Treatment of epileptic seizure disorders

Abstract

Methods of treating a GTC epileptic seizure by administering a THC compound are provided, comprising treatment by administering to a patient a therapeutically effective dose of delta-9-tetrahydrocannabinol, including drocannabinol, and wherein the dose is at a level that produces minimal or no adverse mental effect in the patient. Furthermore, embodiments of methods of treatment are disclosed that include administering another antiepileptic drug in combination with a THC compound, delta-9-tetrahydrocannabinol, or drocannabinol dose.

Description

[0001] This application claims the benefit of priority to U.S. Provisional Application No. 63 / 330,269, filed on April 12, 2022: the entire contents of which are incorporated herein by reference. Background of the Invention

[0003] Epilepsy is a disorder of the central nervous system in which normal brain activity becomes disrupted, resulting in seizures, which can range from unnoticeable and very short-lived to violent and / or prolonged body movements accompanied by loss of consciousness.

[0004] Seizures are often divided into focal and generalized seizures. Focal seizures affect only one part of the brain and may occur with or without loss of consciousness and may also cause involuntary movements of a part of the body.

[0005] Generalized seizures involve both sides of the brain, causing complete loss of consciousness lasting varying periods of time and often accompanied by involuntary movements of the body. Generalized tonic-clonic seizures are associated with involuntary jerking movements along with loss of consciousness and potentially life-threatening consequences.

[0006] Generalized tonic-clonic (GTC) seizures are associated with a significantly higher risk of unexpected death, estimated to be almost 10 times higher in individuals with poorly controlled GTC seizures than in seizure-free epilepsy patients.

[0007] GTC seizures (also called convulsive seizures) occur in many different types of epilepsy, including genetically determined disorders (such as Dravet syndrome) and structural abnormalities (such as post-traumatic epilepsy in individuals who have suffered mechanical brain injury). Despite the availability of a large number of different anti-epileptic drugs, complete control of convulsive seizures has proven difficult, with approximately 30% of patients experiencing persistent seizures, despite taking multiple drugs in many cases.

[0008] As noted above, the persistence of GTC seizures increases the risk of sudden death in this patient population, and multiple studies have shown that reducing the frequency of GTC seizures in these individuals can reduce this risk.

[0009] Brief description

[0010] The present disclosure is directed to several embodiments for treating epileptic seizures in GTCs.

[0011] In certain embodiments, the disclosure relates to methods of treating generalized tonic-clonic seizures (GTCs) in a patient in need thereof, comprising administering to the patient a therapeutically effective dose of a THC compound.

[0012] In certain embodiments, the method further comprises administering another anti-epileptic drug in combination with the THC compound.

[0013] In certain embodiments, the disclosure relates to methods of treating generalized tonic-clonic seizures (GTCs) in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of dronabinol.

[0014] In certain embodiments, the method further comprises administering another anti-epileptic drug in combination with dronabinol.

[0015] In certain embodiments, the disclosure relates to methods of treating generalized tonic-clonic seizures (GTCs) in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of delta-9-tetrahydrocannabinol.

[0016] In certain embodiments, the method further comprises administering another anti-epileptic drug in combination with the delta-9-tetrahydrocannabinol.

[0017] Description of the accompanying drawings: Figure 1

[0018] Figure 1 The effects on seizure scores and percentage of seizures when dronabinol was administered 30 minutes prior to the seizure test as discussed in Example 1 are shown.

[0019] Detailed Description

[0020] The following detailed description and examples illustrate certain embodiments of the present disclosure. Those skilled in the art will recognize that many variations and modifications of the present disclosure are encompassed within its scope. Therefore, the description of certain embodiments should not be considered to limit the scope of the present disclosure.

[0021] In order that the present disclosure may be more readily understood, certain terms are defined throughout the detailed description. Unless otherwise defined herein, all scientific and technical terms used in connection with the present disclosure have the same meaning as commonly understood by one of ordinary skill in the art.

[0022] All references cited in this article, including but not limited to published and unpublished applications, patents and literature references, are incorporated herein by reference in their entirety and are hereby formed as part of this specification. If the cited reference conflicts with the disclosure herein, the specification shall prevail.

[0023] As used herein, the singular form of a word also includes the plural form, unless the context clearly indicates otherwise; for example, the terms "a", "an", and "the" should be understood as singular or plural. As an example, "an element" refers to one or more elements. The term "or" should mean "and / or", unless the specific context indicates otherwise.

[0024] As used herein, ranges include both endpoints and all values ​​between those endpoints.

[0025] "Administered" or "administering" means any suitable route of delivering THC. Such delivery routes include, for example, oral delivery, inhalation or aerosol delivery, dermal delivery, and injection delivery. Oral delivery includes, for example, liquid preparations, capsules, tablets, and other ingestible edible forms (e.g., candy, chewing gum, lozenges). Aerosol delivery includes, for example, nasal sprays, inhalation aerosols, and vaping or smoking. Injection delivery includes, for example, intraperitoneal, intravenous, intramuscular, intradermal, or subcutaneous routes. The formulation may also be administered by a transmucosal route.

[0026] "In combination with" means administering one therapy in addition to another therapy. Thus, "in combination with" includes simultaneous (e.g., concurrent) administration and consecutive administration in any order.

[0027] "Subject" or "patient" means a mammalian patient. In certain embodiments, the mammalian patient is a human.

[0028] "Therapeutically effective amount" means an amount of a compound or pharmaceutical composition sufficient to produce the desired therapeutic effect. For example, in certain embodiments, the desired therapeutic effect is preventing acute or chronic GTC epilepsy or reducing the frequency or incidence of acute or chronic GTC epilepsy, reducing the severity of acute or chronic GTC epilepsy, reducing the severity of post-ictal consequences of acute or chronic GTC epilepsy, and / or using the THC compound as a rescue medication for epileptic seizures.

[0029] "Treatment" or "treatment" means preventing acute or chronic GTC epileptic seizures or reducing the frequency or incidence of acute or chronic GTC epileptic seizures, reducing the severity of acute or chronic GTC epileptic seizures, reducing the severity of post-ictal consequences of acute or chronic GTC epileptic seizures, and / or using THC compounds as a seizure rescue medication.

[0030] "Generalized seizures" affect both sides of the brain, causing complete loss of consciousness lasting for varying periods of time and often accompanied by involuntary movements of the body. "Generalized tonic-clonic seizures" are associated with involuntary jerking movements along with loss of consciousness and potentially life-threatening consequences.

[0031] "THC compound" means delta-9-tetrahydrocannabinol (THC) and known structural and functional analogs, whether synthetic or plant-derived. "THC compound" also includes metabolites of THC and structural and functional analogs of THC. In certain embodiments, the THC compound is dronabinol, delta-9-tetrahydrocannabinol (THC), delta-8-tetrahydrocannabinol (THC), carboxytetrahydrocannabinol (THC-COOH), delta-9-tetrahydrocannabinolic acid (THC-A, A type and B type), delta-8-tetrahydrocannabinolic acid (THC-A, A type and B type), 11-OH-delta-9-tetrahydrocannabinol, 11-OH-delta-8-tetrahydrocannabinol, tetrahydrocannabivarin (THC-V), carboxytetrahydrocannabinol (THCV-COOH), HU-210, Perrottetinene or Perrottetinenic acid or any salt of any of these compounds.

[0032] Treatment of GTC

[0033] In certain embodiments, the disclosure relates to a method of treating generalized tonic-clonic seizures (GTC) in a patient in need thereof, comprising administering to the patient a therapeutically effective dose of a THC compound. In certain embodiments, the method comprises administering the THC compound as a seizure rescue medication. In certain embodiments, when administered as a seizure rescue medication, the THC compound is administered by a transmucosal route. In certain embodiments, when administered as a seizure rescue medication, the THC compound is administered by inhalation.

