 28-57 hours, the active substances can still be detected in blood and urine over several days to weeks. To increase absorption, the solubility of cannabinoids can be improved by taking them with high-fat food or by galenic preparation, e.g. in sesame oil.
Tab. 2. Onset and duration of action in inhalation and oral cannabis use (source: Kiefer A et al. Cannabis for medical purposes and its prescription. Bundesgesundheitsbl 2019 · 62:811–7).
| Effective parameters | Inhalation | Oral intake |
| Onset of action | < 5 minutes | 30 to 90 minutes |
| Maximum effect | < 15 minutes | 2 to 3 hours |
| Duration of effect | 3 to 4 hours | 4 to 8 hours |
When prescribing cannabis flowers or extract, the variety of the hemp plant or the desired amount of THC and CBD (in percent) must be stated on the prescription.
Mechanisms of action
Many effects of herbal and synthetic cannabinoids are mediated in the human body by the endocannabinoid system and its receptors. So far, two types of cell membrane receptors are referred to as cannabinoid receptors: CB1 and C2. The discussion on whether further receptors belong to the endocannabinoid system is ongoing.
Both CBs belong to the inhibitory G-protein-coupled receptors and lead to a decrease in intracellular second messenger substances by inhibiting adenylate cyclase (21). CB1s are present in high density in the cortex and hippocampus, as well as in the basal ganglia and cerebellum. They are therefore found in areas connected with mental performance and motivation, but also with movement coordination and spatial orientation as well as sensory perception. CB1s exert an important protective function in the central nervous system through presynaptic inhibition, which compensates for over- or under-activity of many transmitter systems (22).
CB2s are found on almost all immune system cells and in the central nervous system on microglial cells. They have a mild anti-inflammatory effect and thus modulate acute and chronic inflammatory processes (23).
The natural ligands of both receptor types include anandamides, which are derivatives of arachidonic acid and are referred to as endocannabinoids.
Tetrahydrocannabinol is a partial agonist at both cannabinoid receptors. Its psychotropic effects are mainly due to an activation of CB1. This applies both to therapeutically desirable effects on the sensation of pain, nausea and appetite as well as on motor function, but also to therapeutically adverse effects such as dysphoria, hallucinations, reduced thinking and memory capacity, dizziness and vegetative symptoms (24).
In contrast to THC, CBD only weakly binds to the receptors of the cannabinoid system. As an allosteric modulator to CB1, CBD leads to a reduced binding of and activation by THC (25). The anti-epileptic effect of CBD is thought to result from inhibition of anandamide degradation by the fatty acid amide hydrolase (FAAH). In animal experiments, an increased concentration of anandamide in the cerebrospinal fluid leads to a decrease in the frequency of cramps.
Supportive/palliative care
Description of included studies
Chemotherapy-induced nausea and vomiting
The systematic review by the Cochrane Collaboration included 23 trials and investigated the efficacy of cannabinoids (nabilone in 12 studies, 2-5 x daily 1-2mg PO; and dronabinol in 11 studies 10-15mg/m² or 10-15mg abs., up to 5x daily) against CINV. Almost all of the studies included date from the period between 1975 and 1991, when 5-HT3 or NK1 receptor antagonists were not available. Smith et al. make the following statement: “Cannabis-based medications may be useful for treating refractory chemotherapy-induced nausea and vomiting. However, methodological limitations of the trials limit our conclusions and further research reflecting current chemotherapy regimens and newer anti-emetic drugs is likely to modify these conclusions“ (26).
The systematic review by Tafelski et al. (35) examined six systematic reviews of cannabinoids in CINV. The authors concluded that cannabinoids should only be used in cases of breakthrough or refractory CINV.
There are two RCTs of newer anti-emetic drugs which have not been included in the reviews (27, 28). Meiri et al. (27) investigated the effects of dronabinol and ondansetron on delayed CINV in 64 patients with different types of cancer treated with moderately to severely emetogenic chemotherapy in a randomised, placebo-controlled, four-arm study. All patients received dexamethasone and ondansetron on day 1 for anti-emetic prophylaxis and additionally either dronabinol ("dronabinol group") or placebo ("placebo group"). On days 2-5, the dronabinol group was randomly divided into three additional groups (ondansetron, dronabinol or ondansetron + dronabinol). The placebo group received neither ondansetron nor dronabinol on days 2-5, only placebo (which is why far too few patients had been recruited). There was no difference for the primary endpoint "prevention of delayed nausea" on days 2 to 5 after chemotherapy between the three treatment groups (ondansetron 58%, dronabinol 54%, ondansetron + dronabinol 47%, p=n.s.). Although the proportion of patients without delayed nausea was significantly lower in the placebo group (20%), this difference was not significant, possibly due to the small number of cases (low- quality evidence). For the secondary outcome measures, dronabinol, ondansetron or the combination of the two substances were equally effective and significantly better than placebo in preventing CINV throughout the study period while dronabinol was better than placebo in preventing CINV on day one.
