Treatment of non-convulsive seizure disorders

Abstract

Methods for treating non-convulsive seizures are provided. These include administering THC compounds such as dronabinol or delta-9-tetrahydrocannabinol in therapeutically effective doses to patients. Additional methods include combinations with anti-seizure medications, as a seizure rescue medication. Further methods provide for dosages of THC compounds at levels that minimize or eliminate adverse psychotropic effects.

Description

TREATMENT OF NON-CONVULSIVE SEIZURE DISORDERS REFERENCE TO RELATED APPLICATION

[0001] The application claims benefit of US Provisional Serial No. 63 / 589,473 filed October 11, 2023, the contents of which are incorporated by reference.BACKGROUND

[0002] Epilepsy is a disorder of the central nervous system in which normal brain activity7becomes disordered, resulting in seizures which can range from inapparent and very' short-lived episodes to violent and / or prolonged movement of the body with loss of awareness.

[0003] Seizures are generally’ grouped into focal seizures and generalized seizures. Focal seizures involve only part of the brain and may occur with or without loss of awareness and may also result in involuntary movement of a part of the body.

[0004] Generalized seizures involve both sides of the brain, result in total loss of awareness for varying periods, and are often associated with involuntary movement of the body. Unlike generalized tonic-clonic seizures, non-convulsive seizures do not involve involuntary convulsive movements. Non-convulsive seizures occur in a variety' of epilepsies / seizure disorders and include absence seizures, complex partial seizures (otherwise known as focal impaired awareness seizures or focal onset impaired awareness seizures), focal aware seizures (simple partial seizures), atonic seizures, and myoclonic seizures. Status epilepticus is defined by The International League Against Epilepsy (ILAE) as a condition resulting either from the failure of the mechanisms responsible for seizure termination or from the initiation of mechanisms that lead to abnormally prolonged seizures. The temporal threshold that defines an abnormally prolonged seizure depends on the type of seizure. For convulsive status epilepticus, this duration is five minutes. For non-convulsive status epilepticus (NCSE), defined as status epilepticus without prominent motor symptoms, the threshold is 10 minutes.

[0005] Although convulsive seizures (tonic-clonic seizures) convey the greatest risk for SUDEP (Sudden Unexplained Death due to Epilepsy), sudden death can occur in the absence of tonic-clonic seizures (e.g., in patients with complex partial seizures). Morbidity and mortality of non-convulsive seizures is particularly high if patients are driving or operating machinery’. Impacts of non-convulsive seizures on employment, education, childhood development and ability to interact and participate in typical activities in society are also substantial.

[0006] Complete control of non-convulsive seizures has proven to be difficult, despite the plethora of different anti-epileptic medications now available, with many patients suffering from persistent seizures, despite taking multiple medications in many cases. SUMMARY

[0007] The present disclosure is directed to several embodiments of treating non- convulsive seizures.

[0008] In some embodiments, the disclosure is directed to methods of treating non- convulsive seizures in a patient in need thereof, comprising administering to the patient a THC compound in a therapeutically effective dose.

[0009] In some embodiments, the methods further comprise administering another anti-seizure medication in combination with the THC compound.

[0010] In some embodiments, the disclosure is directed to methods of treating non- convulsive seizures in a patient in need thereof, comprising administering to the patient dronabinol in a therapeutically effective dose.

[0011] In some embodiments, the methods further comprise administering another anti-seizure medication in combination with dronabinol.

[0012] In some embodiments, the disclosure is directed to methods of treating non- convulsive seizures in a patient in need thereof, comprising administering to the patient delta- 9-tetrahydrocannabinol in a therapeutically effective dose.

[0013] In some embodiments, the methods further comprise administering another anti-seizure medication in combination with delta-9-tetrahydrocannabinol.DETAILED DESCRIPTION

[0014] The following detailed description and examples illustrate certain embodiments of the present disclosure. Those of skill in the art will recognize that there are numerous vanations and modifications of this disclosure that are encompassed by its scope. Accordingly, the description of certain embodiments should not be deemed to limit the scope of the present disclosure.

[0015] In order that the disclosure may be more readily understood, certain terms are defined throughout the detailed description. Unless defined otherwise herein, all scientific and technical terms used in connection with the present disclosure have the same meaning as commonly understood by those of ordinary skill in the art.