[0034] In certain embodiments, the present disclosure relates to a method for treating generalized tonic-clonic seizures (GTC) in a patient in need thereof, comprising administering a THC compound to the patient in combination with a therapeutically effective dose of another anti-epileptic drug. Certain exemplary anti-epileptic drugs include, for example, those listed in Table 3 on page 1273 of Kanner et al., "Antiseizure Medications for Adults with Epilepsy—A Review," JAMA, 327(13):1269-1281 (2022). Other exemplary anti-epileptic drugs include, for example, fenfluramine, cenobamate, and the anti-epileptic drugs listed in the Treatment Overview of Example 8 below.

[0035] In certain embodiments, the dosage of the THC compound is at a level that produces minimal or no adverse psychoactive effects in the patient. Certain adverse psychoactive effects include, for example, anxiety, a sense of disconnection, a sense of depersonalization, confusion, and / or paranoia.

[0036] In certain embodiments, the dosage of the THC compound is 2.5 to 150 mg per day, 2.5 to 70 mg per day, 2.5 to 50 mg per day, 5 to 70 mg per day, 2.5 to 50 mg per day, 2.5 to 5 mg per day, 2.5 to 25 mg per day, 2.5 to 12.5 mg per day, 5 to 50 mg per day, 5 to 25 mg per day, 5 to 12.5 mg per day, 2.5 to 20 mg per day, 5 to 20 mg per day, 12.5 to 20 mg per day, 12.5 to 25 mg per day, 12.5 to 50 mg per day, 12.5 to 70 mg per day. mg / kg daily, 0.02 to 4.0 mg / kg daily, 0.02 to 4.0 mg / kg daily, 0.2 to 5 mg / kg daily, 0.2 to 1 mg / kg daily, 0.2 to 4 mg / kg daily, 0.2 to 5 mg / kg daily, 0.2 to 10 mg / kg daily, 0.2 to 12.5 mg / kg daily, 0.2 to 20 mg / kg daily, 0.2 to 25 mg / kg daily, 0.112 to 0.56 mg / kg daily, 0.32 to 0.56 mg / kg daily, or 0.112 to 0.32 mg / kg daily.

[0037] In certain embodiments, the THC compound is contained in a formulation comprising the THC compound and less than 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, or 10% cannabidiol (CBD). In certain embodiments, the THC compound is contained in a formulation comprising the THC compound and not comprising CBD. An example of such a formulation comprising the THC compound and not comprising CBD is dronabinol. An example of administering dronabinol is disclosed in Example 1 below.

[0038] Exemplary embodiments

[0039] The present disclosure relates to several embodiments for treating epileptic seizures in GTC. For example, the present disclosure includes the following embodiments.

[0040] 1. A method for treating generalized tonic-clonic seizures (GTCs) in a patient in need thereof, comprising administering to said patient a therapeutically effective amount of a THC compound.

[0041] 2. The method of the embodiment of claim 1, further comprising administering another anti-epileptic drug in combination with the THC compound.

[0042] 3. A method of treating generalized tonic-clonic seizures (GTCs) in a patient in need thereof, comprising administering to said patient a therapeutically effective amount of dronabinol.

[0043] 4. The method of claim 3, further comprising administering another anti-epileptic drug in combination with dronabinol.

[0044] 5. A method for treating generalized tonic-clonic seizures (GTCs) in a patient in need thereof, comprising administering to said patient a therapeutically effective amount of delta-9-tetrahydrocannabinol.

[0045] 6. The method of embodiment 5, further comprising administering another anti-epileptic drug in combination with the delta-9-tetrahydrocannabinol.

[0046] 7. The method of any one of embodiments 1-6, wherein the dose is at a level that produces minimal or no adverse psychotropic effects in the patient.

[0047] 8. The method of any one of embodiments 1-7, wherein the method comprises administering the THC compound as a seizure rescue medication.

[0048] 9. The method of any one of embodiments 1-8, wherein the dosage is 2.5 to 150 mg per day; 2.5 to 70 mg per day; 2.5 to 50 mg per day; 5 to 70 mg per day; 2.5 to 50 mg per day; 2.5 to 5 mg per day; 2.5 to 25 mg per day; 2.5 to 12.5 mg per day; 5 to 50 mg per day; 5 to 25 mg per day; 5 to 12.5 mg per day; 2.5 to 20 mg per day; 5 to 20 mg per day; 12.5 to 20 mg per day; 12.5 to 25 mg per day; 12.5 to 50 mg per day; 12.5 to 70 mg per day; 0.02 to 4.0 mg / kg per day; 0.02 to 4.0 mg / kg per day; 0.112 to 0.56 mg / kg per day; 0.32 to 0.56 mg / kg per day; or 0.112 to 0.32 mg / kg per day.

[0049] 10. The method of any one of embodiments 1-2, 7-9, wherein the THC compound is dronabinol, delta-9-tetrahydrocannabinol (THC), delta-8-tetrahydrocannabinol (THC), carboxytetrahydrocannabinol (THC-COOH), delta-9-tetrahydrocannabinolic acid (THC-A, types A and B), delta-8-tetrahydrocannabinolic acid (THC-A, types A and B), 11-OH-delta-9-tetrahydrocannabinol, 11-OH-delta-8-tetrahydrocannabinol, cannabivarin (THC-V), carboxytetrahydrocannabinol (THC V-COOH), HU-210, Perrottetinene or Perrottetinenic acid, or any salt of any of these compounds.

[0050] 11. The method of any one of embodiments 2, 4, 6-10, wherein the other anti-epileptic drug is lamotrigine, topiramate, topiramate XR, vagus nerve stimulation, phenytoin, valproic acid, acid, zonisamide, benzodiazepine, surgery, levetiracetam, carbamazepine, oxcarbazepine, lacosamide, perampanel, clonazepam, phenobarbital, pregabalin, gabapentin, rufinamide, CBD (e.g., Epidiolex), clobazam, felbamate, fenfluramine, or phenbarate.

[0051] 12. The method of any one of embodiments 1-11, wherein the method further comprises performing vagus nerve stimulation seizure treatment or surgical seizure treatment on the patient.

[0052] 13. The method of any one of embodiments 1-12, wherein the THC compound, dronabinol or delta-9-tetrahydrocannabinol is delivered by oral delivery, inhalation or aerosol delivery, dermal delivery or injection delivery.

[0053] 14. The method of claim 13, wherein the oral delivery is provided via a liquid formulation, capsule, tablet, or another ingestible edible form (e.g., candy, chewing gum, lozenge).

[0054] 15. The method of claim 13, wherein the aerosol delivery is provided by nasal spray, inhalation aerosol, or vaping or smoking.

[0055] 16. The method of claim 13, wherein the injection delivery is provided by an intraperitoneal, intravenous, intramuscular, intradermal, or subcutaneous route.

[0056] 17. The method of any one of embodiments 1-16, wherein the THC compound dronabinol or delta-9-tetrahydrocannabinol is contained in a formulation comprising a THC compound and less than 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9% or 10% cannabidiol (CBD).

[0057] 18. The method of any one of embodiments 1-17, wherein the THC compound dronabinol or delta-9-tetrahydrocannabinol is contained in a formulation that contains the THC compound and does not contain CBD.

[0058] The following abbreviations in this disclosure have the following meanings.

[0059] BID: twice daily

[0060] TID: three times a day

[0061] HS: Before bed

[0062] CD-1 mice: A hybrid mouse strain derived from a group of hybrid Swiss mice developed by the Anti-Cancer Center in Lausanne, Switzerland

[0063] ECT Unit: Electroconvulsive Therapy for electroconvulsive threshold testing; the device is designed for neurochemical and neuropharmacological research.

