USE OF CANNABIDIOL IN THE TREATMENT OF SEIZURES ASSOCIATED WITH RARE EPILEPSY SYNDROMES RELATED TO BRAIN INJURY

Abstract

The present invention relates to the use of cannabidiol (CBD) for the treatment of seizures associated with rare epilepsy syndromes related to brain injury. In particular the seizures associated with rare epilepsy syndromes that are treated are those which are experienced in patients diagnosed with hypoxic ischaemic encephalopathy (HIE) or anoxia at birth. In a further embodiment the types of seizures include tonic, tonic-clonic, atonic, myoclonic, absence, focal seizures with impairment and spasms. Preferably the dose of CBD is between 5 mg/kg/day to 50 mg/kg/day.

Claims

1. A cannabidiol (CBD) preparation for use in the treatment of seizures associated with hypoxic ischaemic encephalopathy (HIE) or anoxia at birth wherein the CBD preparation comprises greater than 95% (w/w) CBD and between 0.01 and 0.15% (w/w) tetrahydrocannabinol (THC).

2. A CBD preparation for use according to claim 1, wherein the seizures associated with hypoxic ischaemic encephalopathy (HIE) or anoxia at birth are tonic, tonic-clonic, atonic, myoclonic, absence, focal seizures with impairment and spasms.

3. A CBD preparation for use according to any of the preceding claims, wherein the CBD preparation comprises greater than or equal to 98% (w/w) CBD and less than or equal to 2% (w/w) other cannabinoids, wherein the less than or equal to 2% (w/w) other cannabinoids comprise the cannabinoids tetrahydrocannabinol (THC); cannabidiol-C1 (CBD-C1); cannabidivarin (CBDV); and cannabidiol-C4 (CBD-C4), and wherein the THC is present as a mixture of trans-THC and cis-THC.

4. A CBD preparation to any of the preceding claims, wherein the CBD preparation is used in combination with one or more concomitant anti-epileptic drugs (AED).

5. A CBD preparation for use according to claim 5, wherein the one or more AED is selected from the group consisting of: valproic acid, levetiracetam, clobazam, vigabatrin, rufinamide, topiramate, lamotrigine and gabapentin.

6. A CBD preparation for use according to any of the preceding claims, wherein the CBD is present is isolated from cannabis plant material.

7. A CBD preparation for use according to any of the preceding claims, wherein at least a portion of at least one of the cannabinoids present in the CBD preparation is isolated from cannabis plant material.

8. A CBD preparation for use according to claims 1 to 6, wherein the CBD is present as a synthetic preparation.

9. A CBD preparation for use according to claim 9, wherein at least a portion of at least one of the cannabinoids present in the CBD preparation is prepared synthetically.

10. A CBD preparation for use according to any of the preceding claims, wherein the dose of CBD is greater than 5 mg/kg/day.

11. A CBD preparation for use according to any of the preceding claims, wherein the dose of CBD is 20 mg/kg/day.

12. A CBD preparation for use according to any of the preceding claims, wherein the dose of CBD is 25 mg/kg/day.

13. A CBD preparation for use according to any of the preceding claims, wherein the dose of CBD is 50 mg/kg/day.

14. A method of treating seizures associated with hypoxic ischaemic encephalopathy (HIE) or anoxia at birth comprising administering a cannabidiol (CBD) preparation to the subject in need thereof.

Description

DETAILED DESCRIPTION

Preparation of Highly Purified Cbd Extract

[0059] The following describes the production of the highly-purified (>95% w/w) cannabidiol extract which has a known and constant composition.

[0060] In summary the drug substance used is a liquid carbon dioxide extract of high-CBD containing chemotypes of Cannabis sativa L. which had been further purified by a solvent crystallization method to yield CBD. The crystallisation process specifically removes other cannabinoids and plant components to yield greater than or equal to 95% CBD. Although the CBD is highly purified because it is produced from a cannabis plant rather than synthetically there is a small number of other cannabinoids which are co-produced and co-extracted with the CBD. Details of these cannabinoids and the quantities in which they are present in the medication are as described in Table A below.

TABLE-US-00001 Composition of highly purified CBD extract Cannabinoid Concentration CBD > 95% w/w CBDA NMT 0.15% w/w CBDV NMT 1.0% w/w Δ.sup.9 THC NMT 0.15% w/w CBD-C4 NMT 0.5% w/w > - greater than NMT - not more than

Preparation of Botanically Derived Purified Cbd

[0061] The following describes the production of the botanically derived purified CBD which comprises greater than or equal to 98% w/w CBD and less than or equal to other cannabinoids was used in the open label, expanded-access program described in Example 1 below.