[0016] All references cited herein, including, but not limited to, published and unpublished applications, patents, and literature references, are incorporated herein byreference in their entirety and are hereby made a part of this specification. To the extent a cited reference conflicts with the disclosure herein, the specification shall control.

[0017] As used herein, the singular forms of a word also include the plural form, unless the context clearly dictates otherwise; as examples, the terms "a," "an," and "the" are understood to be singular or plural. By way of example, "an element" means one or more element. The term "or" shall mean "and / or" unless the specific context indicates otherwise.

[0018] As used herein, ranges include both endpoints and all values between those endpoints.

[0019] "Administered" or "administration" refers to any appropriate route of delivering THC. Such routes of delivery include, for example, oral delivery, inhaled or aerosol delivery, dermal delivery’, and injectable delivery. Oral delivery includes, for example, liquid formulations, capsules, tablets, and other ingestible edible forms (for example, candy, gum, lozenges). Aerosol delivery includes, for example, nasal sprays, aerosols for inhalation, and vaping or smoking. Injectable delivery' includes, for example, an intraperitoneal, intravenous, intramuscular, intradermal, or subcutaneous route. Formulations may also be administered by transmucosal route.

[0020] "In combination" refers to the administration of one therapy in addition to another therapy. As such, "in combination with" includes simultaneous (e.g., concurrent) and consecutive administration in any order.

[0021] "Subject" or "patient" refers to a mammalian patient. In some embodiments, the mammalian patient is a human.

[0022] "Therapeutically effective amount" refers to an amount of a compound or pharmaceutical composition sufficient to produce a desired therapeutic effect. For example, in some embodiments, the desired therapeutic effect is preventing or reducing the frequency or occurrence of acute or chronic non-convulsive seizures, reducing the severity of acute or chronic non-convulsive seizures, reducing the severity of post-seizure consequences of acute or chronic non-convulsive seizures, and / or use of a THC compound as a seizure rescue medication.

[0023] "Treating" or "treatment" refers to preventing or reducing the frequency or occurrence of acute or chronic non-convulsive seizures, reducing the severity of acute or chronic non-convulsive seizures, reducing the severity of post-seizure consequences of acute or chronic non-convulsive seizures, and / or use of a THC compound as a seizure rescue medication.

[0024] "Generalized seizures" involve both sides of the brain, result in total loss of awareness for varying periods, and are often associated with involuntary movement of the body. "Generalized tonic-clonic seizures" are associated with involuntary convulsive movements along with loss of awareness and potentially life-threatening consequences.

[0025] An "absence seizure" causes a short period of "blanking out" or staring into space. It is a generalized onset seizure, which means it begins in both sides of the brain at the same time. It is also known (previously) as a petit mal seizure. Absence seizures usually affect only a person's awareness of what is going on at that time, with immediate recovery. During an absence seizure, the eyes may turn upwards and eyelids flutter. Smacking the lips or chewing movements may also occur, as can rubbing the fingers together or other hand motions. They are typically short-lived (less than 10 seconds), but atypical absence seizures can last 20 seconds or more.

[0026] "Atonic seizures" are a type of seizure that causes sudden loss of muscle strength. These seizures are also called akinetic seizures, drop attacks or drop seizures. The sudden loss of muscle strength, or tone, can cause the person to fall down. In addition, the eyelids may droop, the head may nod or drop forward and the person may drop things. The person typically remains conscious.

[0027] "Complex partial seizures" are focal seizures that start in one hemisphere of the brain and are associated with impairment in consciousness. They are now typically called focal impaired awareness seizures or focal onset impaired awareness seizures. This is different from focal onset aware seizures (also known as simple partial seizures), which also start in one hemisphere of the brain but cause no loss of awareness.

[0028] "Myoclonic seizures" are brief, shock-like jerks of a muscle or group of muscles. Myoclonic seizures often happen in everyday life (includes hiccups and sudden jerk when falling asleep). In epilepsy, myoclonic seizures usually cause abnormal movements on both sides of the body at the same time. They occur in a variety7of epilepsy syndromes including:Juvenile Myoclonic Epilepsy: seizures usually involve the neck, shoulders and upper arms, and in many patients, soon after waking up. They usually begin around puberty or sometimes in early adulthood in people with a normal range of intelligence.Lennox-Gastaut syndrome: Uncommon syndrome that usually includes other ty pes of seizures as well. Begins in early childhood. The myoclonic seizures usually involve the neck, shoulders, upper arms and often the face. They may be quite strong and difficult to control.Progressive Myoclonic Epilepsy: rare syndromes in this category' feature a combination of myoclonic seizures and tonic-clonic seizures. Treatment is usually not successful for very long, as the patient deteriorates over time.