In the second randomised placebo-controlled study, Duran et al. (28) investigated the effects of nabiximols compared with placebo on delayed CINV in 16 patients undergoing moderately emetogenic chemotherapy who had experienced delayed CINV during the previous chemotherapy cycle despite standard anti-emetic treatment. Upon onset of CINV patients in the intervention group received nabiximols in individual doses from two hours and up to day 4 after chemotherapy with a recommended toxicity-limited maximum dose. All patients received standard anti-emetic treatment as a basis. In the nabiximols group, the incidence of delayed vomiting (primary endpoint) was significantly lower (low-quality evidence). However, mild to moderate adverse events such as anxiety, loss of consciousness, hallucinations, dizziness and dry mouth occurred more frequently in this group.
Radiotherapy-induced nausea
Priestman et al. (29) compared nabilone with metoclopramide for the prophylaxis of radiotherapy-induced nausea in a double-blind, randomised crossover study of 40 patients. They found no difference in the anti-emetic effect of 2mg of nabilone compared to 30mg of metoclopramide, but reported more frequent adverse drug reactions, such as dizziness, disorientation, dry mouth, or fatigue in patients receiving nabilone (low-quality evidence).
Côté et al. (30) investigated the effects of nabilone on nausea (secondary target parameter) during radiotherapy in 56 patients with ENT cancer in a double-blind, randomised, placebo-controlled study. The authors found no differences in nausea between the two groups (moderate-quality evidence). For more details of the study, see “quality of life” below.
Multifactorial nausea
Over a period of 30 days, 112 patients with advanced tumours were observed in a specialised palliative centre, 47 of whom received nabilone, 65 did not (31). The improvement in nausea (and pain) was significantly better when adjusted for propensity score in patients receiving nabilone. No information is available on drug safety. Since the patients were not randomised, no causal relationship can be deduced from this study. (very low-quality evidence)
Cancer cachexia
In a randomised, double-blind, three-arm study by Strasser et al. (36), patients (n= 243) with various advanced tumours who had an unintended weight loss of >5% received either a standardised cannabis extract (twice daily capsule with 2.5mg of THC and 1mg of cannabidiol), pure THC (delta-9-tetrahydrocannabinol; twice daily capsule with 2.5mg of THC) or a placebo over six weeks. The primary endpoints were the change in appetite between the time of study entry and week 6, measured by a visual analogue scale (as mean value of the daily measured values) and the change in quality of life (measured by a shortened form of the EORTC QLQ-C30). The complete EORT-QLQ-C30 as well as an anorexia-cachexia questionnaire were collected every two weeks. The patient's dietary intake, mood and nausea were evaluated daily by means of a visual analogue scale. There was no significant difference in primary endpoints, appetite and quality of life between the three arms after the six weeks). There were also no significant differences in the secondary endpoints. The study was terminated prematurely after an interim evaluation due to the lack of effects (high-quality evidence).
Jatoi et al. (37) investigated oral dronabinol plus placebo in comparison with the progesterone derivative megestrol (plus placebo) in comparison with both of the above-mentioned substances. A total of 469 patients with advanced tumours and weight loss participated in this randomised, double-blind study. Compared with dronabinol, megestrol acetate led to better results in appetite, dietary intake and body weight. The combination of the two substances was not more effective than megestrol alone (high-quality evidence).
Turcott et al. (39) investigated the effects of nabilone on symptoms of anorexia-cachexia syndrome (primary target parameter; AC/S-12 - FAACT) in a double-blind, randomised, placebo-controlled trial of 33 patients with advanced non-small-cell lung cancer. Patients received an increasing dose of nabilone or placebo for eight weeks. The dose of nabilone in the first two weeks was 0.5mg once daily and from the third to the eighth week 1mg once daily. The symptoms of anorexia-cachexia syndrome as well as the body weight did not differ between the groups after four and eight weeks. In the nabilone group, the appetite (VAS) was slightly better (P=0.06) and the functionality, measured with the EORTC QLQ-C30, significantly better (low-quality evidence).
Sense of smell and taste
In the randomised, double-blind study by Brisbois et al. (38), patients (n=46) with advanced or metastasised tumours received either dronabinol (initially 2.5mg with increasing doses) or a placebo for 18 days. The primary endpoint was the measurement of taste and smell using a questionnaire. Secondary endpoints were appetite, nausea, dietary intake (using a food diary) and quality of life (using a FACT questionnaire with an anorexia-cachexia section). Smell, taste and appetite were significantly better in the THC arm than in the placebo arm (low-quality evidence). The amount of food consumed, quality of life and other anorexia-cachexia parameters did not differ significantly between the study groups.