[0064] SEM: Standard error of the mean

[0065] TDD: Total Daily Dose

[0066] Example 1

[0067] Studies in mice

[0068] This study evaluated the antiepileptic effects of low-dose dronabinol at four dose levels in the 6 Hz seizure (22 mA) test in mice. Sixty male CD-1 mice were randomly assigned to one of the seven treatment groups shown in Table 1 below. The mice were purchased from Charles River Laboratories (St. Constant, Quebec, Canada). On the day of the experiment, general health observations and body weight measurements were performed before dosing. Thirty (30) minutes after administration of the treatments specified in Table 1, the animals underwent neurological assessments and were immediately followed by a 6 Hz test. A description of these procedures is provided below.

[0069] Table 1. Summary of treatment groups

[0070]

[0071] IP is intraperitoneal.

[0072] Dronabinol and positive control

[0073] Detailed information for dronabinol and the positive control sodium valproate are provided in Tables 2 and 3, respectively.

[0074] Table 2. Detailed information of dronabinol

[0075]

[0076] Table 3. Positive control details

[0077]

[0078] Experimental protocol

[0079] animal

[0080] Animals were acclimated to the test facility for seven days prior to commencing the experimental phase of the study. Animals in good health, responsive, alert, and with intact fur were selected for the study. Assignments to treatment groups were balanced as far as possible with respect to body weight.

[0081] Animals were housed in groups of 4 or 5 on 1 / 4" Bed-o' Animals were kept in clear polycarbonate cages with straw (Andersons Lab Bedding Products, Maumee, Ohio). Cage changes and enrichment were provided according to the standard operating procedures of the experimental facility. All animal use procedures were conducted in accordance with the principles of the Canadian Council on Animal Care (CCAC).

[0082] The animals were maintained on an automated 12-hour light / 12-hour dark cycle, and all experimental activities were performed during the light cycle of the animals. Heating and cooling were electronically controlled and set to maintain the animal room at a temperature range of approximately 19-22°C with a relative humidity of approximately 50%.

[0083] Certified rodent feed ( 5001) was provided ad libitum in a stainless steel feeder. Animals were not fasted before or after the start of the experiment. Water was provided ad libitum in a glass bottle equipped with a stainless steel straw. All animals had ad libitum access to food and water. Standard rodent chow was provided in a stainless steel feeder. Tap water was provided in a glass water bottle equipped with a rubber stopper and a stainless steel straw.

[0084] Animals were observed daily according to standard operating procedures for any signs of illness that would not be expected in normal mice. No abnormal observations were reported during the study.

[0085] Animals were weighed on each dosing day using a certified and validated scale according to standard operating procedures prior to administration of treatment. Body weight measurements were used for grouping purposes and to calculate accurate dose volumes. The mean body weight of mice at the time of the seizure test was 31.2 ± 0.3 g.

[0086] Neurological evaluation

[0087] A brief neurological assessment was performed immediately prior to each seizure test. Animals were visually observed and scored on a scale of 0-3 according to the system summarized in Table 4 below.

[0088] Table 4. Scoring system for neurological assessment

[0089]

[0090] Seizure testing

[0091] Dronabinol and sodium valproate were dissolved in their respective vehicles on the day of dosing. Treatments were administered intraperitoneally to the right lower quadrant of the abdomen according to standard operating procedures. A summary of treatment groups is included in Table 1.

[0092] On the planned test day, the subjects received the dose of their designated treatment 30 minutes before electrical stimulation. After neurological assessment, the animals then received electrical stimulation (6 Hz, 0.2 millisecond pulse width, 3 second duration, 22 mA) through corneal electrodes moistened with saline (ECT unit 57800; Ugo Basile). In approximately 50% of the control animals, these stimulation parameters should induce psychomotor epileptic seizures within 30 seconds of stimulus delivery, which are defined as exhibiting at least one of the following behaviors: coma / immobility, forelimb clonus, Straub's tail (straub tail) or lateral movement of the head. Protection is defined as the complete disappearance of the following conditions within 30 seconds of stimulus delivery: coma / immobility, forelimb clonus, Straub's tail and / or lateral movement of the head. Based on the number of these behaviors exhibited by the animal after the stimulation was applied, an epileptic seizure score was determined for each animal. Once the animal begins to have an epileptic seizure, or 30 seconds have passed, the endpoint is reached and the animal is immediately euthanized.

[0093] All statistical analyses were performed using GraphPad Prism v.7.03. Total seizure score data were subjected to analysis of variance (ANOVA) using the independent grouping variable of treatment (i.e., test substance dose and control). In the case of significant main effects, post hoc Fisher's least significant difference analysis was performed to compare vehicle and drug treatment.

[0094] result

[0095] The raw data from this study are provided in Table 5 below. A reduced incidence of seizures in the 6HZ seizure test was observed at 4 mg / kg. For doses from 0.002 to 4 mg / kg, the ED 50 4.01 mg / kg (1.36-11.82 mg / kg, 95% confidence limits). In this study, the ED used here to reduce the percentage of epileptic seizures 50 It is an effective dose that reduces the incidence of epileptic seizures by half compared to the incidence of epileptic seizures when the vehicle is administered alone. According to the FDA guidelines, the human equivalent dose corresponding to the mouse dose can be calculated by multiplying the mouse dose by 0.08. "Guidance for Industry, Estimating the Maximum Safe Starting Dose in Initial Clinical Trials for Therapeutics in Adult Healthy Volunteers," U.S. Dept. of Health and Human Services, Food and Drug Administration, Center for Drug Evaluation and Research (CDER), July 2005, Pharmacology and Toxicology, page 7. Using this guide, the human equivalent dose of a 4 mg / kg dose in mice is 0.32 mg / kg, or 22.4 mg per day for a 70 kg person.

[0096] Seizure scores were also analyzed, and a main effect of treatment was identified (F6,53 = 2.459, P = 0.036). Post hoc analysis showed that treatment with 0.02, 2, and 4 mg / kg doses of dronabinol (p < 0.05*) (calculated ED50 = 0.1 mg / kg, 95% CI (0.01-1.05)), and sodium valproate (p < 0.01**) resulted in a decrease in seizure scores (mean ± SEM). In this study, the ED50 used here for the decrease in seizure scores was 50is an effective dose that reduces seizure scores by half compared to seizure scores when vehicle alone is administered. Using the human dose prediction calculations mentioned in the immediately preceding paragraph, based on this preclinical study, the minimum dose at which a reduction in seizure severity scores can be observed in humans is calculated to be 0.0016 mg / kg (0.08 x 0.02 mg / kg) (0.112 mg per day for a 70 kg human), and a reduction in seizure severity scores can be translated into meaningful effects in humans, including a lowered seizure threshold or a reduction in seizure severity. In addition, using this guideline, the 0.1 mg / kg dose in mice (calculated ED for seizure scores in mice) 50 ) is 0.008 mg / kg, or 0.56 mg per day for a 70 kg person. Figure 1 The effects on seizure scores and percentage of seizures when dronabinol was administered 30 minutes prior to the seizure test are shown.

[0097] Treatment with dronabinol produced no measurable effects on behavior as measured by neurological scores, in other words, no significant changes in gait, body posture, or ataxia based on brief visual observations immediately prior to testing. Although no global neurological effects were identified from the ANOVA, sodium valproate produced significant motor impairment in all animals treated with the 600 mg / kg dose. Using the human dose prediction calculations mentioned above, the human equivalent dose was 48 mg / kg (0.08×600 mg / kg), which is above the approved range of 15-45 mg / kg daily dose.