[0029] "Angelman syndrome (AS)" is a rare genetic disorder causing developmental disabilities and nerve-related symptoms. It usually is not detected until developmental delays become noticeable, usually when a baby is about 6 to 12 months old.

[0030] "Doose syndrome" (also known as Myoclonic atonic epilepsy (MAE) is a seizure disorder characterized by frequent myoclonic and myoclonic-atonic seizures. Myoclonic seizures cause jerking or twitching in the arms and legs. Atonic seizures cause a loss of muscle control. It is a rare disease and accounts for 1-2% of all childhood epilepsies. Usually, the first seizure occurs between 2 and 6 years of age (2 / 3 of children diagnosed are boys). Children with Doose syndrome may have multiple seizure types: 1) drop seizures, characterized by an abrupt fall with loss of body tone (atonic) or by a brief body jerk followed by an abrupt fall (myoclonic atonic), occur in every one; 2) generalized tonic-clonic seizures are seen in most children (these may be triggered by fever; 3) absence seizures and myoclonic seizures are seen in many cases; 4) tonic seizures can be seen later in the course of disease and often are predictive of poorer outcomes. About 1 in 3 children with Doose syndrome have episodes of non-convulsive status epilepticus.

[0031] "Mitochondria! encephalomyopathy" is an inherited mitochondrial disease primarily affecting the nervous system and muscles. It presents in children or young adults as recurrent episodes of encephalopathy, myopathy, headache and focal neurological deficits. It is mostly caused by mutations in the genes in mitochondrial DNA, but it can also be caused by mutations in the nuclear DNA. Children with this often have normal early psychomotor development until the onset of symptoms between 2 and 10 years old. Though less common, infantile onset may occur and may present as a failure to thrive, growth retardation and progressive deafness. Onset in older children typically presents as recurrent attacks of a migraine-like headache, anorexia, vomiting and seizures.

[0032] "Dravet syndrome", previously known as severe myoclonic epilepsy of infancy (SMEI), is an autosomal dominant genetic disorder which causes a catastrophic form of epilepsy, with prolonged seizures that are often triggered by hot temperatures or fever. It is very difficult to treat with anticonvulsant medications. It often begins before one year of age, with six months being the age that seizures, characterized by prolonged convulsions and triggered by fever, usually begin. It is a rare disease that occurs in 1 in 20.000 to 40,000 births.

[0033] "Irregular, persistent seizures" means that the timing of when a patient experiences seizures is inconsistent, but the patient continues to experience several seizures over time.

[0034] "THC compound" refers to Delta-9-tetrahydrocannabinol (THC) and known structural and functional analogues, whether synthetic or botanically-derived. "THC compound" also includes metabolites of THC and structural and functional analogues of THC. In some embodiments, 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, ll-OH-Delta-8- tetrahydrocannabinol, Tetrahydrocannabivarin (THC-V), Carboxytetraydrocannabivarin (THCV-COOH), HU-210, Perrottetinene, or Perrottetinenic acid, or any salt of any of these compounds.METHODS OF TREATING NON-CONVULSIVE SEIZURES

[0035] In some embodiments, the present disclosure is directed to methods of treating non-convulsive seizures in a patient in need thereof, compnsing administering to the patient a THC compound in a therapeutically effective dose. In some embodiments, the methods comprise administering the THC compound as a seizure rescue medication. In some embodiments, the THC compound is administered by transmucosal route when administered as a seizure rescue medication. In some embodiments, the THC compound is administered by inhalation when administered as a seizure rescue medication.

[0036] In some embodiments, the present disclosure is directed to methods of treating non-convulsive seizures in a patient in need thereof, comprising administering to the patient a THC compound in combination with another anti-seizure medication in therapeutically effective doses. Certain exemplary anti-seizure medications include, for example, the medications listed in Table 3 at page 1273 of Kanner et al., "Antiseizure Medications for Adults with Epilepsy - A Review," JAMA, 327(13): 1269-1281 (2022). Other exemplary anti-seizure medications include, for example, fenfluramine, cenobamate, and the anti-seizure medications listed in Examples below.