Pain in cancer patients
A recent systematic review with meta-analysis (51) of 5 RCTs including 1534 participants investigated the effect of nabiximols or mucosal THC spray compared to placebo in severe tumour pain despite opiate therapy ((49), (48) 2 studies, (47), (45)). There was no significant improvement in pain with cannabinoids and no difference in side effects grade 3-4. The patients who had received cannabinoids assessed their condition slightly better (p=0.04, NNTB=16), but the drop-out rate due to side effects was higher under nabiximols/THC and there were more neurological and gastrointestinal side effects than with placebo. The authors saw a very low quality of evidence in all five studies.
Neuropathic pain
A Cochrane Review (43) on neuropathic pain (no cancer patients) includes 16 studies with a total of 1750 patients in various meta-analyses. The authors note a limited certainty of results in studies on the use of cannabis preparations (nabiximols, 10 studies; nabilone, 2 studies; dronabinol, 2 studies and inhaled THC/CBD mixture, 2 studies). The evaluation gave an indication of the efficacy of cannabis preparations in neuropathic pain with a pain reduction of 4-8% (very low to moderate quality of evidence). The number of grade 3-4 side effects did not differ, but the cumulative data showed that patients who had received cannabis preparations discontinued the studies more frequently (5% vs 10%) and had more adverse side effects such as drowsiness, confusion, headaches, anxiety, psychotic symptoms, and addiction.
Quality of life
Côté et al. (30) investigated the efficacy of nabilone on quality of life (primary outcome) during radiotherapy in 56 patients with ENT cancer in a double-blind, randomised, placebo-controlled study. Those affected received an increasing dose of nabilone or placebo for the duration of the radiotherapy (7 weeks). The dose of nabilone in the first week was 0.5mg once daily, in the second week 0.5mg twice daily and from the third to the end of radiotherapy 1mg twice daily. Appetite, nausea, pain and radiotherapy-related adverse effects were further outcome measures. The authors found that the time until the quality of life deteriorated during radiotherapy was not prolonged in the group receiving nabilone. The tolerability of nabilone was very good in this study and at this dosage (moderate-quality evidence).
Turcott et al. (39) investigated the effects of nabilone on the functionality (secondary outcome measures; EORTC QLQ-C30) of 33 patients with advanced non-small cell lung cancer in a double-blind, randomised, placebo-controlled study. The authors found better functionality in the nabilone group than in the placebo group (low-quality evidence). For more details of the study, see under “Sense and smell”.
Anti-tumour treatment
We could not locate any controlled clinical studies.
Prevention
We could not locate any studies.
Adverse effects
Effects of medical cannabis on the central nervous system can be desirable or adverse. Depending on the dose, the following effects occur frequently: Mood changes (euphoria as well as dysphoria), depression, anxiety and paranoia, feelings of depersonalisation, hallucinations, memory impairment, blurred vision and dizziness.(17) Adverse cardiovascular effects are hypotension and tachycardia. Dry mouth often occurs when using cannabis.(24)
In the randomised controlled trials, dizziness (15.5%) was the most frequent adverse effect of medical cannabis.(52)
As tolerances for psychotropic and cardiovascular effects develop with prolonged use, longer-term treatment should not be terminated abruptly.(17)
Specific adverse effects of CBD reported in the studies on epilepsy treatment were somnolence, fatigue, vomiting, fever, lethargy and elevated liver values. Overall, CBD had good tolerability in these studies.(10)
Contraindications
Even if causality is not proven, psychotic disorders or a family history of psychotic disorders are considered contraindications for the use of medical cannabis.
THC passes into the placenta and is excreted in breast milk. Data on the influence of cannabinoids on male reproductive ability are controversially discussed, although there is evidence of a reduction in sperm count and sperm motility due to cannabinoids.(53) Medical cannabis or cannabinoids are therefore contraindicated in pregnant and breastfeeding women, as well as men and women who wish to conceive.
Some medical cannabis or cannabinoid preparations contain additives, e.g. sesame oil, which can trigger allergies.(54)
Interactions
The interaction potential of the different preparations of medical cannabis and cannabinoids is low. Previous studies suggest that the ingestion of 200mL of tea made from cannabis flowers, smoking marijuana cigarettes with a THC content of approximately 4% three times a day and oral ingestion of up to 10mg of THC per day do not lead to any clinically relevant influence on the metabolism of CYP450 substrates.
The therapeutic use of cannabidiol can lead to increased plasma levels of drugs that are substrates of CYP3A4 or CYP2C19, especially in children.
Other safety issues/warnings
The use of cannabis-based drugs can affect the ability to drive and operate machinery, especially when increasing the dose.
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