Preclinical Assessment of the Abuse Potential of Purified Botanical Cannabidiol: Self-Administration, Drug Discrimination, and Physical Dependence

ABSTRACT
Cannabidiol (CBD) is a constituent of the cannabis plant with a di verse array of pharmacological activities as well as potential thera peutic uses. An oral formulation of CBD (Epidiolex in the US;
Epidyolex in Europe) is approved for treating seizures associated
with rare and severe forms of epilepsy. These studies, which sup ported the approval of the medication, investigated abuse-related
effects of CBD in rats and nonhuman primates (NHPs) using drug
self-administration, drug discrimination, and physical dependence
procedures and characterized its pharmacokinetics. In NHPs (n 5
5) that self-administered midazolam (0.01 or 0.032 mg/kg/infu sion), CBD (0.1–3.2 mg/kg/infusion) failed to maintain responding
above vehicle levels. CBD maintained very modest levels of self administration in rats (n 5 7–8) that self-administered heroin (0.015
mg/kg/infusion) and did not increase drug-lever responding, up to
a dose of 150 mg/kg (by mouth), in rats (n 5 6) trained to discrimi nate 0.5 mg/kg (i.p.) midazolam. In juvenile (5–6 weeks old) and
adult (10–11 weeks old) male and female rats, discontinuation of
chronic treatment (twice daily for 20 days) with an oral formulation
of CBD (20 or 100 mg/kg, by mouth) did not reliably produce signs
of withdrawal. Pharmacokinetic studies confirmed that the dosing
regimens used in these studies resulted in therapeutically relevant
plasma levels. Taken together, the lack of reliable self-administra tion, the failure to increase drug-lever responding in rats trained to
discriminate midazolam, and the absence of withdrawal signs
upon discontinuation of chronic treatment indicate that CBD has
very low abuse potential and is unlikely to produce physical
dependence