Undesirable Effects
The best data available to characterise the adverse event profile of CBD comes from the phase 3 clinical trial program for an FDA approved medicine which is a CBD oral solution indicated for the treatment of seizures associated with Lennox-Gastaut syndrome (LGS) or Dravet syndrome (DS) in the USA. This product is not approved in New Zealand.
We present the results of the adverse events seen in the clinical trial program for this product as summarised in the approved FDA data sheet. It should be noted that the patient base for this product is a discreet group of epilepsy patients children and young adults and the dose rates used are typically higher than those seen for other uses of CBD. Please note that the adverse events seen reported below may not be representative of those seen with different CBD products in different (lower) doses and in different patient populations. Nevertheless it provides an insight into the potential types of adverse effects prescribers should be aware of in their patients.
Clinical Trials Experience
In controlled and uncontrolled trials in patients with LGS and DS, 689 patients were treated with the CBD product, including 533 patients treated for more than 6 months, and 391 patients treated for more than 1 year. In an expanded access program and other compassionate use programs, 161 patients with DS and LGS were treated with the CBD product, including 109 patients treated for more than 6 months, 91 patients treated for more than 1 year, and 50 patients treated for more than 2 years.
The most common adverse reactions that occurred in treated patients (incidence at least 10% and greater than placebo) were somnolence; decreased appetite; diarrhea; transaminase elevations; fatigue, malaise, and asthenia; rash; insomnia, sleep disorder, and poor quality sleep; and infections. The table below lists the adverse effects that were reported in at least 3% of treated patients and a rate greater than placebo in the placebo controlled trials.
Liver Enzymes
The CBD product caused dose-related elevations of liver transaminases (alanine aminotransferase [ALT] and/or aspartate aminotransferase [AST]). In controlled studies for LGS and DS, the incidence of ALT elevations above 3 times the upper limit of normal (ULN) was 13% in treated patients compared with 1% in patients on placebo. Less than 1% of treated patients had ALT or AST levels greater than 20 times the ULN. There were cases of transaminase elevations associated with hospitalization in patients taking the CBD product. In clinical trials, serum transaminase elevations typically occurred in the first two months of treatment initiation; however, there were some cases observed up to 18 months after initiation of treatment, particularly in patients taking concomitant valproate. Resolution of transaminase elevations occurred with discontinuation of product or reduction of the dose and/or concomitant valproate in about two-thirds of the cases. In about one-third of the cases, transaminase elevations resolved during continued treatment with the CBD product, without dose reduction.
Somnolence and Sedation
The product can cause somnolence and sedation. In controlled studies for LGS and DS, the incidence of somnolence and sedation (including lethargy) was 32% in treated patients, compared with 11% in patients on placebo and was dose-related (34% of patients taking 20 mg/kg/day, compared with 27% in patients taking 10 mg/kg/day). The rate was higher in patients on concomitant clobazam (46% in treated patients taking clobazam compared with 16% in treated patients not on clobazam). In general, these effects were more common early in treatment and may diminish with continued treatment.
Decreased weight
The CBD product can cause weight loss. In the controlled trials of patients with LGS or DS, based on measured weights, 16% of treated patients had a decrease in weight of ≥5% from their baseline weight, compared to 8% of patients on placebo. The decrease in weight appeared to be dose-related, with 18% of patients on 20 mg/kg/day experiencing a decrease in weight ≥5%, compared to 9% in patients on 10 mg/kg/day.
Haematologic Abnormalaties
The CBDproduct can cause decreases in hemoglobin and hematocrit. In controlled trials of patients with LGS or DS, the mean decrease in hemoglobin from baseline to end of treatment was -0.42 g/dL in treated patients and -0.03 g/dL in patients on placebo. A corresponding decrease in hematocrit was also observed, with a mean change of -1.5% in treated patients, and -0.4% in patients on placebo. There was no effect on red blood cell indices. Thirty percent (30%) of treated patients developed a new laboratory-defined anemia during the course of the study (defined as a normal hemoglobin concentration at baseline, with a reported value less than the lower limit of normal at a subsequent time point), versus 13% of patients on placebo.
Increases in Creatinine
The CBD product can cause elevations in serum creatinine. The mechanism has not been determined. In controlled studies in healthy adults and in patients with LGS and DS, an increase in serum creatinine of approximately 10% was observed within 2 weeks of starting treatment. The increase was reversible in healthy adults. Reversibility was not assessed in studies in LGS and DS.
Anti Epilepsy Drugs and Suicide Behaviour and Ideation
In 2008, the U.S. Food and Drug Administration (FDA) published a warning after a meta-analysis of data from all clinical trials involving Anti-epileptic drugs (AEDs) found a suicidality risk of 0.43 per 1000 patients in active drug arms of these clinical trials compared to a rate in the placebo arm of 0.22. While an increased risk for individual AEDs was found in two, the FDA decided to issue a warning for the entire AED class. Consequently the prescribing information for the CBD product contains the mandated class warning.