WHY: EVIDENCE FOR CANNABINOID-BASED MEDICINAL PRODUCTS
There has been a significant amount of research in the field of cannabinoid-based medicinal products, which includes evidence coming from cannabinoid-based medicines and medicinal cannabis. Learn more about the data that supports the various medicinal benefits of cannabis.
For which medical conditions can a physician prescribe medicinal cannabis?
The approval of medicinal cannabis may be different in each country. For information about the approval of medicinal cannabis in certain countries, please follow the links below:
- For Portugal, please click here.
- For Germany, please click here.
- For France, please click here.
- For other countries, please consult your local health authority for further information.
For more information on individual indications and medicinal cannabis, please continue to review other questions in this section of the WE CARE website.
Are there any clinical trials with cannabinoid-based medicinal products?
Yes. On the ClinicalTrials.gov database, there are nearly 700 clinical trials that appear when searching for either “cannabis” or “cannabinoid” or “cannabidiol” or “THC” as one of the possible interventions used in the trial, including 170+ clinical trials that were active (both those recruiting and not recruiting) as of September 1, 2021.1 This search eliminated any clinical trials that were being conducted to assess intoxication, dependence, abuse, or use disorder associated with cannabinoid-based medicinal products. Most of these clinical trials are sponsored by academic institutions or organizations, although companies are sponsors for some clinical trials as well. The active trials span a wide range of indications, including psychotic disorders, many forms of pain, anxiety, schizophrenia, HIV/AIDS, and depression, as well as an assortment of clinical trials assessing the addictive potential and side effects of medicinal cannabis.
What is the role of cannabinoid-based medicinal products in treating pain?
The endocannabinoid system (ECS) is a ubiquitous endogenous pain control pathway.2 To learn more about the endocannabinoid system please review the WHAT: ABOUT MEDICINAL CANNABIS section of this website. The ECS is expressed throughout nociceptive (pain) pathways, including peripherally, spinally, and supraspinally. The CB1 and CB2 receptors have direct implications in pain processes throughout the different nociceptive neurological structures: peripheral, spinal, and supraspinal. CB receptor agonism peripherally suppresses hyperalgesia- and allodynia-related mechanisms, while spinally it modulates central sensitization-related mechanisms. Cannabinoids are also active in pain-related brain areas, such as the periaqueductal grey matter, the ventroposterolateral nucleus, and the thalamus. However, it should also be mentioned that non-CB1 and non-CB2 receptor effects of cannabinoids are also relevant in pain-related processes, including the action of cannabinoids on TRPV1 and pro-inflammatory mediators like TNFα.3
Targeting the ECS system via exogenous cannabinoids can regulate nociceptive input at multiple sites, leading to analgesia. The anti-nociceptive efficacy of THC and CBD has been unequivocally demonstrated in several different models of inflammatory and neuropathic pain. Continue with the next section to learn about which guidelines support the use of medicinal cannabis for treating pain.
Clinical trials with medicinal cannabis preparations containing dronabinol, dried flower, or cannabis-based medicines like nabiximols have shown evidence of the efficacy of cannabinoids in treating chronic pain of various etiologies, especially in cases where conventional treatments have been tried and have failed.4
Do any guidelines support the use of cannabinoid-based medicinal products for treating pain?
Around the world, multiple pain societies and scientific bodies have issued recommendations for the use of cannabis-based medicinal products for pain management. In 2018, the European Pain Federation (EFIC) issued a position paper providing for the use of cannabis-based medicines as third–line therapy for chronic neuropathic pain. For all other chronic pain conditions (cancer, non-neuropathic non-cancer pain), the use of cannabis-based medicines should be regarded as an individual therapeutic trial.5
The guidelines supporting the use of cannabinoid-based medicinal products for pain management may be different in each country. For information about the guidelines supporting the use of cannabinoid-based medicinal products for pain management in certain countries, please follow the links below:
What is the role of cannabinoid-based medicinal products in treating spasticity?
Muscle spasticity occurs in up to 80% of multiple sclerosis (MS) patients. Spasticity is caused by cytokines, prostaglandins, and reactive oxygen species that change neuronal pathways, and lead to fluctuations in motor circuit function and muscle tone. There is a large amount of evidence that the endocannabinoid system (ECS) is involved in the regulation of muscle tone, and that activation of the ECS with exogenous cannabinoids can reduce spasticity. This effect is mediated by the CB1 receptor, leading to activation of a K+ channel, hyperpolarization of the neuronal membrane, and ultimately decreased hyperexcitability of neurons.6
Medicinal cannabis formulations have also been studied in spasticity associated with MS. A cannabis oral solution (containing 2.5 mg Δ9-THC, 1.25mg CBD, and <5% other cannabinoids), or oral Δ9-THC, showed evidence of a significant treatment effect on subjective, patient-reported spasticity and pain, with improvement in spasticity.4 These results were observed in a long-term treatment study for both formulations. The available evidence from clinical studies suggests that dried flower cannabis (limited evidence) and certain cannabinoids (dronabinol, nabiximols, and THC/CBD oral solutions) are associated with some measure of improvement in symptoms encountered in MS including spasticity, spasms, pain, sleep, and symptoms of bladder dysfunction. The same was observed in studies with spinal cord injury patients.4
Do any guidelines support the use of cannabinoid-based medicinal products for treating spasticity?