[0062] In summary the drug substance used in the trials is a liquid carbon dioxide extract of high-CBD containing chemotypes of Cannabis sativa L. which had been further purified by a solvent crystallization method to yield CBD. The crystallisation process specifically removes other cannabinoids and plant components to yield greater than 95% CBD w/w, typically greater than 98% w/w.

[0063] The Cannabis sativa L. plants are grown, harvested, and processed to produce a botanical extract (intermediate) and then purified by crystallization to yield the CBD (botanically derived purified CBD).

[0064] The plant starting material is referred to as Botanical Raw Material (BRM); the botanical extract is the intermediate; and the active pharmaceutical ingredient (API) is CBD, the drug substance.

[0065] All parts of the process are controlled by specifications. The botanical raw material specification is described in Table B and the CBD API is described in Table C.

TABLE-US-00002 CBD botanical raw material specification Test Method Specification Identification: -A Visual Complies -B TLC Corresponds to standard (for CBD & CBDA) -C HPLC/UV Positive for CBDA Assay: In-house NLT 90% of assayed CBDA + CBD (HPLC/UV) cannabinoids by peak area Loss on Drying Ph.Eur. NMT 15% Aflatoxin UKAS method NMT 4 ppb Microbial: Ph.Eur. NMT10.sup.7 cfu/g - TVC NMT10.sup.5 cfu/g - Fungi - E.coli NMT10.sup.2 cfu/g Foreign Matter: Ph.Eur. NMT 2% Residual Herbicides and Pesticides Ph.Eur. Complies

TABLE-US-00003 Specification of an exemplary botanically derived purified CBD preparation Test Test Method Limits Appearance Visual Off-white / pale yellow crystals Identification A HPLC-UV Retention time of major peak corresponds to certified CBD Reference Standard Identification B GC-FID/MS Retention time and mass spectrum of major peak corresponds to certified CBD Reference Standard Identification C FT-IR Conforms to reference spectrum for certified CBD Reference Standard Identification D Melting Point 65 - 67° C. Identification E Specific Optical Rotation Conforms with certified CBD Reference Standard; -110° to -140° (in 95% ethanol) Total Purity Calculation ≥ 98.0% Chromatographic Purity 1 HPLC-UV ≥ 98.0% Chromatographic Purity 2 GC-FID/MS ≥ 98.0 % CBDA NMT 0.15% w/w CBDV 0.2-1.0% w/w THC HPLC-UV 0.01-0.1 % w/w CBD-C4 0.3-0.5% w/w Residual Solvents: Alkane GC NMT 0.5% w/w Ethanol NMT 0.5% w/w Residual Water Karl Fischer NMT 1.0% w/w

[0066] The purity of the botanically derived purified CBD preparation was greater than or equal to 98%. The botanically derived purified CBD includes THC and other cannabinoids, e.g., CBDA, CBDV, CBD-C1, and CBD-C4.

[0067] In some embodiments, the CBD preparation comprises not more than 0.15% THC based on total amount of cannabinoid in the preparation. In some embodiments, the CBD preparation comprises about 0.01% to about 0.1% THC based on total amount of cannabinoid in the preparation. In some embodiments, the CBD preparation comprises about 0.02% to about 0.05% THC based on total amount of cannabinoid in the preparation.

[0068] In some embodiments, the CBD preparation comprises about 0.2% to about 1.0% CBDV based on total amount of cannabinoid in the preparation. In some embodiments, the CBD preparation comprises about 0.2% to about 0.8% CBDV based on total amount of cannabinoid in the preparation.

[0069] In some embodiments, the CBD preparation comprises about 0.3% to about 0.5% CBD-C4 based on total amount of cannabinoid in the preparation. In some embodiments, the CBD preparation comprises about 0.3% to about 0.4% CBD-C4 based on total amount of cannabinoid in the preparation.

[0070] In some embodiments, the CBD preparation comprises about 0.1% to about 0.15% CBD-C1 based on total amount of cannabinoid in the preparation.

[0071] Distinct chemotypes of the Cannabis sativa L. plant have been produced to maximize the output of the specific chemical constituents, the cannabinoids. Certain chemovars produce predominantly CBD. Only the (-)-trans isomer of CBD is believed to occur naturally. During purification, the stereochemistry of CBD is not affected.

