CANNABIDIOL (CBD) Pre-Review Report by WHO

This report has been drafted under the responsibility of 

the WHO Secretariat, Department of Essential Medicines and Health Products, Teams of Innovation, Access and Use and Policy, Governance and Knowledge

(Expert Committee on Drug Dependence. Thirty-ninth Meeting Geneva, 6-10 November 2017)

Summary:

Cannabidiol (CBD) is one of the naturally occurring cannabinoids found in cannabis plants. It is a 21-carbon terpenophenolic compound which is formed following decarboxylation from a cannabidiolic acid precursor, although it can also be produced synthetically, CBD can be converted to tetrahydrocannabinol (THC) under experimental conditions, however, this does not appear to occur to any significant effect in patients undergoing CBD treatment. 

In experimental models of abuse liability, CBD appears to have little effect on conditioned place preference or intracranial self-stimulation. In an animal drug discrimination model CBD failed to substitute for THC. In humans, CBD exhibits no effects indicative of any abuse or dependence potential. There is unsanctioned medical use of CBD based products with oils, supplements, gums, and high concentration extracts available online for the treatment of many ailments.

CBD is generally well tolerated with a good safety profile. Reported adverse effects may be as a result of drug-drug interactions between CBD and patients’ existing medications. Several countries have modified their national controls to accommodate CBD as a medicinal product. To date, there is no evidence of recreational use of CBD or any public health related problems associated with the use of pure CBD.


Spontaneous conversion:

 It has been proposed that the conversion of CBD to delta-9-THC in the presence of acid could occur in the human gut. Such conversion could be of importance if CBD is administered orally. Two in vitro studies have used simulated gastric fluid to demonstrate the potential for this conversion. The first reported the formation of analytically confirmed delta-9-THC and delta-8-THC when CBD was exposed to simulated gastric fluid without enzymes at 37ºC. 

The authors concluded that that the acidic environment during normal gastrointestinal transit could expose orally CBD, treated patients to levels of THC and other psychoactive cannabinoids that may exceed the threshold for a physiological response. The second in vitro study also reported the formation of delta-9-THC along with other cannabinoid products in artificial gastric juice without pepsin. The conversion rate of CBD to THC was only 2.9%.  

The predictive value of these in vitro studies for humans administering cannabidiol orally has been questioned as simulated gastric fluid does not exactly replicate physiological conditions in the stomach. Furthermore, spontaneous conversion of CBD to delta-9-THC has not been demonstrated in humans undergoing CBD treatment.

For example, in a six week clinical study in Huntington’s disease patients who were administered CBD 700 mg/day, the CBD average plasma concentration range was 5.9-11.2 ng/mL with no delta-9-THC detected. In humans, THC effects are characterised by impairment of psychomotor and cognitive performance, and a range of physical effects including increased heart rate and dry mouth. In general, clinical studies have reported that even high doses of oral CBD do not cause the those effects that are characteristic for THC and for cannabis rich in THC. 

For example, in a study of healthy volunteers administered 200mg oral CBD, CBD did not produce any impairments of motor or psychomotor performance. A number of other studies involving high doses of CBD were recently summarized by Grotenhermen et al. they concluded that high doses of oral CBD consistently fail to demonstrate significant effects or demonstrate effects opposite to those of THC. 

While it has been suggested that further large-scale human studies are needed to explore the gastric conversion and potential THC-like side effects following oral CBD administration, it is very unlikely that oral cannabidiol will be shown to result in THC concentrations sufficient to induce any meaningful effects. 

Toxicology:

The potential toxic effects of CBD have been extensively reviewed  with a recent update of the literature.  In general, CBD has been found to have relatively low toxicity, although not all potential effects have been explored.

The following are some of the relevant findings to date from in vitro and animal studies: 

• CBD affects growth of tumoral cell lines, but has no effect in most nontumour cells. However, a pro-apoptotic effect has been observed in lymphocytes. 
• It has no effect on embryonic development (limited research) 
• Evidence on potential hormonal changes is mixed, with some evidence of possible effects and other studies suggesting no effect, depending on the method used and the particular hormone 
• It has no effect on a wide range of physiological and biochemical parameters or significant effects on animal behaviour unless extremely high doses are administered 
• Effects on the immune system are unclear; there is evidence of immune suppression at higher concentrations, but immune stimulation may occur at lower concentrations. 
• There is potential for CBD to be associated with drug interactions through inhibition of some cytochrome P450 enzymes, but it is not yet clear whether these effects occur at physiological concentrations. 

Adverse Reactions in Humans:

 As noted above, CBD does not produce the effects that are typically seen with cannabinoids such as THC. It also failed to produce significant effects in a human study of abuse potential discussed below. Across a number of controlled and open label trials CBD of the potential therapeutic effects of CBD it is generally well  tolerated, with a good safety profile.

Read the full report here: https://www.who.int/medicines