Several medical societies have issued recommendations for the use of cannabis-based medicines for spasticity. In 2020, the European Academy of Neurology (EAN) recommended nabiximols to reduce spasticity in patients with severe MS. This was determined to be a “strong recommendation” based on “moderate certainty evidence.” Furthermore, the EAN indicated that other products available in the form of medicinal cannabis (e.g., Cannabis sativa plant extract) might reduce spasticity in patients with severe MS. This was a “weak recommendation” based on “moderate certainty evidence”.7
The guidelines supporting the use of cannabinoid-based medicinal products for the treatment of spasticity may be different in each country. For information about the guidelines supporting the use of cannabinoid-based medicinal products for the treatment of spasticity in certain countries, please follow the links below:
What is the role of cannabinoid-based medicinal products in treating loss of appetite?
Severe appetite loss is a common symptom of many chronic illnesses and is frequently associated with cancer and HIV/AIDS. Cannabis has long been associated with an improvement in appetite, decreased nausea, and enhanced food taste. We now know that endogenous cannabinoids like anandamide increase appetite by their action on the CB1 receptor. In this manner, cannabinoids increase the level of Neuropeptide Y in the hypothalamus, which results in the stimulation of AMP-activated protein kinase, which is directly responsible for feeding processes.8 Furthermore, there is evidence that anandamide acts as a ‘hunger signal’ in the intestines. This signal is transmitted to the brain through the vagus nerve. More recently, some research has shown that cannabinoids influence ghrelin, which again induces appetite.8
The available evidence from human clinical studies suggests that cannabis (limited evidence) and dronabinol may increase appetite and caloric intake and promote weight gain in patients with HIV/AIDS. The evidence for dronabinol is mixed and the effects modest for patients with cancer.4 Dronabinol is available in the USA as a cannabinoid-based medicine and approved for anorexia associated with weight loss in patients with AIDS, and for nausea and vomiting associated with cancer chemotherapy in patients who have failed to respond adequately to conventional antiemetic treatments. In addition, several observational studies conducted in patients with cancer have been published recently, showing an improvement in appetite stimulation with medicinal cannabis preparations, mainly with dried flower.4
Do any guidelines support the use of cannabinoid-based medicinal products for treating loss of appetite?
Unfortunately, there are no guidelines yet that strongly recommend the use of cannabinoid-based medicinal products for treating loss of appetite. In 2010, the European Palliative Care Research Collaborative determined that cannabinoids may increase appetite in selected patients, but overall, there is not enough evidence to support their use (level of recommendation: weak negative; mean consensus 7).9 In 2017, the European Society for Clinical Nutrition and Metabolism (ESPEN) determined that dronabinol (synthetic cannabinoid) may have the potential to improve appetite in patients with cancer anorexia. However, the evidence was found to be limited and inconsistent, and so ESPEN was unable to support a recommendation.10
What is the role of cannabinoid-based medicinal products in treating nausea and vomiting?
Nausea and vomiting are common side effects for patients with cancer, and even certain other serious diseases. Nausea and vomiting can be caused by the disease itself, chemotherapy, or even radiation therapy. The vomiting reflex originates in the medulla, and it is influenced by a number of neuronal pathways. Cannabinoids act as neuromodulators on pre-synaptic CB1 receptors present in the CNS, where they modulate not only appetite (discussed above) but also nausea and vomiting.11 THC has been shown to reduce nausea and vomiting, consistent with its action at the CB1 receptor; however, THC also has an ability to antagonize the 5-HT3 receptor, which might also aid in its regulation of nausea and vomiting.
Whereas chemotherapy-induced vomiting generally appears to be well-controlled with current first-line therapies/triple combination therapies (e.g., 5-HT3 antagonists, neurokinin-1 antagonists, and corticosteroids), the associated acute, delayed, and especially anticipatory nausea remain more poorly controlled, and the use of cannabis/cannabinoids may provide some measure of benefit in such cases.4,12
Dronabinol is available in the USA as a cannabinoid-based medicine and approved for anorexia associated with weight loss in patients with AIDS, and for nausea and vomiting associated with cancer chemotherapy in patients who have failed to respond adequately to conventional antiemetic treatments. In 2015, Whiting et al. conducted a meta-analysis of studies including dronabinol, nabilone, and nabiximols, as well as other cannabinoids, and showed that the average number of patients with a complete nausea and vomiting response was greater with cannabinoids than placebo, namely with dronabinol and nabiximols.13
In addition, several observational studies conducted in patients with cancer have been published recently, showing an improvement in nausea and vomiting with medicinal cannabis preparations, mainly with dried flower.4
Do any guidelines support the use of cannabinoid-based medicinal products for treating nausea and vomiting?