Production of CBD Botanical Drug Substance

[0072] An overview of the steps to produce a botanical extract, the intermediate, are as follows: [0073] a) Growing [0074] b) Direct drying [0075] c) Decarboxylation [0076] d) Extraction - using liquid CO.sub.2 [0077] e) Winterization using ethanol [0078] f) Filtration [0079] g) Evaporation

[0080] High CBD chemovars were grown, harvested, dried, baled and stored in a dry room until required. The botanical raw material (BRM) was finely chopped using an Apex mill fitted with a 1 mm screen. The milled BRM was stored in a freezer prior to extraction.

[0081] Decarboxylation of CBDA to CBD was carried out using heat. BRM was decarboxylated at 115° C. for 60 minutes.

[0082] Extraction was performed using liquid CO.sub.2 to produce botanical drug substance (BDS), which was then crystalized to produce the test material. The crude CBD BDS was winterized to refine the extract under standard conditions (2 volumes of ethanol at -20° C. for approximately 50 hours). The precipitated waxes were removed by filtration and the solvent was removed to yield the BDS.

Production of Botanically Derived Purified CBD Preparation

[0083] The manufacturing steps to produce the botanically derived purified CBD preparation from BDS were as follows: [0084] a) Crystallization using C.sub.5-C.sub.12 straight chain or branched alkane [0085] b) Filtration [0086] c) Vacuum drying

[0087] The BDS produced using the methodology above was dispersed in C.sub.5-C.sub.12 straight chain or branched alkane. The mixture was manually agitated to break up any lumps and the sealed container then placed in a freezer for approximately 48 hours. The crystals were isolated via vacuum filtration, washed with aliquots of cold C.sub.5-C.sub.12 straight chain or branched alkane, and dried under a vacuum of <10 mb at a temperature of 60° C. until dry. The botanically derived purified CBD preparation was stored in a freezer at -20° C. in a pharmaceutical grade stainless steel container, with FDA food grade approved silicone seal and clamps.

Physicochemical Properties of the Botanically Derived Purified CBD

[0088] The botanically derived purified CBD used in the clinical trial described in the invention comprises greater than or equal to 98% (w/w) CBD and less than or equal to 2% (w/w) of other cannabinoids. The other cannabinoids present are THC at a concentration of less than or equal to 0.1% (w/w); CBD-C1 at a concentration of less than or equal to 0.15% (w/w); CBDV at a concentration of less than or equal to 0.8% (w/w); and CBD-C4 at a concentration of less than or equal to 0.4% (w/w).

[0089] The botanically derived purified CBD used additionally comprises a mixture of both trans-THC and cis-THC. It was found that the ratio of the trans-THC to cis-THC is altered and can be controlled by the processing and purification process, ranging from 3.3:1 (trans-THC:cis-THC) in its unrefined decarboxylated state to 0.8:1 (trans-THC:cis-THC) when highly purified.

[0090] Furthermore, the cis-THC found in botanically derived purified CBD is present as a mixture of both the (+)-cis-THC and the (-)-cis-THC isoforms.

[0091] Clearly a CBD preparation could be produced synthetically by producing a composition with duplicate components.

[0092] Example 1 below describes the use of a botanically derived purified CBD in an open label, expanded-access program to investigate the clinical efficacy and safety of purified pharmaceutical cannabidiol formulation (CBD) in the treatment of patients diagnosed with hypoxic ischaemic encephalopathy (HIE) or anoxia at birth.

EXAMPLE 1: CLINICAL EFFICACY AND SAFETY OF PURIFIED PHARMACEUTICAL CANNABIDIOL (CBD) IN THE TREATMENT OF PATIENTS DIAGNOSED WITH HYPOXIC ISCHAEMIC ENCEPHALOPATHY (HIE) OR ANOXIA AT BIRTH

Study Design

[0093] Subjects were required to be on one or more AEDs at stable doses for a minimum of two weeks prior to baseline and to have stable vagus nerve stimulation (VNS) settings and ketogenic diet ratios for a minimum of four weeks prior to baseline.

[0094] Patients were administered botanically derived purified CBD in a 100 mg/mL sesame oilbased solution most patients were took an initial dose of five milligrams per kilogram per day (mg/kg/day) in two divided doses. Dose was then increased weekly by 5 mg/kg/day to a goal of 20 to 25 mg/kg/day.