[0098] Table 5: Effects of dronabinol on 6 Hz seizure test: raw data

[0099]

[0100] Example 2

[0101] Human patients

[0102] A female patient first began to have seizures at six months of age and was subsequently diagnosed with Dravet syndrome at one year of age. Initially, she had seizures approximately every two weeks, with a cluster of 2 GTC seizures per day lasting 2 days. Keppra was ineffective, as were other combinations of anti-epileptic drugs. Several different combinations were tried, and by the time of her first visit for cannabinoid treatment evaluation on July 8, 2014, she was taking Depakote 125 mg BID, Clonazepam 0.5 mg TID, and Versed / Diastat for rescue when needed, but still had clusters of GTC seizures every two weeks. The patient started using a CBD product on July 3, 2014 (product analysis: 11.2 mg CBD / gram and 0.38 mg THC / gram, at a dose of 0.7 mL TID (unknown concentration per mL), but seizures continued to occur irregularly—mainly a series of 1-2 GTCs per day every two weeks, with rare atonia and occasional eye-flutters.

[0103] As of April 17, 2015, the CBD product had been changed to a 26:1 CBD product (0.65 mL + 0.15 mL THC tincture). The same dosing regimen of the same prescribed anti-epileptic medications was continued. The patient continued to experience two GTC seizures per month. Two drops of THC were applied to the patient's gums as rescue medication, which was effective quickly. The patient weighed 13.2 kg.

[0104] Between April 17, 2015 and April 4, 2016, the anti-epileptic medication regimen had been changed to the following: Onfi 5 ml BID and Depakote 125 mg BID. The patient was also administered the following oral dose of THC / CBD: 2 drops of THC tincture (estimated 0.43 mg per drop) to CBD tincture, 3.33 mg / mL, 0.8 ml TID (8 mg CBD + 0.86 mg THC / day). The patient weighed 15.5 kg. The patient continued to experience 5-6 GTC seizures per month while on this regimen, along with multiple myoclonic seizures.

[0105] Between April 4, 2016 and April 25, 2017, the CBD / THC treatment regimen was changed to 20 mg CBD + 20 mg THC TID. The same Onfi and Depakote regimen was continued. GTC seizures were reduced from once a month to once every other month, with significantly fewer myoclonic seizures. Cognitive function was significantly better with this THC regimen. The patient continued to receive 2 drops of THC applied to the gums as first aid with a rapid effect.

[0106] THC was removed from the regimen between April 25, 2017, and December 3, 2017. The frequency and severity of all seizure types increased when the patient was not receiving THC. THC was added back to the regimen (5 mg, at bedtime), and CBD was removed, and the number and severity of all seizure types improved.

[0107] Between December 3, 2017, and April 13, 2018, stiripentol (exact dose unknown) was added to Depakote and Onfi, and myoclonic seizures resolved. From December 3, 2017, to April 13, 2018, no GTC seizures occurred.

[0108] The patient remained seizure free for 15 months on Depakote + Onfi + stiripentol + 5mg THC HS as of April 4, 2019. At one point in mid-2018, the specific brand Onfi was replaced with its generic form clobazam, after which the patient had two GTC seizures, the generic form was switched back to brand Onfi, and the patient has had no further GTC seizures while on the previous regimen with 5mg THC (administered at bedtime).

[0109] Between April 9, 2019, and May 5, 2020, the patient had six seizures, none of which were convulsive, and all of which were rapidly terminated using THC applied to the oral mucosa as a rescue medication. The parents noted that the prescribed rescue medications caused her to "stop breathing" (a known complication of benzodiazepines) and that she would be "wiped out" when using those medications, whereas THC did not cause behavioral impairment when used as a rescue medication.

[0110] The patient has not experienced any type of seizure since September 2, 2019, and remained seizure-free at his most recent evaluation on April 27, 2021.

[0111] Example 3

[0112] Human patients

[0113] A male patient first began experiencing GTC and complex partial (CP) seizures at age 22. The patient was initially prescribed Depakote, but due to its debilitating side effects (including ataxia), Depakote was discontinued after 6 months and the patient was switched to topiramate. The patient was referred for evaluation in March 2014 at age 24 and treatment with cannabinoids / THC was initiated. At the time of the initial visit in March 2014, the patient was not yet using any cannabinoid treatment and was taking topiramate (100 mg in the morning and 150 mg in the evening) and was still experiencing seizures.

[0114] He was followed up on January 12, 2015, and his seizures had not improved after he started using the CBD patch and oral CBD spray. In February 2015, he started oral administration of 0.48 mg / kg or 50 mg of CBD daily along with topiramate, but there was no improvement and he continued to have seizures with no change in frequency or type.

[0115] Prior to his next follow-up evaluation on March 28, 2015, the patient had been switched from topiramate to lamotrigine 60 mg twice daily, but continued to experience seizures.

[0116] After this evaluation, the patient began inhaling 16 mg of cannabis wax once in the morning and taking an oral dose of 20 mg of THC cannabis extract in the evening, and was seizure-free until his next evaluation on March 11, 2016.

[0117] By the time of his next evaluation on March 3, 2017, he had discontinued his inhaled THC dosing and was taking 20 mg THC cannabis extract orally in the morning and 5 mg THC pills in the evening and had remained seizure-free on this dosing regimen. The patient continued this dosing until his last visit on May 23, 2019, and had been seizure-free since at least March 11, 2016 until that date.

[0118] Example 4

[0119] Human patients

[0120] A 36-year-old male was first evaluated for cannabinoid therapy on February 16, 2010. The patient had experienced idiopathic GTC seizures but had never used anti-epileptic medications because his seizures were well controlled by inhaled and oral THC cannabis products, which he began taking for pain from a work-related back injury that was poorly controlled by opioid analgesics. Initially in 2010, the patient smoked cannabis during the day and took oral THC cannabis extracts at night.

[0121] In mid-November 2014, the patient stopped taking cannabis and seizures recurred. The patient resumed his regimen of occasional cannabis use during the day and oral THC cannabis extract in the evening, and seizures ceased.

[0122] In December 2016, the patient again stopped taking THC, and seizures recurred and were again well controlled after resuming THC administration. This pattern repeated in 2016, but by February 2018, the patient had established a consistent THC regimen of daytime marijuana and 12.5 mg of THC orally at bedtime and remained seizure-free. He remained seizure-free for 4 years until his last visit on February 3, 2022.

[0123] Example 5

[0124] Human patients

[0125] A female patient first began experiencing GTC seizures in 2007 at age 52, caused by a cerebral aneurysm. She was prescribed multiple anti-epileptic medications, which did not fully control her seizures and caused severe side effects, including drowsiness, which prevented her from working. By the time she was first evaluated in July 2010, she had begun using inhaled cannabis therapy, which successfully controlled her seizures. The absence of seizures allowed her to stop taking lamotrigine, and the resolution of medication side effects allowed her to return to work.

[0126] The patient's first cannabinoid treatment evaluation was in July 2010 at age 56. The only prescription medication she was taking at the time was Effexor XR for depression. By her third evaluation in August 2012, she had changed her THC dosing regimen to a commercially available oral THC product and inhaled THC using a nebulizer, and by November 2013, the patient had discontinued inhaled THC and was only using oral THC-infused candies and beverages. She remained seizure-free.

[0127] Between November 2013 and October 2014, the patient tapered and ultimately discontinued Effexor XR with no recurrence of depression or seizure activity.

[0128] During 2015, the patient took marijuana extract containing 150 mg of THC orally at bedtime. From 2015 to 2016, she reduced her maintenance dose of oral THC to 70 mg at bedtime and continued to be seizure-free.

[0129] The patient continued on this dose and remained seizure-free at her last evaluation on September 9, 2021.

[0130] Example 6

[0131] Human patients

[0132] A 16-year-old female patient with a long history of GTC and CPS seizures (since 1 year of age) was evaluated for surgical intervention and underwent right temporal lobectomy in 2013. She had been free of seizure activity for 9 months; thereafter, epilepsy recurred with weekly GTC seizures requiring hospitalization.

