Excerpt from the World Health Organization on Epilepsy

The clinical use of CBD is most advanced in the treatment of epilepsy. In clinical trials, CBD has been demonstrated as an effective treatment for at least some forms of epilepsy, with one pure CBD product (Epidiolex®) currently in Phase III trials.

The use of CBD for this purpose is based on a number of studies in animals dating back to the 1970s. [62] These studies demonstrated the anti-seizure activity of cannabidiol in a number of animal models. Based on this research, cannabidiol has been tested in patients with epilepsy.
In a very early small-scale double-blind placebo-controlled trial, patients received either 200 mg CBD daily (4 patients) or placebo (5 patients) for a 3-month period, in addition to their habitual medication. In the CBD group, two patients had no seizures for the entire 3-month period, one partially improved, and the fourth had no improvement. No improvements were observed in the placebo group and no toxic effects were reported for either group. This study has a number of limitations, including the small sample size, unclear design as to blinding, and lack of definition of partial improvement. [63]

In another study, 15 patients with “secondarily generalized epilepsy with temporal focus,” were randomly divided into two groups. In a double-blind procedure, each patient received 200-300 mg daily of CBD or placebo for up to four and a half months in combination with their existing prescribed antiepileptic medications (which were no longer effective in the control of their symptoms). CBD was tolerated in all patients, with no signs of toxicity or serious side effects. Of the eight participants in the CBD treatment group, four were reported to be almost free of seizure episodes throughout the trial, whereas three others showed partial clinical improvement. CBD was ineffective in one patient. In comparison, the clinical condition of seven placebo patients remained unchanged with one patient showing improvement. [64]

There have also been some negative reports regarding the effectiveness of CBD. In a trial reported in 1986, a dose of CBD of 200–300 mg/day for a month resulted in no significant differences between the treatment and placebo groups. [65] Similarly, a 6- month double blind study administering CBD 100 mg 3 times each day did not result in any changes in seizure frequency or improvement in cognition or behaviour. [66]

The results of several trials examining the effects of CBD in patients with severe, intractable, childhood-onset, treatment-resistant epilepsy have been reported. The first was an open label study of 214 patients (aged 1–30 years) who were receiving stable doses of antiepileptic drugs before study entry. Patients were given oral cannabidiol, initially at 2–5 mg/kg per day, and then titrated until intolerance or to a maximum dose of 25 mg/kg or 50 mg/kg per day, dependent on study site. The primary measure was the percentage change in the frequency of seizures. In the CBD group, the median monthly frequency of motor seizures reduced from 30·0 at baseline to 15·8 over the 12-week treatment period. The trial was also designed to assess safety, but the absence of a control group means that the results cannot be used to assess the likelihood of CBD producing particular effects. Adverse events reported in more than 10% of patients were somnolence, decreased appetite, diarrhoea, fatigue, and convulsion. Five (3%) patients discontinued treatment because of an adverse event. Serious adverse events were reported in 48 (30%) patients, of which 20 (12%) experienced severe adverse events possibly related to cannabidiol use, the most common of which was status epilepticus (n=9 [6%]). [67]

The same research group reported the results of a controlled trial of CBD treatment for Dravet syndrome, a complex childhood epilepsy disorder that is associated with drug- resistant seizures and a high mortality rate. In a double-blind, placebo-controlled trial, 120 children and young adults with Dravet syndrome were randomly assigned to receive either cannabidiol oral solution (20 mg per kilogram per day) or placebo, in addition to standard antiepileptic treatment (a median of 3.0 drugs). The authors reported that cannabidiol decreased the median frequency of convulsive seizures per month from 12.4 to 5.9, as compared with a decrease from 14.9 to 14.1 with placebo. A small percentage (5%) of patients in the CBD group became seizure free as compared to zero in the placebo group. Adverse events that occurred more frequently in the cannabidiol group than in the placebo group included diarrhoea (31% vs 10%), loss of appetite (28% vs 5%) and somnolence (36% vs 10%). Other adverse effects noticed were vomiting, fatigue, pyrexia and abnormal results on liver-function tests.