[0037] In some embodiments, the dose of the THC compound is at a level that results in minimal or no untoward psychotropic effects in the patient. Certain untoward psychotropic effects include, for example, anxiety, a feeling of being disconnected, a feeling of depersonalization, confusion, and / or paranoia.

[0038] In some embodiments, the dose of the THC compound is 2.5 to 150 mg daily, 2.5 to 70 mg daily, 2.5 to 50 mg daily, 5 to 70 mg daily, 2.5 to 50 mg daily, 2.5 to 5 mg daily, 2.5 to 25 mg daily, 2.5 to 12.5 mg daily, 5 to 50 mg daily, 5 to 25 mg daily, 5 to 12.5 mg daily, 2.5 to 20 mg daily, 5 to 20 mg daily, 12.5 to 20 mg daily, 12.5 to 25 mg daily, 12.5 to 50 mg daily, 12.5 to 70 mg 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 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.

[0039] In some embodiments, the THC compound is included in a formulation that comprises the THC compound and less than 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, or 10% cannabidiol (CBD). In some embodiments, the THC compound is included in a formulation that comprises the THC compound and no CBD. An example of such a formulation that comprises the THC compound and no CBD is dronabinol.EXEMPLARY EMBODIMENTS

[0040] The present disclosure is directed to several embodiments of treating non- convulsive seizures. For example, the disclosure includes the following embodiments.

[0041] 1. A method of treating non-convulsive seizures in a patient in need thereof, comprising administering to the patient a THC compound in a therapeutically effective dose.

[0042] 2. The method of embodiment of claim 1, further comprising administering another anti-seizure medication in combination with the THC compound.

[0043] 3. A method of treating non-convulsive seizures in a patient in need thereof, comprising administering to the patient dronabinol in a therapeutically effective dose.

[0044] 4. The method of embodiment of claim 3, further comprising administering another anti-seizure medication in combination with dronabinol.

[0045] 5. A method of treating non-convulsive seizures in a patient in need thereof, comprising administering to the patient delta-9-tetrahydrocannabinol in a therapeutically effective dose.

[0046] 6. The method of embodiment 5, further comprising administering another anti-seizure medication in combination with delta-9-tetrahydrocannabinol.

[0047] 7. The method of any of embodiments 1-6, wherein the dose is at a level that results in minimal or no untoward psychotropic effects in the patient.

[0048] 8. The method of any of embodiments 1-7, wherein the method comprises administering the THC compound as a seizure rescue medication.

[0049] 9. The method of any of embodiments 1-8, wherein the dose is 2.5 to 150 mg daily: 2.5 to 70 mg daily; 2.5 to 50 mg daily; 5 to 70 mg daily; 2.5 to 50 mg daily; 2.5 to 5 mg daily; 2.5 to 25 mg daily; 2.5 to 12.5 mg daily; 5 to 50 mg daily; 5 to 25 mg daily; 5 to 12.5 mg daily; 2.5 to 20 mg daily; 5 to 20 mg daily; 12.5 to 20 mg daily; 12.5 to 25 mg daily; 12.5 to 50 mg daily; 12.5 to 70 mg daily; 0.02 to 4.0 mg / kg daily; 0.02 to 4.0 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.

[0050] 10. The method of any of embodiments 1-2, 7-9, wherein the THC compound is Dronabinol, Delta-9-tetrahydrocannabinol (THC), Delta-8-tetrahydrocannabinol (THC), Carboxy tetrahydrocannabinol (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-tetrahy drocannabinol,Tetrahydrocannabivarin (THC-V), Carboxytetraydrocannabivarin (THCV-COOH), HU-210, Perrottetinene, or Perrottetinenic acid, or any salt of any of these compounds. 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-tetrahy drocannabinol, 1 l-OH-Delta-8-tetrahy drocannabinol, Tetrahydrocannabivarin (THC- V), Carboxytetraydrocannabivarin (THCV-COOH), HU-210, Perrottetinene, or Perrottetinenic acid, or any salt of any of these compounds.