[0095] A maximum dose of 50 mg/kg/day could be utilised for patients who were tolerating the medication but had not achieved seizure control; these patients had further weekly titration by 5 mg/kg/day.

[0096] There were ten patients in this study, and each received CBD for various durations of time. Modifications were made to concomitant AEDs as per clinical indication.

[0097] Seizure frequency, intensity, and duration were recorded by caregivers in a diary during a baseline period of at least 28 days. Changes in seizure frequency relative to baseline were calculated after at least 2 weeks and at defined timepoints of treatment.

Statistical Methods

[0098] Patients may be defined as responders if they had more than 50% reduction in seizure frequency compared to baseline. The percent change in seizure frequency was calculated as follows:

[00001]$\begin{array}{l}\%\text{change}\text{seizure}\text{frequencey}\\ =\frac{\left(\text{weekly}\text{seizure}\text{frequency}timeinterval\right)-\left(\text{weekly}\text{seizure}\text{frequency}Baseline\right)}{\left(\text{weekly}\text{seizure}\text{frequency}Baseline\right)}\end{array}$

[0099] The percent change of seizure frequency may be calculated for any time interval where seizure number has been recorded. For the purpose of this example the percent change of seizure frequency for the end of the treatment period was calculated as follows:

[00002]$\begin{array}{l}\%\text{reduction}\text{seizure}\text{frequency}=\\ \frac{\left(\left(\text{weekly}\text{seizure}\text{frequency}Baseline\right)\text{-}\left(\text{weekly}\text{seizure}\text{frequency}End\right)\right)}{\left(\text{weekly}\text{seizure}\text{frequency}Baseline\right)}\times 100\end{array}$

RESULTS

Patient Description

[0100] The ten patients enrolled in the open label; expanded-access program were diagnosed with hypoxic ischaemic encephalopathy (HIE) or anoxia at birth. These patients experienced a range of different seizure types including tonic, tonic-clonic, atonic, myoclonic, absence, focal seizures without impairment, focal seizures with impairment, focal seizures with secondary generalisation, and spasms.

[0101] The age of patients ranged from 2-14 years, five were male and five were female as detailed in Table 1 below.

TABLE-US-00004 Patient demographics, seizure type and concomitant medication Patient Number Age (years) Sex Seizure types Concomitant AEDs 1 2.65 F Tonic Spasms VPA, LTG 2 3.09 F Absence Spasms CLB VGB, GBP 3 6.02 M Tonic Tonic-clonic Focal with impairment CLB, RFN 4 7.66 M Tonic Tonic-clonic Atonic CLB 5 8.1 M Focal without impairment Focal with secondary generalisation LEV 6 6.57 M Tonic-clonic Spasms CLB, LEV, TPM 7 14.0 F Tonic-clonic Myoclonic Focal with impairment CLB, LTG 8 8.98 F Absence CLB, VPA, LTG 9 7.19 M Tonic Myoclonic CLB, RFN 10 9.66 F Absence CLB VPA = valporic acid, LEV = levetiracetam, CLB = clobazam, VGB = vigabatrin, RFN = rufinamide, TPM = topiramate, LTG = lamotrigine, GBP = gabapentin

Study Medication and Concomitant Medications

[0102] Patients on the study were titrated up to various doses of CBD, eight patients were titrated up to at least 25 mg/kg/day (#1-3,5, 7-10), and one patients was titrated up to 50 mg/kg/day (#3).

[0103] Patients had tried an average of two AEDs prior to enrolment (range: 1-3 AEDs). Eight patients were taking clobazam (CLB).

Clinical Changes

[0104] Tables 2A-2J illustrate the seizure frequency for each patient as well as the dose of CBD given.

TABLE-US-00005 Seizure frequency data for Patient 1 Patient 1 Time Seizure Type Dose CBD (mg/kg/day) Tonic Spasm Baseline 1057.0 124.0 - 2 weeks 1044.0 108.0 8.3 4 weeks 904.0 102.8 20.8 8 weeks 770.0 50.8 25.2 16 weeks 764.8 78.0 23.4 24 weeks 917.2 48.0 22.9 36 weeks 634.0 51.2 25.7 48 weeks 424.8 69.2 21.8

[0105] Patient 1 was treated for 48 weeks and experienced a 59.8% reduction in tonic seizures and a 44.2% reduction in spasms over the treatment period.

