Cannabidiol

Cannabidiol (CBD) is one of the cannabinoids naturally occurring in hemp (Cannabis sativa). Cannabis sativa was originally native to Asia and is mainly known for its psychotropic ingredients, especially THC (tetrahydrocannabinol). In recent years the spotlight was mainly on CBD, which effects differ significantly from the effects of THC (2).  According to the current state of knowledge, CBD has no effects in humans that indicate a potential for abuse or dependence apart from good tolerability (3). In several clinical studies, CBD has been shown to be effective in the treatment of epilepsy. However, the therapeutic spectrum also includes other potential areas of application, such as smoking cessation, schizophrenia or Parkinson's disease.
 

The studies carried out in recent years on CBD in the treatment of epileptic disorders have a generally high level of evidence. Three randomized controlled trials (RCTs) on Dravet and Lennox-Gastaut syndrome are particularly noteworthy, which attest CBD a very high anticonvulsant potential. Dravet syndrome is also known as severe early childhood myoclonic epilepsy and is the umbrella term for a rare genetic encephalopathy with myoclonic epilepsy that is very difficult to treat. Lennox-Gastaut Syndrome describes a severe form of epilepsy that usually begins in children between the ages of two and six years and is attributed to various types of brain damage. The first and to date only RCT on CBD and Dravet syndrome was published in summer 2017 and involved a sample of 120 children with Dravet syndrome who received either CBD at a daily dose of 20 mg/kg body weight or a placebo. In order to ensure as uniform study conditions as possible, only subjects were recruited who had experienced at least four seizures one month before the study started. The CBD or placebo administration was in addition to the standard medication, with 65% of the children examined being treated with clobazam. The intervention with CBD resulted in 23 % fewer seizures than with placebo, with the seizure frequency decreasing by more than 50 % in 43 % of the CBD patients, compared to 27 % within the placebo group. Two RCTs dealt with CBD and Lennox-Gastaut syndrome. The first study had 171 participants, used an oral CBD dosage of 20 mg/kg body weight and showed a 22% reduction in the number of seizures compared to placebo. In addition, 44% of CBD patients were able to reduce their seizure frequency by half, whereas only 24% of the participants with placebo succeeded in doing so. The results of the second RCT with 225 subjects were similarly clear. However, it should be noted that CBD and placebo were also administered here in addition to the standard medication. Although the studies mentioned above clearly emphasize the great potential of CBD, it has not yet been clearly proven that the beneficial effects on epilepsy are due to the sole and direct effect of CBD. The reason for this is the fact that CBD has led to an increased concentration of N-desmethylclobazam, the main metabolite clobazam, by a factor of 5 and could therefore also have an indirect effect (5).
 

The primary treatment for schizophrenia is the use of antipsychotics, which act as D2 receptor antagonists. Although this therapy method is successful in the majority of patients, up to one third of people suffering from schizophrenia do not respond to it. This is attributed to the fact that there are no elevated dopamine levels in this group. Compounds that influence the course of schizophrenia via other molecular mechanisms are therefore required. First indications of CBD as an alternative treatment method were given in a case report of a schizophrenia patient who did not respond to treatment with Haloperidol but experienced an improvement in symptoms due to CBD. An RCT then compared the administration of CBD with placebo and referred to a study collective of 88 schizophrenia patients. The intervention with CBD was carried out in addition to the standard drug therapy; a number of survey instruments such as PANSS (Positive and Negative Syndrome Scale) and CGI-I (Clinical Global Impressions Scale) were used to record the symptomatic changes. The results were clear: Supplementation with CBD led not only to a significant reduction in positive symptoms (determined by PANSS), but also to a higher number of patients whose general health status (determined by CGI-I) improved. In addition, no differences between the intervention and placebo group could be detected with regard to occurring side effects. Since all patients were treated with D2-receptor antagonists in parallel and improvements were nevertheless observed, it is obvious that CBD acts D2-receptor-independently (6).
 

