in man is not unlike that observed withD^9 -THC, with hydroxylation, further
oxidation to the carboxylic acid and subsequent glucuronidation occurring exten-
sively (Harvey and Mechoulam 1990 ; Mechoulam and Hanus 2002 ). Due to the
variable absorption and extensive first-pass metabolism, the bioavailability of
CBD is only about 6% after oral (Hawksworth and McArdle 2004 ) or sublingual
(Guy and Robson 2003 ) administration, compared to about 30% after aerosol
inhalation (Ohlsson et al. 1984 ) or intranasal administration. The cytochrome P450
enzymes CYP2C9, CYP2C19 and CYP3A4 catalyze most of the hydroxylations of
the principal phytocannabinoids, including CBD, which raises concern for
drug-drug interactions. Based on CBD’s inhibitory constants across the various
P450s, clinically relevant inhibition of enzymatic activity is most likely to occur
through the CYP1A1, 2B6, 2C19, 3A4 and 3A5 isozymes (the Ki for
CBD 1 lM at these CYPs) (Zendulka et al. 2016 ). The likelihood of drug-drug
interactions through these enzymes is dose and time dependent (e.g., acute and
cumulative exposures after chronic administration); therefore; their potential for
clinical significance requires further evaluation in the context of the therapeutic
dose levels of drugs required for efficacy and the pharmacokinetics involved in
specific patient populations.
CBD is a Schedule I controlled substance in the US, despite its lack of the
psychotomimetic activity and abuse liability associated with cannabis andD^9 -THC.
Furthermore, the U.S. Department of Agriculture, in consultation with the Drug
Enforcement Administration (DEA) and the U.S. Food and Drug Administration
(FDA), also published a Statement of Principles regarding Section 7606 of the
Agricultural Act of 2014. As such, CBD formulations can only be produced for
research, and all products (including hemp-oil extracts) containing CBD that are sold
in the U.S. for recreational or medicinal use are currently illegal under federal law.
The continued scheduling of CBD as a Schedule I substance may reflect the fact that
it can readily be cyclized toD^9 -THC under acidic conditions (Adams et al. 1940 ;
Gaoni and Mechoulam 1968 ), including conditions commonly encountered in gastric
juices (Watanabe et al. 2007 ). Thus, it may be considered a synthetic precursor of
THC, and chronic oral administration of large amounts may lead to conversion and
absorption of detectable amounts ofD^9 -THC in biologicalfluids and excreta.
There is mounting interest in medicinal use of cannabis and phytocannabinoids,
particularly CBD, as an antiseizure/antiepileptic drug, and the DEA and FDA have
taken steps to facilitate research and development of CBD-containing formulations
(U.S. Drug Enforcment Administration 2015 ). In the few clinical trials that have
been conducted in adults, CBD was well tolerated across a wide dosage range,
including doses of up to 1500/day p.o. chronic and 30/day i.v. acute administration
(Bergamaschi et al. 2011 ). The safety of CBD in infants, adolescents and geriatric
patients has not been thoroughly established. This chapter is a brief overview of the
key researchfindings from a selection of nonclinical and clinical studies providing
the current scientific foundation for CBD as a therapeutic treatment for seizures,
convulsions and epilepsy.
11 Cannabidiol as a Treatment for Seizures, Convulsions and Epilepsy 251