[0133] Lamotrigine 225 mg twice daily was started, which reduced seizure activity, but was discontinued for unknown reasons, which resulted in a marked increase in seizure frequency. After restarting lamotrigine, seizures decreased to approximately 1 GTC seizure per month and have been maintained at this frequency.

[0134] The patient was first evaluated for cannabinoid therapy on February 11, 2016, at the age of 27 years, along with her parents (caregivers). She was still experiencing approximately 1 GTC seizure per month at this time. On physical examination, her neurological status was essentially within normal limits. The patient's mental status was assessed as obtuse, but she was responsive and fully oriented. At the time of this initial visit, she had not previously received cannabinoid therapy.

[0135] The patient was prescribed 50 mg CBD (2.5-3 mg THC) daily oral R4 tincture (loVia) (6% THC, 94% CBD), specifically 20 mg CBD in the morning and 30 mg CBD at bedtime. The label for the CBD drug Epidiolex includes a starting dose of 5 mg / kg daily for all indications, and an increase to a maintenance dose of 10 mg / kg or 20 mg / kg for Lennox-Gestault syndrome and Dravet syndrome, and an increase to a maintenance dose of 25 mg / kg daily for Tuberous Sclerosis Complex. The 50 mg CBD daily dose is much lower than the therapeutic dose of Epidiolex. She was instructed to continue her other current medications (lamotrigine and metformin).

[0136] The patient's next visit was on February 21, 2017. She stated that her last seizure prior to starting cannabinoid therapy was in January 2016. Cannabinoid therapy was started on February 28, 2016, with ioVia tincture (38 mg CBD and 2 mg THC per mL once daily), with only 1 seizure (GTC seizure) in July 2016. She confirmed that she currently uses 1 mL of ioVia tincture twice daily, containing 38 mg CBD and 2 mg THC per mL. After the seizure in July 2016, the dose was increased (doubled), and she has not experienced additional seizures since then. She reported no adverse events with this regimen, and there were no changes in her concomitant medications. The cannabinoid regimen prescribed for her was slightly modified so that she continued to take ioVia oral tincture containing 38 mg CBD and 2 mg THC twice daily, with an additional 2 mg THC added to bring the THC level to approximately 10% of the CBD daily dose. The 76mg CBD daily dose is far below the therapeutic dose of Epidiolex.

[0137] The patient's next visit was on March 1, 2018. She reported that her lamotrigine had been discontinued and her only medication was 1000 mg of metformin at bedtime. The patient had had a GTC seizure in October 2017 after discontinuing lamotrigine and had not had another seizure until 3 days before this appointment, when she had another brief GTC seizure. According to the patient's parents, the patient did not increase her THC dose as prescribed on February 21, 2017, but continued on a regimen of 38 mg CBD / 2 mg THC twice daily.

[0138] The cannabinoid regimen was discussed with the patient's parents, who were pleased with the current status, with seizure frequency having been substantially reduced from her baseline of 1 GTC seizure per month (ie, only 2 seizures in the past year, even after discontinuation of lamotrigine).

[0139] Example 7

[0140] Human patients

[0141] A male patient was first diagnosed with refractory GTC seizures without status epilepticus in 2001 at age 21. At that time, he was prescribed Trileptal, which had worrisome side effects. He subsequently began using cannabis, which resulted in seizure remission.

[0142] In late 2012, he developed complex partial seizures (2–3 episodes) and was started on Tegretol (dose unknown), but also experienced worrisome side effects. His treatment was then changed to clonazepam, 2 mg twice daily.

[0143] The patient was first treated with cannabinoids on May 24, 2013 at the age of 32. At the time he was a PhD student in economics. The patient's medical history is significant, he was in a car accident at the age of 16, with a concussion and "scarring". At the age of 21, he developed GTC seizures, which occurred 3 times a month. He started taking Trileptal, had side effects, and started using cannabis, which relieved his seizures...then stopped Trileptal. In 2008, he began to use recreational cannabis occasionally, but not regularly.

[0144] The patient began taking 5 mg of CBD and 5 mg of THC (Wana or Incredibles brand) orally daily at bedtime on May 24, 2013. He continued to take the prescribed clonazepam, 2 mg twice daily.

[0145] The patient was seen on June 19, 2014. The patient has been restarted on Trileptal, along with clonazepam and cannabinoids. He was seizure free before he left state in February 2014 and stopped cannabinoids, and had 2 complex partial seizures since restarting cannabinoids (Wana or Incredibles brands) with 10 mg THC and 10 mg CBD orally daily at bedtime and has not had a seizure.

[0146] The patient was seen on October 31, 2017. He continued to take the 1:1 THC / CBD product orally, but split the dose so that he was taking 5mg THC / 5mg CBD twice daily. He stated that he had completed his doctorate, was off all of his prescription anti-seizure medications, and was no longer having GTC seizures with the 1:1 THC / CBD product (5mg THC / 5mg CBD twice daily). The cannabinoid regimen continued to be 5mg THC and 5mg CBD taken orally twice daily. The 10mg CBD daily dose is much lower than the therapeutic dose of Epidiolex.

[0147] The patient's last visit was on November 27, 2018. The patient confirmed that he was still on his prescribed daily cannabinoid regimen, had what were likely complex partial seizures when he was sleep deprived, and admitted that he may have forgotten to take his cannabinoids that day. He has not had a GTC seizure since earning his doctorate and has been gainfully employed. He continues to be prescribed 5 mg THC 1:1 orally with 5 mg CBD twice daily and remains off any other anti-epileptic medications.

[0148] Example 8

[0149] Several patients

[0150] Results Overview

[0151] Several patients began treatment with THC after their initial visit. More details on treatment are provided below. The group included a total of 82 adult patients and a total of 12 pediatric patients. Of those 94 patients, 34 adult patients and 10 pediatric patients had experienced at least one GTC seizure in the year prior to their initial visit. At the time of their initial visit, 14 of the 34 adult patients and 8 of the 10 pediatric patients had never taken THC. At the time of their initial visit, 5 of the 34 adult patients and 2 of the 10 pediatric patients were taking THC continuously / regularly. At the time of their initial visit, 15 of the 34 adult patients and none of the 10 pediatric patients were taking THC intermittently / irregularly or had taken THC at some time in the past and were no longer taking THC.

[0152] At the time of the first visit, 16 of the 34 adult patients had refractory epilepsy, meaning that GTC seizures persisted despite the patient taking two different anti-epileptic drugs at or before the first visit. All 10 pediatric patients had refractory epilepsy at the time of the first visit.

[0153] Prior to starting THC treatment, the adult and pediatric patients had epilepsy for up to 46 years and 16 years, respectively.

[0154] Table 6 below shows the responder rate and one-year remission rate for 34 adult patients and 10 pediatric patients who experienced at least one GTC seizure within the year prior to the first visit. The first visit was the date the patient first visited the clinic to evaluate THC treatment for GTC seizures. The responder rate was the percentage of patients who had a reduction in GTC seizure frequency of at least 50% during the one-year treatment period with THC. The one-year remission rate was the percentage of patients who did not experience a GTC seizure within one year after starting THC treatment.

[0155] Among 34 adult patients and 10 pediatric patients who had at least one GTC seizure within the year before the first visit, the response rate to treatment with THC was 71% in adult patients and 60% in pediatric patients. Among 34 adult patients and 10 pediatric patients who had at least one GTC within the year before the first visit, the one-year remission rate for treatment with THC was 44% in adult patients and 40% in pediatric patients. Among the 34 adult patients, seven patients had refractory epilepsy and had never taken THC before the first visit. Among those seven adult patients, the response rate was 71% (5 of 7), and the one-year remission rate was 29% (2 of 7). Among the 10 pediatric patients, eight patients had refractory epilepsy and had never taken THC before the first visit. Among those eight pediatric patients, the response rate was 75% (6 of 8), and the one-year remission rate was 37.5% (3 of 8). (All 10 pediatric patients had refractory epilepsy.) Additionally, of the 34 adult patients, 14 had never taken THC prior to their first visit. Of those 14 adult patients, the responder rate was 71% (10 of 14) and the one-year remission rate was 36% (5 of 14). (Of those 14 patients, some had refractory epilepsy and some did not.)