[0051] 11. The method of any of embodiments 2, 4, 6-10, wherein the another antiseizure medication is lamotrigine, topiramate, topiramate XR, vagus nerve stimulation, phenytoin, valproic acid, zonisamide, benzodiazepine, surgery, levetiracetam, carbamazepine, oxcarbazepine, lacosamide, perampanel, clonazepam, phenobarbial, pregabalin, gabapentin, rufmamide, CBD (e.g.. Epidiolex), clobazam, felbamate, fenfluramine, or cenobamate.

[0052] 12. The method of any of embodiments 1-11, wherein the method further includes subjecting the patient to vagus nen e stimulation seizure treatment or surgery seizure treatment.

[0053] 13. The method of any of embodiments 1-12, wherein the THC compound, the dronabinol, or the delta-9-tetrahydrocannabinol is delivered by oral delivery, inhaled or aerosol delivery, dermal deliver}', or injectable delivery.

[0054] 14. The method of claim 13, wherein the oral delivery' is provided by a liquid formulation, a capsule, a tablet, or another ingestible edible form (for example, candy, gum, lozenges).

[0055] 15. The method of claim 13, wherein the aerosol delivery is provided by a nasal spray, an aerosol for inhalation, or vaping or smoking.

[0056] 16. The method of claim 13, wherein the injectable delivery is provided by an intraperitoneal, intravenous, intramuscular, intradermal, or subcutaneous route.

[0057] 17. The method of any of embodiments 1-16, wherein the THC compound, the dronabinol, or the delta-9-tetrahydrocannabinol is included in a formulation that comprises THC compound and less than 1%, 2%. 3%, 4%, 5%, 6%, 7%. 8%, 9%. or 10% cannabidiol (CBD).

[0058] 18. The method of any of embodiments 1-17, wherein the THC compound, the dronabinol, or the delta-9-tetrahydrocannabinol is included in a formulation that comprises the THC compound and no CBD.

[0059] The following abbreviations in this disclosure have the following meanings.

[0060] Abs or ABS: absence

[0061] CPS: complex partial seizure

[0062] DS: Dravet Syndrome

[0063] Mito Enceph: Mitochondrial encephalomyopathy

[0064] Myo or MYO: myoclonic seizure

[0065] TDD: Total Daily Dose

[0066] FV : first visit

[0067] Occ: occasional

[0068] DPH: phenytoin

[0069] VPA: valproic acid

[0070] ZNS: zonisamide

[0071] Benzo: benzodiazepine

[0072] LTG: lamotrigine

[0073] LEV: levetiracetam

[0074] CBZ: carbamazepine

[0075] TPX: topiramate XR

[0076] OXC: oxcarbazepine

[0077] GBP: gabapentin

[0078] CLZ: clonazepam

[0079] CB: cannabinoid

[0080] TPM: topiramate

[0081] FBT: felbamate

[0082] RFM: rufinamide

[0083] LCM: lacosamide

[0084] PER: perampanel

[0085] PGB: pregabalin

[0086] PB: phenobarbital

[0087] VNS: vagus nerve stimulationEXAMPLES

[0088] All of the patients in the following examples were not taking THC prior to the first visit to the doctor ("first visit") unless noted otherwise. None of the patients in the following examples experienced THC-related adverse effects. Additional information for the patients in the following examples is provided in Table 1 and Table 2 below.EXAMPLE 1

[0089] In the year prior to the first visit, a 56-year old male patient was experiencing two to three absence seizures a month. Prior to the first visit, the patient was taking LTG and VNS, which treatment continued after the first visit. After the first visit, the patient was taking THC by smoking cannabis daily, so the dosage and timing of the dosage was unknown. Because CBD is delivered at sub-therapeutic levels when marijuana is smoked, it is acceptable to attribute any therapeutic effect to THC. The label for the CBD drug Epidiolex includes dosages starting at 5 mg / kg daily for all indications, and increasing to maintenance doses of 10 mg / kg or 20 mg / kg for Lennox-Gestault Syndrome and Dravet Syndrome, and increasing to maintenance doses of 25 mg / kg per day for Tuberous Sclerosis Complex. When 1 gram of cannabis is smoked, it delivers CBD to the lungs in doses well below- the therapeutic dose levels prescribed for Epidiolex.

