Artisanal (non-pharmaceutical) cannabidiol (CBD) products have become popular in recent years for their apparent therapeutic effects. CBD — a naturally occurring compound of the cannabis plant legally derived from hemp — is used widely as a naturopathic remedy for a number of health conditions, including epilepsy and seizure disorders. Now, Johns Hopkins Medicine researchers, in collaboration with the Realm of Caring Foundation and other institutions, have conducted an observational study with participant-reported data to better understand the impact these products may have on people with epilepsy.
For their evaluation, the researchers analyzed data gathered between April 2016 and July 2020 from 418 participants — 230 women and 188 men — with 205 (49%) at least age 18 and 213 (51%) age 18 or younger. The participants included 71 adults with epilepsy who used artisanal CBD products for medicinal purposes and 209 who were caregivers of children or dependent adults to whom artisanal CBD products were given. The control group consisted of 29 adults with epilepsy who were considering the use of CBD products and 109 caregivers who were considering it for a dependent child or adult patient.
Epilepsy, one of the most common nervous system disorders affecting people of all ages, is a neurological condition characterized by recurrent seizures. Treatment for epilepsy includes anti-seizure medications and diet therapy, such as forms of the ketogenic diet. Surgery may be an alternative treatment, especially when medications or diet fail to control seizures, or if drug side effects — including dizziness, nausea, headache, fatigue, vertigo and blurred vision — are too difficult for a patient to tolerate.
The first studies of pure CBD in the treatment of drug-resistant epilepsy date back to the late 70s and the 80s and explored oral doses in the range of 200 to 300 mg/day.112–115 Despite the fact that all four studies included placebo as a control, only one trial was truly double-blind, the largest sample size was only 15 patients, critical details were lacking, and there were other methodological shortcomings.37 These trials were evaluated in a Cochrane review which included a systematic literature search up to September 2013, and the conclusion was reached that ‘no reliable conclusions can be drawn at present regarding the efficacy of cannabinoids as a treatment for epilepsy’.116 Similar conclusions were reached in a 2014 report of the Guideline Development Subcommittee of the American Academy of Neurology.117
Cannabinoids have numerous and complex pharmacological properties. In experimental models, for example, THC displays complex psychoactive effects, variable anticonvulsant effects, and analgesic, cognitive, muscle relaxant, anti-inflammatory, appetite stimulant, and antiemetic activity.9,12,22 On the other hand, CBD is mostly devoid of adverse psychoactive effects and possesses anticonvulsant, analgesic, anti-anxiety, antiemetic, immune-modulating, anti-inflammatory, neuroprotectant, and anti-tumorigenic properties.9,12,22 In the case of THC, anti-seizure activity seems to be mediated to an important extent by its partial agonist action on the CB1 receptor, which is also primarily involved in the expression of psychoactive effects.9,13,23 CBD, on the other hand, has very weak affinity for the CB1 and CB2 receptors and its anti-seizure activity at clinically relevant concentrations is considered to be mediated by other mechanisms,13,24,25 possibly including functional agonism or antagonism at multiple 7-transmembrane receptors, ion channels, and neurotransmitter transporters ( Table 1 ).24–35 In particular, an effect on adenosine reuptake and antagonism of G protein-coupled receptor 55 (GPR55) have been recently suggested to play an important role in CBD anti-seizure activity.36
The genus Cannabis refers to a flowering plant of which there are three main species, Cannabis sativa, Cannabis indica and Cannabis ruderalis. These plants contain over 100 biologically active chemicals called cannabinoids, with the most abundant and best characterized among those being THC and CBD ( Fig. 2 ).7 Crude preparations of cannabis include dried leaves, stems and flower pods (marijuana), resins (hashish), and oily extracts (hashish oil), all of which have been used through the centuries mostly for their psychoactive properties. In general, cannabis products derived from Cannabis sativa exhibit a higher CBD/THC ratio than products derived from Cannabis indica. Different Cannabis strains have been bred either to maximize THC content or, conversely, to reduce THC content and increase the concentration of CBD and other non-psychoactive ingredients.8
The history of human use of the Cannabis plant goes back to the dawn of mankind. The plant, which originated in Central Asia or in the foothills of the Himalayas, was initially cultivated in China for fiber and seed production, and in India for resin production.1 For many centuries, European and East Asian societies have used mostly Cannabis strains containing low amounts (< 1% dry weight) of the psychoactive principle 9-Δ-tetrahydrocannabidiol (THC), and their main utilization was for fiber and food. Conversely, African, Middle-Eastern, South Asian, and Southeast Asian societies have used cannabis primarily for its psychoactive properties, with strains from these regions often containing 5–10% THC.1
Overall the results of these trials demonstrate that at dosages of 10 to 20 mg/kg/day CBD is superior to placebo in reducing the frequency of drop seizures in patients with Lennox-Gastaut syndrome. Published reports, however, provide no information on concomitant therapies, and most notably whether, and to what extent, the clinical improvement on CBD therapy could be related to elevation in serum concentrations of other medications, most notably clobazam and N-desmethylclobazam.
The pharmacokinetics of CBDV have not been reported in detail. In a recently completed Phase I study, healthy subjects were given single oral doses ranging between 25 and 800 mg, as well as multiple doses of 800 mg once daily over 5 days.36 Peak plasma concentrations and areas under the plasma concentration-time curve were found to be dose proportional. The 7-hydroxy- and 6-hydroxy-metabolites could be detected shortly after dosing.
Adverse events deemed to be related to the study treatment were reported in 75% of patients in the CBD group and 36% of those in the placebo group. Somnolence, diarrhea, and decreased appetite were the most common CBD-associated adverse events ( Table 2 ). Eighteen of the 22 CBD-treated patients who developed somnolence were on clobazam comedication. Adverse events appeared mostly during the first two weeks of therapy, and there were instances in which the dose of CBD or other medications were reduced. No information, however, was reported on how often the dose of concomitant clobazam was reduced. Eight patients in the CBD group discontinued the trial prematurely due to adverse events (in three cases, marked elevation of liver enzymes), compared with one patient in the placebo group who also had a marked elevation in liver enzymes. Overall, elevated aminotransferases levels occurred in 12 patients in the CBD group and one in the placebo group, all of whom were on concomitant valproate therapy. In the nine patients with raised aminotransferases who did not discontinued treatment, liver enzymes reverted to normal on continuation of therapy.
Structure of CBD.
Six randomized, double-blind, placebo-controlled studies were funded by GW Pharmaceuticals for evaluated the activity of the new formulation of purified CBD oral solution (GWP42003-P or Epidiolex), an epileptic medication and now Food and Drug Administration (FDA) approved for the treatment of seizures associated with DS and LGS in patients two years of age or older.
5. Cannabidiol: Clinical Trials for Epilepsy
A randomized controlled trial <"type":"clinical-trial","attrs":<"text":"NCT02565108","term_id":"NCT02565108">> NCT02565108 (phase 2) included twenty patients (aged 18 to 65 years) with diagnosed epilepsy treated with CLB. This study examined the possible drug-drug interactions between CLB and CBD. Participants before enrolment followed a stable therapy for at least a month with antiepileptic drugs, including CLB. Patients received CBD oral solution (GWP42003-P) at a dose of 20 mg/kg/day after taking CLB for 21 consecutive days. 75% of patients in the CBD group and 50% of patients in the placebo group showed non-serious AEs (diarrhea, nausea, vomiting, dizziness, somnolence, sedation, dermatitis). Results showed that all participants reduced the maintenance dose of CBD of 10%/day.