TABLE-US-00006 Seizure frequency data for Patient 2 Patient 2 Time Seizure Type Dose CBD (mg/kg/day) Absence Spasm Baseline 64.0 580.0 - 4 weeks 52.0 440.0 20.0 8 weeks 52.0 600.0 25.0 16 weeks 12.0 632.0 25.0 24 weeks 24.0 580.0 25.0 36 weeks 0 560.0 25.0 48 weeks 0 490.0 25.0 60 weeks 0 196.0 25.0 72 weeks 0 300.0 25.0 84 weeks 0 340.0 25.0

[0106] Patient 2 was treated for 84 weeks and experienced a 100% reduction in absence seizures and a 41.4% reduction in spasms over the treatment period.

TABLE-US-00007 Seizure frequency data for Patient 3 Patient 3 Time Seizure Type Dose CBD (mg/kg/day) Tonic Tonic-clonic Focal with impairment Baseline 0.0 12.0 313.0 - 4 weeks 193.0 2.0 43.0 5.0 8 weeks 132.0 0 132.0 20.0 12 weeks 123.0 0 38.0 25.0 16 weeks 120.0 6.0 46.0 25.0 24 weeks 122.0 4.8 51.2 30.0 36 weeks 124.8 20.0 115.0 40.0 48 weeks 136.0 11.2 38.8 50.0 72 weeks 94.7 4.0 53.0 50.0 84 weeks 72.0 5.7 53.0 50.0 96 weeks 70.0 11.6 46.3 50.0 108 weeks 35.0 10.4 46.4 50.0 120 weeks 46.8 9.8 62.8 50.0 132 weeks 54.4 12.0 77.2 50.0 144 weeks 62.4 21.2 72.0 50.0

[0107] Patient 3 was treated for 144 weeks and experienced a 77% reduction in focal seizures with impairment over the treatment period.

TABLE-US-00008 Seizure frequency data for Patient 4 Patient 4 Time Seizure Type Dose CBD (mg/kg/day) Tonic Tonic-clonic Atonic Baseline 150.0 150.0 2.0 - 4 weeks 4.0 13.0 0 5.0 8 weeks 3.0 18.0 0 5.0 12 weeks 0 10.0 0 10.0 24 weeks 0 0.6 6.0 15.0 36 weeks 0 0 1.7 15.0 48 weeks 0 3.3 0 15.0 60 weeks 0 19.3 4.0 20.0

[0108] Patient 4 was treated for 60 weeks and experienced a 100% reduction in tonic seizures and an 87.1% reduction in tonic-clonic seizures over the treatment period.

TABLE-US-00009 Seizure frequency data for Patient 5 Patient 5 Time Seizure Type Dose CBD (mg/kg/day) Focal without impairment Focal secondary generalisation Baseline 1.0 104.0 - 2 weeks 0 114.0 10.0 4 weeks 2.0 106.0 20.0 8 weeks 1.9 112.8 25.0 12 weeks 2.1 111.0 25.0 16 weeks 3.9 125.5 25.0

[0109] Patient 5 was treated for 16 weeks and did not experience a reduction in seizures over the treatment period.

TABLE-US-00010 Seizure frequency data for Patient 6 Patient 6 Time Seizure Type Dose CBD (mg/kg/day) Tonic-clonic Spasm Baseline 14.0 217.0 - 2 weeks 10.0 100.0 10.0

[0110] Patient 6 was treated for 2 weeks and experienced a 28.6% reduction in tonic-clonic seizures and an 53.9% reduction in spasms over the treatment period.

TABLE-US-00011 Seizure frequency data for Patient 7 Patient 7 Time Seizure Type Dose CBD (mg/kg/day) Tonic-clonic Myoclonic Focal with impairment Baseline 42.0 10.0 43.2 - 2 weeks 74.0 58.0 70.0 5.0 4 weeks 102.0 18.0 78.0 10.0 8 weeks 86.7 65.3 65.3 20.0 12 weeks 65.0 7.0 71.0 25.0

[0111] Patient 7 was treated for 12 weeks and experienced a 30% reduction in myoclonic seizures over the treatment period.

TABLE-US-00012 Seizure frequency data for Patient 8 Patient 8 Time Seizure Type Dose CBD (mg/kg/day) Absence Baseline 7560.0 - 4 weeks 5376.0 5.0 8 weeks 4803.0 5.0 12 weeks 3514.0 10.0 24 weeks 4284.0 15.0 36 weeks 2989.3 20.0 48 weeks 3360.0 25.0 60 weeks 3136.0 25.0 72 weeks 2968.0 25.0 84 weeks 2718.0 25.0

[0112] Patient 8 was treated for 84 weeks and experienced a 64% reduction in absence seizures over the treatment period.

