support for complex interactions of CBD with CB1 comes from a study in the
mouse vas deferens demonstrating that it can increase the amplitude of electrically
evoked contractions, which suggests negative allosteric modulation of endo-
cannabinoid tone since it can also antagonize orthosteric agonists with a greater
potency than predicted by its affinity for cannabinoid receptors (Pertwee et al.
2002 ).
In addition to direct interaction, CBD can indirectly affect signaling at cannabi-
noid receptors through its modulation of endocannabinoid levels. For example, at
relatively high concentrations CBD inhibits the hydrolysis of anandamide (AEA) by
fatty acid amide hydrolase (FAAH) (Watanabe et al. 1998 ; De Petrocellis et al. 2011 ;
Leweke et al. 2012 ) with a pooled mean IC 50 = 19.8±4.77lM (McPartland et al.
2015 ), and also inhibits the putative AEA transporter (Bisogno et al.2001a)witha
pooled mean IC 50 = 10.2±3.03lM (McPartland et al. 2015 ). In one clinical study
over 4 weeks, patients who received CBD (200mg/day increased stepwise by 200
mg each day to a dose of 200mg four times daily, total 800 mg per day within the
first week) had elevated serum levels of the FAAH substrates AEA, palmi-
toylethanolamide (PEA) and oleoylethanolamide (OEA) (Leweke et al. 2012 )
compared to baseline. While this study measured serum and not cerebrospinalfluid,
it suggests that AEA levels may be elevated after high daily doses of CBD to an
extent that would increase CB1 and CB2 receptor signaling. Since presynaptic CB1
receptor signaling can modulate neuronal excitability (Alger 2004 ; Vaughan and
Christie 2005 ), it remains possible that some of the antiepileptic effects of CBD
involve altered endocannabinoid signaling.
11.2.2 Other Neuronal Mechanisms of Action
of Cannabidiol
Cannabidiol produces several effects on ion channels and exchange proteins that
modulate neuronal excitability, and this might relate to its ability to treat epilepsy
syndromes. In vitro and in situ electrophysiology has demonstrated that CBD
inhibits epileptiform activity in both high K+, free Mg2+and 4-aminopyridine
treated hippocampal brain slice models of seizure (Ryan et al. 2009 ; Jones et al.
2010 ). A role for CBD at sodium-calcium exchanger protein (NCX) in mito-
chondria was demonstrated using dual-loaded hippocampal neurons with Ca2+-
sensitive and selective probes for mitochondrial and cytosolic compartments (Ryan
et al. 2009 ). This observation is consistent with previous observations that influx of
Na+into the cell associated with ischemia and excitotoxic events causes release of
Ca2+from mitochondrial NCX (Zhang and Lipton 1999 ). Hence, the ability of CBD
to modulate intracellular Ca2+levels through mitochondrial NCX might be a par-
ticularly important mechanism in the treatment of epilepsy and other disease states
that involve hyperexcitability (Ryan et al. 2009 ). Studies in primary hippocampal
cell cultures or brain slices have also revealed that some modulation by CBD of
11 Cannabidiol as a Treatment for Seizures, Convulsions and Epilepsy 253