## 5 _Cannabis sativa_ L. in Cancer Clinical Trials  
The role of _Cannabis sativa_ in medicine is rapidly evolving. More than 30 countries worldwide have now legalized access to medical use of _Cannabis_[146; 147]. A prospective observational study showed that many cancer-related symptoms improve significantly with _Cannabis_ consumption. Similarly, another study, performed on over 3000 cancer patients, showed that cannabis use determines significant improvements in the controlof common symptoms, including sleep problems (70.8%), fatigue (55.9%), anxiety and depression (74.1%), and nausea and vomiting (54.7%) [148]. Compared to THC, CBD-based preparations seem to be more promising, having diverse medicinal properties, such as anti-nausea, anti-emetic, anti-tumor, anti-inflammatory, antidepressant, anti-psychotic, and anti-anxiolytic effects [149]. To date, some information has been collected also in relation to the anticancer effects of CBD [92; 150], as well as for the management of cancer pain, cancer-related anorexia and cachexia, and chemotherapy-induced nausea and vomiting (CINV) [151; 152; 153]. Clinical data are available about CBD use for the treatment of glioblastoma. A clinical trial analyzed the effect of CBD as a single agent against glioblastoma (clinical trial: NCT02255292) while another placebo-controlled phase II clinical trial analyzed the effect of the combination of THC and CBD as adjuvant in the chemotherapy (clinical trial: NCT01812603) [[[https://clinicaltrials.gov/ct2/show](https://clinicaltrials.gov/ct2/show)]([https://clinicaltrials.gov/ct2/show](https://clinicaltrials.gov/ct2/show)) accessed on 30 April 2021]. Both trials report very promising effects in terms of cancer regression. Similarly, a clinical trial, regarding 119 patients with different solid tumors (e.g., breast, prostate, and esophageal), was conducted over a four-year framed period: in 92% of the patients, a reduction in tumor size was obtained when CBD oil was administered [154]. Besides trials aiming at validating anti-cancer properties, the effects of CBD-based preparations on cancer pain patients are finding a wide interest [155; 156; 157; 158; 159]. A significant analgesic effect has been assessed in patients with malignant disease in 15 of 18 trials as compared to placebo [160]. Several data have demonstrated improved average pain score and an increased good quality of life [161; 162; 163]. Additionally, when using various THC dosages or synthetic analogs for cancer-related pain, an improved pain relief was found [164; 165]. Even in cancer patients suffering from inadequate analgesia control with opioid therapy, a combination of THC and CBD can reduce pain score more than 30% from baseline [166; 167], while the THC group showed a non-significant improvement [37]. However, the main limitation of THC remains sedation [168; 169], while the long-term use of the THC/CBD spray is generally well-tolerated for as long as 2 years [170]. CB receptors, highly expressed in the neuronal tracts for emesis, have been chosen for treating CINV [171]. Results from several preclinical studies suggest that THC and CBD have anti-inflammatory, analgesic, anti-nausea, anti-specific, anti-psychotic, anti-ischemic, anxiolytic, and anti-epileptic impact [172; 173; 174]. In a small, controlled, randomized, \"double-blind\" experiment, oral THC reduces vomiting caused by chemotherapeutic agents [175]. Finally, the use of cannabinoids is linked to the increase of appetite and the gain of weight (ClinicalTrials.gov accessed on 14 March 2021, NCT02359123) [151]. However, cannabis extract and THC were tested in a Phase III clinical trial with no significant differences among patients with cancer-related anorexia-cachexia syndrome in terms of appetite [152]. More promising results have been later obtained that described a relevant increase in appetite [176]. Finally, in cachetic NSCLC patients, the use of a synthetic analog of THC, in a Phase II trial, significantly increases appetite and caloric intake [23].