[0156] Table 6 also shows Jazz Pharmaceuticals CBD products Table 6 shows that the response rate and one-year remission rate of 100 mg / dL were obtained from pediatric randomized controlled clinical trials (RCTs) and expanded access programs (EAPs) for adults and pediatrics. The response rate and one-year remission rate of treatment were lower than those of treatment with THC.

[0157] As shown in Table 6, the expected baseline one-year remission rate for persons with refractory epilepsy is 5%. Thus, treatment with THC provides an improvement over the expected one-year remission rate.

[0158] Table 6 also shows that among the 82 adults treated with THC, only two patients experienced THC-related adverse effects. One patient felt drowsy, and another patient felt decreased mental clarity. Among the 12 children, none experienced adverse effects.

[0159]

[0160] RCT = randomized controlled trial

[0161] EAP = Extended Access Program

[0162] N / A = Not Available

[0163] SZ = Seizures

[0164] DS = Dravet syndrome (GTC)

[0165] LGS = Lennox-Gastaut syndrome

[0166] TSC = Tuberous sclerosis complex (including but not limited to GTC)

[0167] TRE = refractory epilepsy (including but not limited to GTC)

[0168] GTC = generalized tonic-clonic seizure

[0169] *THC responder rates and THC 1-year remission rates include both: (1) 7 adult and 8 pediatric patients with refractory epilepsy who had not previously used THC and (2) the entire group of 34 adult and 10 pediatric patients who had at least one GTC seizure in the year before the index visit.

[0170] **Calculated using 29% (2 / 7) response rate.

[0171] ***Calculated using 37.5% (3 / 8) response rate.

[0172] Treatment Overview

[0173] All 34 adult patients and 10 pediatric patients were taking other anti-epileptic drugs or receiving other anti-epileptic treatments at the time of their first visit. Some patients continued their anti-epileptic medications while being treated with THC, while others did not. Those anti-epileptic drugs and other anti-epileptic treatments included: lamotrigine, topiramate, topiramate XR, vagus nerve stimulation, phenytoin, valproate, zonisamide, benzodiazepines, surgery, levetiracetam, carbamazepine, oxcarbazepine, lacosamide, perampanel, clonazepam, phenobarbital, pregabalin, gabapentin, rufinamide, CBD (e.g., Epidiolex), clobazam, and felbamate. In addition, all patients who were using oral doses of THC were using products that did not contain CBD or that contained CBD in doses much lower than the therapeutic dose of Epidiolex.

[0174] THC treatments for the 82 adult patients varied. Many patients smoked marijuana, so the dose and / or timing of medication were unknown. Because CBD is delivered at subtherapeutic levels when marijuana is smoked, it is acceptable to attribute any therapeutic effects to THC. The labeling for the CBD drug Epidiolex includes a dose starting at 5 mg / kg daily for all indications and increasing gradually to a maintenance dose of 10 mg / kg or 20 mg / kg for Lennox-Gestault syndrome and Dravet syndrome, and gradually increasing to a maintenance dose of 25 mg / kg daily for tuberous sclerosis. When 1 gram of marijuana is smoked, it delivers CBD to the lungs at a dose far below the therapeutic dose level prescribed for Epidiolex. Some other patients took unknown doses of THC orally.

[0175] A summary of THC dosing in 82 adult patients is provided below.

[0176] For the 34 patients who had at least one GTC seizure in the year before their first visit, dosing was as follows.

[0177] For the 15 patients who achieved a 50% reduction in GTC seizure rate within one year of THC treatment and were GTC seizure free within one year of THC treatment, the dosage was as follows.

[0178] Three patients: Uncertain dosage. At the time of the first visit, two of those patients were taking THC intermittently / irregularly or had taken THC at some time in the past and no longer were taking THC. At the time of the first visit, one of those patients was taking THC regularly.

[0179] Two patients: Undetermined doses of THC administered by snorting and orally. At the time of the first visit, one of those patients was taking THC on and off / irregularly, or had taken THC at some time in the past and no longer takes THC. At the time of the first visit, one of those patients was taking THC regularly.

[0180] Two patients: Uncertain THC oral dose. At the time of the first visit, two of those patients were taking THC on and off / irregularly or had taken THC at some time in the past and were no longer taking THC.

[0181] One patient: Uncertain THC dose. At the time of the first visit, this patient had never taken THC.

[0182] One patient: Uncertain smoking dose and 5-20mg THC oral TDD. At the time of the first visit, the patient was taking THC on and off / irregularly or had taken THC at some time in the past and was no longer taking THC.

[0183] One patient: 2.5-5mg THC oral TDD. At the time of the first visit, the patient had never taken THC.

[0184] One patient: 5-10 mg THC oral TDD (before bedtime). At the time of the first visit, the patient was taking THC on and off / irregularly or had taken THC at some time in the past and was no longer taking THC.

[0185] One patient: 5mg THC and unknown dose of CBD oral TDD (before bedtime), changed to 5mg THC and 5mg CBD oral TDD (before bedtime). This CBD dose of 5mg TDD is much lower than the daily therapeutic dose of Epidiolex. At the time of the first visit, this patient had never taken THC.

[0186] One patient: 0.5mg THC and 9.5mg CBD orally TDD (before bedtime). This CBD dose is much lower than the daily therapeutic dose of Epidiolex. At the time of the first visit, the patient had never taken THC.

[0187] One patient: Uncertain smoking dose and 6mg THC inhalation TDD. At the time of the first visit, the patient was taking THC on and off / irregularly or had taken THC at some time in the past and was no longer taking THC.

[0188] One patient: 5mg THC and 20mg CBD orally TDD (before bedtime). This CBD dose is much lower than the daily therapeutic dose of Epidiolex. At the time of the first visit, the patient had never taken THC.

[0189] For the nine patients who had a 50% reduction in GTC seizure rate within one year of THC treatment but still had seizures one year after THC treatment, the dosage was as follows.

[0190] Two patients: Uncertain dosage. At the time of the first visit, one of these patients was taking THC intermittently / irregularly or had taken THC at some time in the past and no longer was taking THC. At the time of the first visit, one of these patients was taking THC regularly.

[0191] One patient: 3-6mg THC and 76mg CBD oral TDD. This CBD dose is much lower than the daily therapeutic dose of Epidiolex. At the time of the first visit, this patient had never taken THC.

[0192] One patient: 1.5mg THC and 28.5mg CBD oral TDD, changed to 4.5mg THC and 28.5mg CBD oral TDD, changed to 9mg THC and 57mg CBD oral TDD. Both of these CBD doses are much lower than the daily therapeutic dose of Epidiolex. At the time of the first visit, this patient had never taken THC.

[0193] One patient: 5-15mg THC and 2-6mg CBD oral TDD. This CBD dose is much lower than the daily therapeutic dose of Epidiolex. At the time of the first visit, this patient had never taken THC.

[0194] One patient: 1mg THC and 19mg CBD orally TDD. Increased dose to 1.5mg THC and 30mg CBD orally TDD. Both CBD doses are well below the daily therapeutic dose of Epidiolex. At the time of the first visit, this patient had never taken THC.

[0195] One patient: 4mg THC and 40mg CBD oral TDD. This CBD dose is much lower than the daily therapeutic dose of Epidiolex. At the time of the first visit, this patient had never taken THC.

