EVIDENCE FOR 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.

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:

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

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:

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

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

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:

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.

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.