TABLE-US-00013 Seizure frequency data for Patient 9 Patient 9 Time Seizure Type Dose CBD (mg/kg/day) Tonic Myoclonic Baseline 93.0 1.0 - 2 weeks 118.0 2.0 15.0 4 weeks 88.0 1.0 20.0 8 weeks 48.0 0 25.0 12 weeks 92.0 0 25.0 16 weeks 90.0 0 25.0 24 weeks 142.4 0 25.0 36 weeks 53.0 0 25.0 48 weeks 98.0 0 25.0 60 weeks 95.6 0 25.0 72 weeks 96.0 0 25.0 84 weeks 99.2 0 25.0 108 weeks 69.0 0 25.0 132 weeks 76.8 0 25.0 144 weeks 79.6 0 25.0

[0113] Patient 9 was treated for 144 weeks and experienced a 14.4% reduction in tonic seizures and a 100% reduction in myoclonic seizures over the treatment period.

TABLE-US-00014 Seizure frequency data for Patient 10 Patient 10 Time Seizure Type Dose CBD (mg/kg/day) Absence Baseline 3000.0 - 4 weeks 10.0 5.0 8 weeks 1435.0 5.0 12 weeks 610.0 10.0 24 weeks 304.0 15.0 36 weeks 2184.6 20.0 48 weeks 1957.3 25.0 60 weeks 1520.3 25.0 72 weeks 1655.6 25.0 84 weeks 1626.6 25.0 96 weeks 1678.3 25.0 120 weeks 1644.5 25.0 132 weeks 1370.8 25.0

[0114] Patient 10 was treated for 132 weeks and experienced a 54.3% reduction in absence seizures over the treatment period.

[0115] Overall, patients reported reductions of 14.4-100.0% in seizures over period of treatment with CBD.

[0116] CBD was effective in reducing the frequency of the following seizure types: tonic, tonic-clonic, atonic, myoclonic, absence, focal seizures with impairment and spasms.

[0117] Significantly, two patients became seizure free of tonic seizures after 36 weeks and 12 weeks (patients #2 and 4 respectively) of CBD treatment.

CONCLUSIONS

[0118] These data indicate that CBD was able to significantly reduce the number of seizures associated with hypoxic ischaemic encephalopathy (HIE) or anoxia at birth. Clearly the treatment is of significant benefit in this difficult to treat epilepsy syndrome given the high responder rate experienced in many of the patients.

[0119] Of interest is that patients with tonic seizures (patients 2 and 4) who obtained significant benefit whereby both were completely seizure free between 12 and 36 weeks of treatment.

[0120] In conclusion, this study signifies the use of CBD for treatment of seizures associated with hypoxic ischaemic encephalopathy (HIE) or anoxia at birth. Seizure types include tonic, tonic-clonic, atonic, myoclonic, absence, focal seizures with impairment and spasms for which seizure frequency rates decreased by significant rates, by 14.4-100.0%.

REFERENCES

[0121] 1. Lafuente et al. (2016) “Effects of Cannabidiol and Hypothermia on Short-Term Brain Damage in New-Born Piglets after Acute Hypoxia-Ischemia” Frontier in Neuroscience. [0122] 2. https://www.abclawcenters.com/blog/2019/07/12/clinical-trial-of-cannabidiol-cbd-in-newborns-with-hypoxic-ischemic-encephalopathy/#.~:text=Research%20has%20shown%20that%20cannabidiol,and%20reduce %20glutamate%2Drelated%20excitotoxicity.&text=Despite%20this%20challenge%2C%20resea rch%20on,approved%20for%20a%20clinical%20trial. [0123] 3. Morales et al. (2017) “Use of cannabidiol (RSHO) in the treatment of refractory epilepsy (Lennox-Gastaut Syndrome), experience of 38 cases.” Epilepsia; 58, Supplement 5, Special Issue, abstract S53 (p0222) [0124] 4. Zollner et al. (2019) “Improving post-hypoxic myclonus using cannabidiol.” Seizure, (2019), 67, 38-39 [0125] 5. Alvarez et al. (2008) “Neuroprotective Effects of the Nonpsychoactive Cannabinoid Cannabidiol in Hypoxic-Ischemic Newborn Piglets.” Pediatric Research, 2008, 64(6), 653-658