[0196] One patient: 1.5mg THC and 28.5mg CBD oral TDD, changed to 7.5mg THC and 28.5mg CBD oral TDD. This CBD dose is much lower than the daily therapeutic dose of Epidiolex. At the time of the first visit, this patient had never taken THC.

[0197] One patient: Uncertain smoking dose, uncertain amount of CBD, and 5-10 mg THC oral TDD. This patient had a reduced GTC seizure rate during the first six years of taking THC. After the first six years, the patient's GTC seizure rate increased. The patient smoked a large amount of marijuana after the first six years for pain caused by injuries sustained in an accident. At the time of the first visit, the patient was taking THC regularly.

[0198] For the 10 patients who did not have a 50% reduction in GTC seizure rate within one year of THC treatment and who still had GTC seizures after one year of THC treatment, the dosage was as follows.

[0199] Three patients: Uncertain dosage. At the time of the first visit, two of those patients were taking THC intermittently / irregularly or had taken THC at some time in the past and no longer took THC. At the time of the first visit, one of those patients was taking THC regularly.

[0200] One patient: Uncertain oral dose. At the time of the first visit, the patient was taking THC on and off / irregularly or had taken THC at some time in the past and was no longer taking THC.

[0201] One patient: Uncertain oral and vaping doses. At the time of initial presentation, the patient had never taken THC.

[0202] One patient: Synthetic THC (dronabinol) 6-10 mg oral TDD, but occasionally not used due to lack of access to medication. At the time of the first visit, the patient was taking THC on and off / irregularly, or had taken THC at some point in the past and was no longer taking THC.

[0203] One patient: 257.2 mg THC and 423.9 mg CBD oral TDD (before bedtime). At the time of the first visit, the patient had never taken THC.

[0204] One patient: Undetermined smoking dose followed by 6.25 mg THC oral TDD. At the time of the first visit, the patient was taking THC on and off / irregularly or had taken THC at some point in the past and was no longer taking THC.

[0205] One patient: 5-10mg THC and 25mg CBD oral TDD. This CBD dose is much lower than the daily therapeutic dose of Epidiolex. At the time of the first visit, this patient had never taken THC.

[0206] One patient: 5-20 mg THC oral TDD. At the time of the first visit, the patient was taking THC on and off / irregularly or had taken THC at some time in the past and was no longer taking THC.

[0207] For the 48 patients who were not included in the efficacy evaluation because they had no seizures within a year before their first visit, the dosages were as follows. For some of these patients, THC was administered at a daily oral dose of 0.4-80 mg THC. Some of these patients used CBD at doses of 7-32 in addition to THC. Some of these patients used unknown amounts of THC by smoking, taking it orally, or inhaling it. These patients, along with 34 other adult patients, were included in the safety evaluation. One of these patients who used an unknown amount of THC orally experienced confusion, an adverse event associated with THC. One of these patients who took 2-3 mg THC and 38 mg CBD orally for TDD experienced drowsiness, an adverse event associated with THC.

[0208] THC treatment also differed for the 10 pediatric patients who had at least one GTC seizure in the year before their first visit, as follows.

[0209] One patient: 5-10mg THC + 10-20mg CBD oral total daily dose (TDD) before bedtime. The patient was 34.1kg, so the CBD daily dose was 0.29-0.59mg / kg (much lower than the therapeutic dose of Epidiolex). The patient had a 50% reduction in GTC seizure rate within one year of THC treatment and no GTC seizures within one year of THC treatment. At the time of the first visit, the patient had never taken THC.

[0210] Patient: 2-3mg THC + 30mg CBD oral, BID. The patient is 17.3kg, so the CBD daily dose is 3.47mg / kg (much lower than the therapeutic dose of Epidiolex). The patient has a 50% reduction in GTC seizure rate within one year of THC treatment and no GTC seizures within one year of THC treatment. At the time of the first visit, the patient had never taken THC.

[0211] Two patients: 4-12mg THC TDD. One of those patients had a 50% reduction in GTC seizure rate within one year after THC treatment and no GTC seizures within one year after THC treatment. The other patient had a 50% reduction in GTC seizure rate within one year after THC treatment. None of these patients had ever taken THC at the time of their first visit.

[0212] One patient: (This patient was not one of the patients who had a 50% reduction in GTC seizures in one year or GTC seizure remission for one year) 5mg TDD THC (with 2 drops of THC tincture for rescue treatment when necessary). At the time of the first visit, this patient had never taken THC.

[0213] A patient: was diagnosed with GTCs and cerebral palsy. Had daily GTCs since age 2. After years of receiving numerous prescription anti-epileptic medications, the patient was prescribed cannabinoids (CBD 20mg and 6% THC (1.2mg) orally daily; however, actual doses taken are uncertain due to use of various preparations) at age 16, with resolution of all GTC seizure activity; a few years later, after a serious motor vehicle accident, the patient increased the dose to 60-70mg THC orally TDD (administered in 2 equally divided doses morning and evening), with continued seizure resolution and improvement of the combined pain, spasticity, and migraines caused by the accident. The patient had a 50% reduction in GTC seizure rate within one year of THC treatment and was GTC seizure free within one year of THC treatment. At the time of the initial visit, the patient was taking THC regularly.

[0214] One patient: 1.8mg THC transdermal patch daily + 2.5mg oral THC before bed, 5mg CBD BID. The patient was 63.3kg, so the CBD daily dose was 0.157mg / kg (much lower than the therapeutic dose of Epidiolex). This patient had a 50% reduction in GTC seizure rate within one year of THC treatment. At the time of the first visit, the patient was taking THC regularly.

[0215] One patient: (This patient was not one of the patients who achieved a 50% reduction in GTC seizures within one year or one year of GTC seizure remission) was initially on 5% THC (lovia) TDD and 10mg CBD TDD (started 18 / 10 / 2013); in 2015, the patient switched to 30mg CBD only (increased seizure frequency and severity); on 27 / 10 / 2015, the patient switched to daily 30mg CBD and 2mg THC oral tincture, and 5mg 1:1 CBD / THC transdermal cream TDD. At the time of the initial visit, the patient had never taken THC.

[0216] One patient: (This patient was not one of the patients who had a 50% reduction in GTC seizures within one year or a one-year remission of GTC seizures.) This patient had a single GTC seizure in 1998 at 18 months of age. However, since June 17, 2013, his neurologist prescribed Keprofen (Levetiracetam) 250 mg BID. The patient was initially evaluated for cannabinoids on December 6, 2013, and was prescribed an oral regimen of 5% THC (lovia) TDD and 20 mg CBD TDD in addition to maintaining his daily Keppra regimen; in February 2014, the patient switched to Charlotte's Web (0.5 mL, containing 25 mg CBD) only and discontinued THC and Keppra; this resulted in the patient experiencing several complex partial seizures per day and a GTC seizure 3 weeks prior to the April 11, 2015 visit); on April 11, 2015, the patient was switched to an oral tincture of 20 mg CBD and 1 mg THC twice daily (lovia) and was placed on a regimen of increasing the amount of THC and resuming Keppra (the patient did not return to the clinic after April 11, 2015). At the time of the initial visit, the patient had never taken THC.