Adverse effects led to the withdrawal of eight patients in the cannabidiol group compared with one in the placebo group. [68]

A similar study was recently conducted and reported on the safety and efficacy of CBD in patients with Lennox-Gastaut syndrome, a severe form of epileptic encephalopathy that produces various types of seizures (including drop seizures) that are often treatment-resistant. Across 24 clinical sites (located in US, the Netherlands and Poland), a total of 171 patients ages 2-55 years old, were randomized to receive active CBD [200 mg/kg, oral solution] (n=86) or matched placebo (n=85) as an add- on to their antiepileptic regimen (average of 3 medications/patient in each group). CBD was administered daily for 14 weeks: 2 weeks of dose escalation (starting dose of 2.5 mg/kg, PO) and 12 weeks of maintenance (200 mg/kg, PO); a 10-day dose taper was also included at the end of treatment. The authors report that CBD treatment decreased drop seizure frequency by a median of 43.9% (71.4 seizures per patient/month at baseline; 31.4 during treatment), compared to a 21.8% reduction in the placebo group (74.7 at baseline, 56.3 during treatment). CBD also increased the number of patients experiencing ≥50% reduction in drop seizure frequency (44% patients (n=38) in the CBD group compared to 24% (n=20) in the placebo group). CBD also reduced other non-drop seizures (49.4% reduction in CBD group, 22.9% in the placebo group). A small number of patients in the CBD group (n=3) were seizure free during the 12 weeks of maintenance dosing, compared to zero in the placebo group. Treatment related adverse events occurred more frequently in the cannabidiol group than in the placebo group and were similar to those reported in previous trials: diarrhea (13% vs 4%), somnolence (14% vs. 8%), decreased appetite (9% vs 1%), vomiting (7% vs. 5%) and pyrexia (1% in both groups). Increases in liver function tests (>3 times the upper limit of normal) occurred in 20 patients in the CBD group and 1 patient in the placebo group. [69]

It has been suggested that some of the adverse effects of cannabidiol observed in the clinical studies may relate to interactions with other antiepileptic drugs. For example, a recent study evaluated thirteen subjects with refractory epilepsy concomitantly taking clobazam and CBD. Nine of 13 subjects had a >50% decrease in seizures, corresponding to a responder rate of 70%. Side effects were reported in 10 (77%) of the 13 subjects, but were alleviated with clobazam dose reduction. All subjects tolerated CBD well. [70]

Cannabidiol (as Epidiolex®; GW Pharmaceuticals) was submitted in 2017 for regulatory approval to the U.S. Food and Drug Administration for treatment of seizures related to Lennox-Gastaut and Dravet syndromes in patients two years of age and older. A public advisory committee was held in April 2018 with the committee voting in favor of approval of CBD; while the committee approval is not binding but rather advisory, it is most common for the FDA to concur with committee votes.

Other indications
There is also evidence that CBD may be a useful treatment for a number of other medical conditions. However, this research is considerably less advanced than for treatment of epilepsy. For most indications, there is only pre-clinical evidence, while for some there is a combination of pre-clinical and limited clinical evidence. The range of conditions for which CBD has been assessed is diverse, consistent with its neuroprotective, antiepileptic, hypoxia-ischemia, anxiolytic, antipsychotic, analgesic, anti-inflammatory, anti-asthmatic, and antitumor properties. [39, 53, 71] The evidence for some of these indications was recently reviewed by Pisanti et al.,.[72]

Additionally, recent human studies have reported a therapeutic signal for CBD for transplant acceptance (decreasing the development of graft vs. host disease after hematopoietic cell transplants) [73] and reducing some of the positive symptoms of schizophrenia (1000 mg/day, PO) [74]. Other recent reports have failed to demonstrate CBD efficacy to reduce symptoms of ulcerative colitis (up to 500 mg/day, PO) [75], chronic pain in kidney transplant patients (50 – 300 mg/day, PO) [76], and experimentally-induced anxiety (600 mg, PO). [77]

Another possible therapeutic application which has been investigated is the use of CBD to treat drug addiction. A recent systematic review concluded that there were a limited number of preclinical studies which suggest that CBD may have therapeutic properties on opioid, cocaine, and psychostimulant addiction, and some preliminary data suggest that it may be beneficial in cannabis and tobacco addiction in humans. However, considerably more research is required to evaluate CBD as a potential treatment. [78]

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