Since the endocannabinoid system has a strong influence on the human psyche, CBD is increasingly discussed in the context of the treatment of Parkinson's disease. An important tool for evaluating disease-related limitations is the PDQ-39 questionnaire. This questionnaire evaluates the patient's self-assessment of symptoms, participative possibilities and disabilities in everyday activities and mobility. It also assesses the patient's communication, cognition, emotional well-being and social support. Using PDQ-39, Brazilian scientists evaluated the effects of CBD on Parkinson's symptoms and found significantly better test scores compared to the placebo group. The greatest improvements were recorded in the areas of "everyday activities" and "stigma" - various forms of (self-)discrimination - of Parkinson's patients. Nevertheless, CBD did not have any effect on motor and general symptoms of PD, which underlines the need for further studies on this topic (7).
 

The endocannabinoid system not only regulates food intake and energy homeostasis, but is also significantly involved in the development of obesity and type 2 diabetes in chronic overactivation. For this reason, the cannabinoid receptor antagonist rimonabant has enjoyed particular popularity in the past, as it not only reduces body weight in type 2 diabetics, but also reduces hip circumference and triglyceride levels while simultaneously increasing HDL cholesterol and reducing HbA1c levels. However, severe side effects ultimately cost him marketing approval. Since CBD in animal experiments showed a 55% increase in HDL cholesterol and a reduction in total cholesterol by more than 25%, a recent RCT investigated the effects of various phytocannabinoids on the lipid profile and various parameters relevant for blood sugar regulation in type 2 diabetics. Although neither primary nor secondary outcomes were achieved by CBD intervention, it led to a significant reduction of the hormone resistin and an increase of the glucose-dependent insulinotropic peptide (GIP). And these observations are certainly relevant: High levels of resistin are generally associated with obesity and insulin resistance. GIP is a peptide hormone produced in the K cells of the duodenum that stimulates insulin secretion and protects the β cells of the pancreas. Nevertheless, no improvements in glycemic control have been observed (9).
 

CBD already showed anti-inflammatory as well as immunosuppressive properties in model experiments. An example of this is its use in animal experiments to accompany the treatment of inflammatory diseases, such as multiple sclerosis, rheumatoid arthritis, chronic inflammatory bowel disease and diabetes. A new field of application for CBD is the treatment of graft-versus-host disease (GvHD), which is the immunological response to a bone marrow or stem cell transplant from a foreign donor. In this case, it is mainly the T-lymphocytes of the donor transplant that react against the recipient organism. This is particularly relevant for the transplantation of blood stem cells, after which GvHD occurs in up to 70% of cases. In 2015 a team of researchers investigated whether daily administration of 300 mg CBD - in addition to standard prophylaxis with cyclosporine, methotrexate and antithymocyte globulin - weakens the graft-versus-host reaction. The results were convincing: Intervention with CBD resulted in only 12 % of the subjects developing second- to fourth-degree GvHD. In comparison, the control group without CBD showed an incidence of 46 %. The intervention with CBD was reflected in a hazard ratio of 0.3, which corresponds to a 70% reduction in the risk of developing GvHD (10).
 

CBD unfolds its effects via the endocannabinoid system, which has a major influence on addictive behaviour and the neuronal reward system. It is therefore obvious that CBD is also of direct benefit in nicotine withdrawal. This hypothesis is based, among other things, on the Cochrane Review, according to which rimonabant increased the chance of complete nicotine withdrawal and thus the withdrawal from addiction by 50%. The drug rimonabant affects the endocannabinoid system and thus the release of the happiness hormone dopamine via CB1 receptors, but lost its approval for the European market due to severe side effects. The search for side-effect free alternatives was quickly found: CBD, which in contrast to rimonabant has an excellent safety profile. Proof of the benefits of CBD in the attempt to quit smoking or reduce nicotine consumption was provided by an RCT from 2013. Compared to the placebo group, the number of cigarettes smoked was reduced by about 40% by using low doses of CBD; a result that can be described as quite remarkable after an intervention period of only one week (11).
 

In an observational study over six weeks, the influence of a hemp oil-hemp extract preparation with low-dose CBD (30 mg CBD/d) on healthy persons with sleep problems was investigated. The results show highly significant positive changes in all aspects of sleep and sleep quality, stress perception and well-being. The fact that the improvement of sleep quality, the reduction of stress and the increase of well-being can be proven simultaneously and consistently, suggests a fundamental and comprehensive physiological effect of the hemp plant and the CBDs it contains. With the available results, the potential of a nutritional intervention with a combination of hemp oil, hemp extract and CBD in low doses could be proven for the first time (12).