[0217] One patient: (This patient was not one of the patients who achieved a 50% reduction in GTC seizures in one year or a one-year remission of GTC seizures). Prior to receiving any cannabinoids, this patient was diagnosed with GTCs and absence seizures at age 8 and had been treated with multiple anti-epileptic drug regimens, all unsuccessfully, including his current regimen of Lamotrigine XR and Topomax. He was initially prescribed an oral THC tincture of 1 mg THC and 20 mg CBD twice daily in combination with his current ASM regimen. The patient’s caregiver changed the regimen to a CBD-only product, which resulted in the patient experiencing frequent “violent” GTC seizures. Compliance review revealed that the patient was taking 134 mg CBD daily and no THC. The patient’s regimen was subsequently changed to 50 mg CBD and 2.5 mg THC orally daily. Based on seizure frequency and severity, subsequent regimens included oral administration of 1.5 mg / lb body weight (200 mg) CBD and 5 mg THC in 2 divided doses daily, and oral administration of 0.5 mg / lb body weight (65 mg) CBD and 10% THC (6-7 mg) daily, combined with a maintenance regimen of other anti-epileptic drugs, including different combinations of Lamotrigine XR, Keppra, Depakote, Topomax, and / or Trilepta. The patient was 60 kg, so the 200 mg CBD daily dose was 3.3 mg / kg (much lower than the therapeutic dose of Epidiolex). Starting in 2016 (15 years old), the patient began using THC (only) as rescue treatment (10 mg / mL, using 1-3 mg THC as rescue, complete remission of seizures). At the time of the first visit, the patient had never taken THC.

[0218] For two pediatric patients, dosed as follows, they were not included in the efficacy evaluation because they had no seizures in the year before their first visit. These patients were included in the safety evaluation along with 10 other pediatric patients.

[0219] A female patient was diagnosed with atonic seizures, myoclonic seizures, and Doose syndrome since approximately 3 months of age. Despite trying multiple combinations of prescription anti-epileptic medications, THC-A transdermal patches, and CBD (Charlotte's Web) oral tincture and CBD transdermal patches, she continued to experience several seizures of all types daily until her first evaluation for cannabinoid therapy (March 8, 2016, at age 4.5 years). Charlotte's Web CBD tincture made all types of seizures more severe, more frequent, and longer in duration, while the CBD patch exacerbated seizures in a dose-related manner. She was then prescribed 1 mg of oral THC tincture three times daily. On March 8, 2018, the patient returned for follow-up and was informed that all cannabinoids had been discontinued. A 24-hour EEG evaluation showed 1500 abnormalities without cannabinoids. THC-A transdermal patch was restarted at 1.875 mg / day, and the EEG abnormalities decreased to 400 / 24 ​​hours. Oral THC 2.5 mg BID was then restarted, and the EEG abnormalities further decreased to 20 / 24 hours. No seizures were observed. Due to the significant reduction in pre-epileptic activity in the brain after restarting THC use, and concerns about differences in effective doses between transdermal products, the patient was then prescribed oral THC 2.5 mg BID, which she continues to take.

[0220] Another pediatric patient was a male patient who was diagnosed with Lennox-Gastout syndrome in 2008 at age 2 years, had multiple epilepsy types, and underwent corpus callosotomy in January 2017 after vagus nerve stimulation (VNS) failed. The surgery resulted in a reduction in tonic and myoclonic seizures with apnea from frequent and continuous seizures to multiple myoclonic and tonic seizures lasting 15 minutes with apneas of 4 minutes or less and fewer apneic episodes. The patient was first evaluated for cannabinoid therapy on August 3, 2017 at age 11 years and was prescribed CBD and 0.3% THC 10mg BID (Charlotte's Web). This treatment was found to be ineffective and the patient was hospitalized for 10 days in the summer of 2018 for status epilepticus with complex partial seizures and GTCs that were stopped only by felbamate. After discharge, the patient's GTCs worsened and he no longer responded to felbamate. Subsequently, the patient’s cannabinoid regimen was changed to ioVia tincture 38mg CBD + 2mg THC three times daily (October 25, 2018), which resulted in a reduction in the number and duration of seizures. The patient was 35.45kg, so the CBD daily dose was 3.3mg / kg (much lower than the therapeutic dose of Epidiolex). However, the patient continued to have frequent daily tonic, myoclonic, and GTC seizures. Over the next two years, the patient’s cannabinoid regimen was further adjusted, gradually increasing the amount of THC to 8mg BID (16mg TDD) orally, combined with Epidiolex (CBD) 150mg BID, with further reductions in seizure frequency and duration; however, the seizures had become all clonic seizures and some infantile spasmodic seizures at the last visit (no more GTCs or complex partial seizures). At the dose of 300 mg Epidiolex daily, the patient was 40.5 kg, so the CBD daily dose was 7.4 mg / kg (lower than the therapeutic dose of Epidiolex for Lennox-Gastaut syndrome).

[0221] Those of ordinary skill in the art will appreciate that the present disclosure may be modified in a manner not specifically described herein. The scope of the present disclosure is not limited to the specific embodiments described herein, which are for illustrative purposes only. The present disclosure includes any modifications and variations, including all functionally equivalent products, compositions and methods.

Claims

1. A method for treating generalized tonic-clonic seizures (GTCs) in a patient in need thereof, comprising administering to said patient a therapeutically effective amount of a THC compound.

2. The method of claim 1, further comprising administering another anti-epileptic drug in combination with the THC compound.

3. A method of treating generalized tonic-clonic seizures (GTCs) in a patient in need thereof, comprising administering to said patient a therapeutically effective amount of dronabinol.

4. The method of claim 3, further comprising administering another anti-epileptic drug in combination with dronabinol.

5. A method for treating generalized tonic-clonic seizures (GTCs) in a patient in need thereof, comprising administering to said patient a therapeutically effective amount of delta-9-tetrahydrocannabinol.

6. The method of claim 5, further comprising administering another anti-epileptic drug in combination with the delta-9-tetrahydrocannabinol.

7. The method of any one of claims 1-6, wherein the dosage is at a level that produces minimal or no adverse psychotropic effects in the patient.

8. The method of any one of claims 1-7, wherein the method comprises administering the THC compound as a seizure rescue medication.

9. The method of any one of claims 1-8, wherein the dosage is 2.5 to 150 mg per day.

10. The method of any one of claims 1-8, wherein the dosage is 2.5 to 70 mg per day.

11. The method of any one of claims 1-8, wherein the dosage is 2.5 to 50 mg per day.

12. The method of any one of claims 1-8, wherein the dosage is 5 to 70 mg per day.

13. The method of any one of claims 1-8, wherein the dosage is 2.5 to 50 mg per day.

14. The method of any one of claims 1-8, wherein the dosage is 2.5 to 5 mg per day.

15. The method of any one of claims 1-8, wherein the dosage is 2.5 to 25 mg per day.

16. The method of any one of claims 1-8, wherein the dosage is 2.5 to 12.5 mg per day.

17. The method of any one of claims 1-8, wherein the dosage is 5 to 50 mg per day.

18. The method of any one of claims 1-8, wherein the dosage is 5 to 25 mg per day.

19. The method of any one of claims 1-8, wherein the dosage is 5 to 12.5 mg per day.

20. The method of any one of claims 1-8, wherein the dosage is 2.5 to 20 mg per day.

21. The method of any one of claims 1-8, wherein the dosage is 5 to 20 mg per day.

22. The method of any one of claims 1-8, wherein the dosage is 12.5 to 20 mg per day.

23. The method of any one of claims 1-8, wherein the dosage is 12.5 to 25 mg per day.

24. The method of any one of claims 1-8, wherein the dosage is 12.5 to 50 mg per day.

25. The method of any one of claims 1-8, wherein the dosage is 12.5 to 70 mg per day.

26. The method of any one of claims 1-8, wherein the dosage is 0.02 to 4.0 mg / kg per day.

27. The method of any one of claims 1-8, wherein the dosage is 0.02 to 4.0 mg / kg per day.

28. The method of any one of claims 1-8, wherein the dosage is 0.112 to 0.56 mg / kg per day.

29. The method of any one of claims 1-8, wherein the dosage is 0.32 to 0.56 mg / kg per day.

30. The method of any one of claims 1-8, wherein the dosage is 0.112 to 0.32 mg / kg per day.

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