[0090] During the year after commencing THC, the patient had no non-convulsive seizures, including no absence seizures.EXAMPLE 2

[0091] In the year prior to the first visit, a 19-year old male patient was experiencing one or two complex partial seizures a day. Prior to the first visit, the patient was taking VP A, ZNS. and Benzo, which treatment continued after the first visit. After the first visit, the patient initially was taking 4 mg THC orally per day and 175 mg CBD per day (lovia oral tincture). The 4 mg daily dose of THC w as continually increased up to 12 mg THC orally per day over time over 5 annual visits.

[0092] The label for the CBD drug Epidiolex includes dosages starting at 5 mg / kg daily for all indications, and increasing to maintenance doses of 10 mg / kg or 20 mg / kg forLennox-Gestault Syndrome and Dravet Syndrome, and increasing to maintenance doses of 25 mg / kg per day for Tuberous Sclerosis Complex. The 175 mg CBD daily dose in this patient (2.75 mg / kg) was well below the therapeutic dosages for Epidiolex.

[0093] At the first annual follow-up visit, the patient was having two to three complex partial seizures per week. At the 4th annual visit, the patient was having one to two generalized tonic-clonic (GTC) seizures or complex partial seizures per week. (The patient had also had GTC seizures prior to the first visit.) At the 5th annual visit, the patient was having occasional myoclonic seizures and one GTC seizure or CPS seizure per week. The improvement was based on the continual increase of the THC dosage.EXAMPLE 3

[0094] In the year prior to the first visit, a 27-year old female patient was experiencing four to five absence seizures per year. Prior to the first visit, the patient was taking LTG, which treatment continued after the first visit. After the first visit, the patient was prescribed 1 mg THC orally per day for three years.

[0095] During the three years after commencing THC, the patient had no non- convulsive seizures, including no absence seizures. The patient experienced one to three "auralike deja vu" episodes per year after starting THC.EXAMPLE 4

[0096] In the year prior to the first visit, a 29-year old female patient was experiencing daily complex partial seizures with absence seizures. Prior to the first visit, the patient was taking LTG and LEV, which treatment continued after the first visit. After the first visit, the patient initially was taking 8 mg THC orally per day. The 8 mg daily dose of THC was increased over time to 12 mg THC orally per day.

[0097] During the year after commencing THC, the patient had no non-convulsive seizures, including no complex partial seizures and no absence seizures. Daily auras persisted after starting THC.EXAMPLE 5

[0098] In the year prior to the first visit, an 18-year old female patient was experiencing six to ten GTC seizures, absence seizures, or atonic seizures per month. Prior to the first visit, the patient was taking LTG and TPX, which treatment continued after the first visit. After the first visit, the patient was initially taking 1.5 mg THC and 28.5 mg CBD orally daily. That dose was changed to 4.5 mg THC and 28.5 mg CBD orally daily, and then changed to 9 mg THC and 57 mg CBD daily.

[0099] The label for the CBD drug Epidiolex includes dosages starting at 5 mg / kg daily for all indications, and increasing to maintenance doses of 10 mg / kg or 20 mg / kg for Lennox-Gestault Syndrome and Dravet Syndrome, and increasing to maintenance doses of 25 mg / kg per day for Tuberous Sclerosis Complex. The 57 mg CBD daily dose (0.71 mg / kg) was well below the therapeutic dosages for Epidiolex.

[0100] At the first follow-up visit, the patient was having four to six GTC seizures and 10 to 20 myoclonic seizures per month. At the fourth follow-up visit, the patient was experiencing reduction in seizure frequency of all types for extended periods of time and was seizure free for 40 days on 9 mg THC daily.EXAMPLE 6

[0101] In the year prior to the first visit, a 55-year old male patient was experiencing four absence seizures per year. Prior to the first visit, the patient was taking OXC, which treatment continued after the first visit. After the first visit, the patient was taking THC daily by smoking cannabis, so the dosage and timing of the dosage was unknown. Because CBD is delivered at sub-therapeutic levels when marijuana is smoked, it is acceptable to attribute any therapeutic effect to THC. The label for the CBD drug Epidiolex includes dosages starting at 5 mg / kg daily for all indications, and increasing to maintenance doses of 10 mg / kg or 20 mg / kg for Lennox-Gestault Syndrome and Dravet Syndrome, and increasing to maintenance doses of 25 mg / kg per day for Tuberous Sclerosis Complex. When 1 gram of cannabis is smoked, it delivers CBD to the lungs in doses well below the therapeutic dose levels prescribed for Epidiolex.During the five years after commencing THC, the patient had one absence seizure per year and no other non-convulsive or convulsive seizures.EXAMPLE 7

