WHO Expert Committee on Drug Dependence Critical Review: Cannabidiol (CBD) Expert Peer Review 1

1. Comments based on the review report

a. Evidence on dependence and abuse potential

Dependence potential:
The review could not identify studies regarding the potential physical dependence effects of CBD in laboratory animals nor in human subjects. The review indicates that tolerance to the effects of CBD could not be induced in at least one study, however, it does not indicate tolerance to what effects. Regarding the possibility that CBD can produce THC-like effect, the review indicates “…there is no evidence of
that oral CBD administration in humans results in clinically relevant THC-like subjective or physiological effects, or appreciable plasma concentrations of THC or its metabolites.”

Abuse potential:
CBD does not appear to act directly at CB1 receptors; the receptor thought by many to mediate the abuse-related effects of cannabis. Additionally, it does not produce THC-like effects in the mouse tetrad assay. Generally, the effects of CBD do not indicate the likelihood for abuse in preclinical studies in that: it elevates ICSS thresholds; it does not increase dopamine release in the mesolimbic VTA-n. accumbens pathway; it does not induce conditioned place preference; nor does it generalize to the THC discriminative stimulus in rats or pigeons.
In human experimental studies the review indicates that “While the number of studies is limited, the evidence from well controlled human experimental research indicates that CBD is not associated with abuse potential.” Indeed, the literature appears limited for only two studies were cited to support this statement. In one study, 600 mg of CBD given orally did not produce effects different effect from placebo  in healthy subjects on the Addiction Research Center Inventory (ARC). In a randomized. In a randomized, double-blind study using cannabis smokers, CBD administered by itself up to 800 mg p.o. produced no significant psychoactive, cardiovascular or other effects and was ar or other effects and was ar or other effects and was ar or other effects and was ar or other effects and was ar or other effects and was ar or other effects and was ar or other effects and was ar or other effects and was ar or other effects and was ar or other effects and was without abuse-related indicators in a variety of testsrs in a variety of tests rs in a variety of tests rs in a variety of testsrs in a variety of tests rs in a variety of testsrs in a variety of tests.

b. Risks to individual and society because of misuse

The review indicates that CBD has been found to have relatively low toxicity, although it also indicates that not all potential effects have been explored. None of the toxic effects specifically identified in the review appeared particularly troublesome. Unfortunately, the entire toxicology section appears to be based on one review and its one update of the review without references to primary scientific sources. Adverse events reported in clinical studies investigating the therapeutic possibilities of CBD included, but were not limited to, somnolence, decreased appetite, diarrhoea, and fatigue.

c. Magnitude of the problem in countries (misuse, illicit production, smuggling etc)

The review indicates that “At present no public health problems (e.g. driving under the influence of drugs cases, comorbidities) have been associated with the use of pure CBD.” In addition, the review indicated that there were no published statistics on seizures of illicit CBD available. There is, however, unsanctioned medical use of CBD-based products that are distributed in a variety of forms for a variety of ailments from cancer to PTSD. At the time of this peer review (20180517), Annex data from participating states were not available for comment.

d. Need of the substance for medical (including veterinary) practice

Cannabidiol is not listed on the WHO Model List of Essential Medicines (20th List) or the WHO Model List of Essential Medicines for Children (6th List). CBD is presently marketed by GW Pharmaceuticals in a number of countries in combination with THC in a 1:1 ratio (Sativex®). The review, however, indicates that “Currently there are no approved marketed pure CBD medicinal products, although several are in development.” CBD is in development for a variety of therapeutic applications including schizophrenia, Fragile X syndrome, encephalopathies, childhood absence seizures, Neonatal Hypoxic-Ischemic Encephalopathy (NHIE), and perinatal asphyxia. Perhaps CBD is most established for epilepsy. This peer reviewer considers it important to note that CBD has been found effective in clinical studies of Lennox-Gastaut and Dravet syndromes that are often resistant to other forms of medication; this observation may identify a therapeutic use of CBD for an under-served patient population. Not specifically discussed in the review was the possibility that the metabolites of CBD are responsible for any therapeutic effect it may have and not CBD itself. For example, see review (not cited) by Ujvary and Hanus (Human Metabolites of Cannabidiol: A Review on Their Formation, Biological Activity, and Relevance in Therapy. Cannabis Cannabinoid Res, 2016, 1: 90-101). This possibility has importance for drug development, and for assumptions made of the properties of the parent molecule.

e. Need of the substance for other purposes (e.g. industrial)

No legitimate industrial or other use of CBD was identified although the review did indicate that some people were using CBD in skin and beauty products such as shampoos and skin creams.

f. Measures taken by countries to curb misuse

The review identifies six countries that control CBD. The ANNEX was not available to the peer reviewer at the time of his review (20180521) to evaluate what other countries may control it. Some countries, such as Canada, Australia and New Zealand, have relaxed control over CBD in recent years in part, to make it more accessible for medical use or research.

g. Impact if this substance is scheduled

Cannabidiol that is produced from an extract of cannabis is included in the 1961 Single Convention. There likely would be a profound impact if CBD were unscheduled on the global accessibility of this compound for medical research. An associated effect could be the increase in cultivation of cannabis sativa for purposes of obtaining CBD.

2. Are there absent data that would be determinative for scheduling?

Cannabidiol is already scheduled, the present consideration regards if it should remain scheduled as is, or be scheduled elsewhere, or be unscheduled. If it is decided that CBD should be removed from the 1961 Convention, and if it is decided that THC should remain scheduled in the 1971 Convention, more information regarding the yields from laboratory conversion of CBD to THC would be helpful to consider its listing in the 1987 Convention as a precursor. The Critical Review identifies this laboratory conversion, but it is unclear how feasible this synthesis is or what magnitude of yields are possible through it. In addition, the pharmacodynamics and toxicology sections have essential limitations making it difficult to understand the possible interactions CBD may have with other drugs of abuse. Only two studies were cited regarding the abuse potential of CBD in human studies making it challenging to draw conclusions just based upon their results.

3. Other comments or opinions

The Pharmacodynamics section has limitations. The review indicates that “Some studies have shown that CBD may reduce or antagonize some of the effects of THC.” but doesn’t discuss these studies in any detail, nor does it mention that there are studies that actually report just the opposite, including those that augment the abuse-related effects of THC (e.g., see McMahon LR. Enhanced discriminative stimulus effects of Delta(9)-THC in the presence of cannabidiol and 8-OH-DPAT in rhesus monkeys. Drug and Alcohol Dependence, 2016, 165: 87-93.” Overall, there is substantial scientific literature characterizing the interactions of CBD and THC and other drugs that were not covered in the review. The entire toxicology section appears to be based upon one review article and its update without a reference to a primary scientific source.

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