Several medical societies have issued recommendations for the use of cannabis-based medicinal products for nausea and vomiting. The guidelines supporting the use of cannabinoid-based medicinal products in treating nausea and vomiting may be different in each country. In the USA, the National Comprehensive Cancer Network (NCCN) considers cannabinoids for patients with refractory or breakthrough CINV.14 For information about the guidelines supporting the use of cannabinoid-based medicinal products in treating nausea and vomiting in certain countries, please follow the links below:
What is the role of cannabinoid-based medicinal products in treating epilepsy?
For many years, research has shown a role for cannabinoids in epilepsy. The endocannabinoid system (ECS) regulates cortical excitability, and it has been suggested that endocannabinoids can produce a stabilizing effect on the balance between excitatory and inhibitory neurotransmitters in the CNS.15 During epilepsy, there is a change in CB1 receptor and DAGL expression in the hippocampus, as well as changes in anandamide (endocannabinoid) levels.16 This suggests that the ECS plays a role in epilepsy. In addition to the ECS, cannabidiol (CBD) has other anticonvulsant mechanisms that also appear to be involved in epilepsy. CBD reduces neuronal hyperexcitability through modulation of GPR55 and TRPV1 , as well as modulation of adenosine-mediated signaling through inhibition of adenosine cellular uptake via ENT-1.16
In 2019, cannabidiol (Epidyolex®) was approved by the European Medicines Authority (EMA) for the treatment of seizures in patients aged two or over with Lennox-Gastaut syndrome and Dravet syndrome, in conjunction with clobazam.17 These are two rare but extremely debilitating forms of epilepsy. The approval was based on results from four clinical trials in more than 700 patients.17 CBD was found to be superior to placebo in reducing the frequency of convulsive (tonic-clonic, tonic, clonic, and atonic) seizures in patients with Dravet syndrome, and the frequency of drop seizures in patients with Lennox-Gastaut syndrome.
Other studies (e.g., Phase II open label or observational studies) have been conducted in pediatric patients with drug-resistant epilepsy with cannabidiol formulations that have included a small concentration of THC, namely 2mg/ml THC:100 mg/ml CBD, 1:20 THC:CBD or 1:25 THC:CBD, in an attempt to show that patients could benefit from the anti-epileptic properties of THC in addition to CBD.18-21 In general. these studies have shown good tolerability and have added to the evidence that cannabinoids have a role in the treatment of children with uncontrolled epilepsy.
Do any guidelines support the use of cannabinoid-based medicinal products for treating epilepsy?
Unfortunately, since cannabidiol was only recently approved for epilepsy, there are no guidelines yet that strongly recommend the use of cannabinoid-based medicinal products for treating epilepsy.
1. US National Library of Medicine. ClinicalTrials.gov: Cannabis studies. Accessed September 1, 2021: https://clinicaltrials.gov/ct2/results?cond=&term=Cannabis&cntry=&state=&city=&dist=
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3. Woodhams SG, Chapman V, Finn DP, Hohmann AG, Neugebauer V. The cannabinoid system and pain. Neuropharmacology. 2017 Sep; 124: 105-120.
4. Health Canada. Information for Health Care Professionals: Cannabis and the cannabinoids. October 2018. ISBN: 978-0-660-27828-5.
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6. Centonze D. Advances in the management of multiple sclerosis spasticity: multiple sclerosis spasticity nervous pathways.Eur Neurol. 2014 Sep;72 Suppl 1: 6-8.
7. Solari A, Giordano A, Sastre-Garriga J, et al. EAN guideline on palliative care of people with severe, progressive multiple sclerosis. Eur J Neurol. 2020 Aug;27(8): 1510-29.
(Loss of appetite)
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(Nausea & vomiting)
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12. Tramèr MR, Carroll D, Campbell FA, Reynolds DJ, Moore RA, McQuay HJ. Cannabinoids for control of chemotherapy induced nausea and vomiting: quantitative systematic review. BMJ. 2001 Jul 7;323(7303):16-21.
13. Whiting PF, Wolff RF, Deshpande S, et al. Cannabinoids for medical use: a systematic review and meta-analysis. JAMA. 2015 Jun 23-30;313(24): 2456-73. Erratum in: JAMA. 2015 Aug 4;314(5):520. Erratum in: JAMA. 2015 Aug 25;314(8):837. Erratum in: JAMA. 2015 Dec 1;314(21): 2308. Erratum in: JAMA. 2016 Apr 12;315(14): 1522.
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15. Perucca E. Cannabinoids in the treatment of epilepsy: hard evidence at last? J Epilepsy Res. 2017 Dec;7(2): 61-76.
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17. Epidyolex® Summary of Product Characteristics. GW Pharma. July 2021.
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19. Huntsman RJ, Tang-Wai R, Alcorn J, et al. Dosage related efficacy and tolerability of cannabidiol in children with treatment-resistant epileptic encephalopathy: preliminary results of the CARE-E study. Front Neurol. 2019 Jul; 10: 716.
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21. Caraballo R, Valenzuela GR. Cannabidiol-enriched medical cannabis as add-on therapy in children with treatment-resistant West syndrome: A study of eight patients. Seizure. 2021 Nov;92: 238-243.