Evaluation Prospectively the Level of Reduction in Cognitive Functions of Cancer Patients Who Are on Active Oncology Treatments and Use Cannabis. The Second Goal is to Identify High-risk Groups for Cognitive Impairment Due to Cannabis Use.

Cannabis sativa is one of the most ancient psychotropic drugs known to humanity. Evidence of the use of cannabis for medicinal and ceremonial purposes goes back 4000 years. In 1854, the plant appeared in the United States Dispensatory and was sold freely in pharmacies in Western countries. It also appeared in the British Pharmacopoeia as an extract and tincture for over 100 years. In 1942, cannabis was removed from the United States Pharmacopoeia and, with that, its legal medicinal use was stopped. Only in 1971 did Britain and most of the European countries outlaw the use of cannabis according to the UN Convention of Psychotropic Substances \[1\]. Regardless, a rising number of states in the USA, Canada and several European countries allow medicinal use of cannabis subject to a doctor's recommendation. Along with the popularity of the cannabis plant as an effective treatment for disease symptoms in oncology patients and for various medicinal indications unrelated to cancer patients, there is growing evidence to demonstrate interest in the use of cannabinoids in medicine, although high quality studies are still missing. In oncology, the beneficial effects of treatment with the plant, or treatment with medicine produced from its components, are related to symptoms of the disease: pain, nausea and vomiting, loss of appetite and weight loss. The clinical evidence of the efficacy of cannabis for these indications is only partial. Improvement in mood swings and sleep disorders has also been reported, although these were not goals of the research \[2\]. There is a basic difficulty in conducting randomized, double-blind statistical power research in products that are extracted from plants. This difficulty arises from the lack of a driving economic source and from difficulty in reaching set standards regarding the product and its quality over time, the method of consumption, and the diversity of the population. In Israel, according to Ministry of Health regulations, permission to use medicinal cannabis for oncology patients can be given for two indications: to relieve disease-related symptoms in advanced disease or during chemotherapy treatment in order to reduce side effects. The indications are very wide and allow a great deal of freedom for the physician's decisions, but also cause high demands for cannabis from patients. The cannabis plant and the synthetic drugs based on the plant are considered to be medically safe. The main reason for this is the lack of cannabis receptors in the brain stem, a fact that prevents life-threatening side effects which exist, for example, in morphine-based drugs. The side effects can be divided into acute and chronic, and are a result of prolonged use of cannabis. As cannabinoid receptors are present in other tissues throughout the body, adverse effects include redness of the eyes, tachycardia, bronchodilation, muscle relaxation, and decreased gastrointestinal motility \[3\]. Most of the adverse effects are related to the fact that the plant and the drugs are psychoactive, mostly depending on their concentration and on the THC dosage. Among the effects named were dizziness, euphoria, difficulty concentrating, disturbances in thinking, memory loss, and loss of coordination \[4\]. Recently, we published the results of a prospective, observational study evaluating the medical necessity for medicinal cannabis treatment in cancer patients on supportive or palliative care. Of the 211 patients who had a first interview, only 131 had the second interview, 25 of whom stopped treatment after less than a week. All cancer- or anti-cancer treatment-related symptoms showed significant improvement (p\<0.001). No significant side effects, except for memory lessening in patients with prolonged cannabis use (p=0.002), were noted \[5\]. Chemotherapy-related cognitive impairment (CRCI) is a phenomenon of cognitive decline that patients may experience during or after chemotherapy \[6\]. Memory loss and lack of concentration and attention are the most frequent symptoms encountered \[7\]. Other complaints include difficulties with multi-tasking, organizing and planning, as well as difficulty in thinking and other subtle cognitive changes \[8\]. CRCI is now one of the most common post-treatment symptoms reported by breast cancer survivors and may also represent the most troublesome symptom \[9\]. Evidence suggests that CRCI is of significant concern to patients and has become a major quality-of-life issue for survivors, and estimates of its frequency range from 14% to 85% of patients \[10\]. For some cancer survivors, the cognitive effects of chemotherapy linger on for years after treatment, and even mild impairment may impact the survivors' ability to function, both at home and at work \[9,10\]. The influences of cannabis use on cognitive functions of oncology patients have never been tested. Theoretically, the combination of chemotherapy and cannabis can cause severe reduction in cognitive functions in additive or synergistic ways. However, this hypothesis has never been tested, although the number of patients using cannabis during chemotherapy treatments in Israel and in other Western countries is growing.