CBD in epilepsy treatment

    August 20, 2022 5 min read

    CBD in epilepsy treatment

    Highly purified, plant-derived cannabidiol (CBD) has been approved for several years in the treatment of Dravet syndrome (DS) and Lennox-Gastaut syndrome, two forms of epilepsy. Much is known about the mechanisms of action underlying this cannabinoid’s apparent anti-convulsant effect, and how it is absorbed, metabolized, and cleared from the body, but much also remains to be clarified. As well, how CBD interacts with other forms of therapy is yet to be ascertained. Trials are underway, and they will add to the data fund as CBD’s usefulness becomes clear in these and other forms of epilepsy. 

    CBD’s action in seizures is complex. It appears to be independent of the two known neural receptor sites for cannabinoids, spoken of as ‘CB1’ and ‘CB2’. However, it can antagonize CB1 action at very low concentrations, even in spite of its generally low affinity for binding there.  It may function as an inverse agonist, acting as a negative allosteric modulator. 

    One possible target is the orphan G protein-coupled receptor GPR55, located in excitatory axonal terminals, where it may affect Glut release via intracellular Ca2+ level modulation, possibly contributing to short-term potentiation in the hippocampus. CBD has been shown to act as a GPR55 antagonist, reducing Glut exocytosis and dampening neuronal excitability. This signaling pathway is not active at baseline conditions. 

    CBD also regulates levels of adenosine, which is thought to have a role in seizure termination. It works by blocking the equilibrative nucleotide transporter, which inhibits adenosine re-uptake by astrocytes. Elevated adenosine could reduce Glut release, by interacting with the A1 or A2 receptors. 

    Other targets in epilepsy might be 5HT receptors, coupled with Gi/o proteins, that reduce neurotransmitter release, and GABAA receptors, where CBT appears to act as a positive allosteric modulator. 

    Voltage-gated sodium channels as well may be useful targets. CBD has been shown to inhibit human Nav1.1.-1.7 currents, potentially of use in therapeutic settings. CBD also reduces sodium currents in wild-type and mutant Nav1.6 channels. Encoded by SCN8A, these mutations associate with severe epileptic encephalopathy. 

    There may be another route to tackling neuronal excitability, in transient receptor potential cation channels, that appear to be involved in CBD signaling. At the vanilloid type 1 TRP channels, CBD acts as an agonist, and may function in decreasing calcium levels. CBD might also act as on the ankyrin type 1 and melastatin type 8 TRP channels as well. 

    Other possible receptors, ion channels, and enzymes on which CBD is supposed act are VGCC, of T- and L-type, mitochondrial Na+/Ca2+ exchange, α3 glycine receptors and μ/δ opioid receptors, α1 adrenoreceptors and Dopamine 2 receptors. CBD could also influence endocannabinoid signaling by modulating fatty acid amide hydrolase, which is responsible for AEA metabolism.

    Neural inflammation has a role to play in epilepsy. In combatting this, CBD may well have a role to play, such as through its known mobilization of arachidonic acid and mediating its metabolite synthesis, reduction of nitrous oxide, and modulating anti-inflammatory cytokines. CBD is also an anti-oxidant, in which gene transcription modulation through the peroxisome proliferator-activator receptor γ (PPARγ) might play a role. Finally, CBD influences neutrophil chemotaxis and interacts with microglia, that express CB2 receptors, and endocannabinoids, where it may exert an anti-inflammatory effect.

    The approved CBD pharmaceutical preparation contains 100 mg/mL in sesame seed oil with sucralose and fruit flavoring. It is lipophilic, absorbs slowly, and in pharmacokinetics needs to distribute extensively into tissues. It has a 94% plasma protein binding rate. It reaches peak concentration in about 3 hours, and achieves steady state after 2 days. Bioavailability, estimated at ~6%, may be a function of solubility-related decrease in absorption rate, and poor gastrointestinal absorption generally. High-fat meals, unsurprisingly, dramatically increase exposure to CBD. The importance of feeding status has suggested that delivery mode, such as by soft gelatin capsules versus liquid preparations, may matter greatly. CBD is extensively metabolized in the liver, chiefly by cytochrome P450 3A4 and 2C19, and there is warrant for considering dose adjustment in patients with hepatic dysfunction. In pediatric population studies, there has been wide inter-individual variability in exposure parameters of CBD, though always dose-dependent. Infants appear to have reliably lower CBD concentrations versus children and adolescents, regardless of dose.

    There are known reactions between CBD and other anti-convulsant medications, notably Clobazam. Clobazam is metabolized by CYP3A4 and CYP2C19 intoN-desmethylclobazam (norclobazam, nCLB), and further converted by CYP2C19 into inactive metabolites. The introduction of CBD has been associated with an increase of Clobazam levels. Preclinical findings suggest the possibility of a pharmacodynamic (and pharmacokinetic) interaction through positive allosteric modulation of GABAA receptors. Synergy between CBD and Clobazam has not been demonstrated.

    In human studies, CBD has not been shown to change serum concentrations of valproate, but does seem to raise exposure parameters of stiripentol, probably by inhibition of CYP2C19. Stirpentol may also prevent CBD-mediated increase in nCLB levels, by ameliorating its effect on CYP2C19. This same dynamic appears possibly to function with topiramate and rufinamide, and eslicarbazepine and zonisamide. One small study, finally, suggests that the introduction of CBD can associate with a 95–280% increase in brivaracetam plasma levels, though the mechanisms that would underlie this are not known.

    Efficacy trials of CBD in epilepsy have been numerous, but have frequently been flawed methodologically. Final approval and licensing in Dravet syndrome was achieved when studies showed, among other endpoints, a median change in convulsive seizure frequency of −38.9% (from a median of 12.4 seizures/month at baseline to 5.9) compared with −13.3% (from 14.9 to 14.1) in the placebo group, resulting in the adjusted median difference of −22.8% (p=0.01). Total seizures per month decreased by 28.6% in patients on CBD versus 9% in those receiving placebo, with an adjusted median difference of around 19% (p=0.03). The responder rate did not support the superiority of the active drug over placebo, nor did the reduction in nonconvulsive seizures alone, but the positive general effect of CBD treatment was confirmed by changes in the CGIC wellness scale, showing an improvement in 62% of children receiving active treatment versus 34% of those taking placebo (p=0.02). Subsequent studies have buttressed this global conclusion. In Lennox-Gastaut syndrome, results of numerous trials have been analogous, supporting CBD effectiveness in treating all seizure types. The clinical benefit appears to persist over time. Open-label trials continue, and suggest so far that seizure frequency and severity appears independent of concomitant treatments. Trials in other forms of epilepsy, in which CBD may qualify as an orphan drug by the FDA and the EMA, for concomitant treatment, are forthcoming. 

    Tolerability studies do turn up adverse events. In a well publicized one 79% of patients reported side effects, the most common being somnolence (25%), decreased appetite (19%), diarrhea (19%), fatigue (13%) and convulsions (11%). Only 3% of patients withdrew CBD because of adverse events. Higher doses in other studies correspond with higher withdrawal rates. Transaminase level increase is the most common cause of AE-related withdrawal. This does not typically end in liver injury, and the effect appears transient. CBD does not appear to affect sleep quality, cognition or behavior, which was as expected. Open-label extension studies for long-term tolerability are still needed. Real-world studies on larger populations will help further.

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    The foregoing is a report on trends and developments in the cannabinoid industry. No product described herein is intended to diagnose, treat, cure or prevent any disease or syndrome.