[0102] In the year prior to the first visit, a 34-year old male patient was experiencing irregular, persistent absence seizures. "Irregular, persistent seizures" means that the timing of when a patient experienced seizures was inconsistent, but the patient continued to experience several seizures over time. For example, a patient may have five seizures a week, followed by weeks of having no seizures, and then have a week with three seizures.

[0103] Prior to the first visit, the patient was taking DPH, which treatment continued after the first visit. After the first visit, the patient was taking THC by smoking cannabis, so the dosage and timing of the dosage was unknown. Because CBD is delivered at sub-therapeutic levels when marijuana is smoked, it is acceptable to attribute any therapeutic effect to THC. The label for the CBD drug Epidiolex includes dosages starting at 5 mg / kg dailyfor all indications, and increasing to maintenance doses of 10 mg / kg or 20 mg / kg for Lennox- Gestault Syndrome and Dravet Syndrome, and increasing to maintenance doses of 25 mg / kg per day for Tuberous Sclerosis Complex. When 1 gram of cannabis is smoked, it delivers CBD to the lungs in doses well below the therapeutic dose levels prescribed for Epidiolex.

[0104] During the three years after commencing THC, the patient had no non- convulsive seizures of any type, including no absence seizures.EXAMPLE 8

[0105] In the year prior to the first visit, a 32-year old male patient was experiencing irregular, persistent polymorphic seizures, including GTC seizures, absence seizures, myoclonic seizures, and complex partial seizures. Prior to the first visit, the patient was taking LEV. which treatment continued after the first visit. After the first visit, the patient was taking unknown amounts of THC by smoking cannabis or taking oral THC, so the dosage and timing of the dosage was unknown. Because CBD is delivered at sub-therapeutic levels when marijuana is smoked, it is acceptable to attribute any therapeutic effect to THC. The label for the CBD drug Epidiolex includes dosages starting at 5 mg / kg daily for all indications, and increasing to maintenance doses of 10 mg / kg or 20 mg / kg for Lennox-Gestault Syndrome and Dravet Syndrome, and increasing to maintenance doses of 25 mg / kg per day for Tuberous Sclerosis Complex. When 1 gram of cannabis is smoked, it delivers CBD to the lungs in doses well below the therapeutic dose levels prescribed for Epidiolex.

[0106] During the year after commencing THC. the patient had no seizures of any type.EXAMPLE 9

[0107] In the year prior to the first visit, a 49-year old female patient was experiencing one absence seizure per year. Prior to the first visit, the patient was taking LEV, which treatment continued after the first visit. After the first visit, the patient was taking 0.5 mg THC and 9.5 mg CBD orally daily at bedtime by tincture.

[0108] The label for the CBD drug Epidiolex includes dosages starting at 5 mg / kg daily for all indications, and increasing to maintenance doses of 10 mg / kg or 20 mg / kg for Lennox-Gestault Syndrome and Dravet Syndrome, and increasing to maintenance doses of 25 mg / kg per day for Tuberous Sclerosis Complex. The 9.5 mg CBD daily dose (0.16 mg / kg) was well below the therapeutic dosages for Epidiolex.

[0109] During the year after commencing THC the patient had no non-convulsive seizures, including no absence seizures.EXAMPLE 10

[0110] In the year prior to the first visit, a 34-year old male patient was experiencing irregular, persistent complex partial seizures, including multiple complex partial seizures every week. Prior to the first visit, the patient was taking LTG, CBZ, CLZ, PB, PGB, and Benzo, which treatment continued after the first visit. After the first visit, the patient was taking unknown amounts of THC by smoking 3.5 g cannabis per week or vaporizing several times / day (unknown dose of THC). Because CBD is delivered at sub-therapeutic levels when marijuana is smoked, it is acceptable to attribute any therapeutic effect to THC. The label for the CBD drug Epidiolex includes dosages starting at 5 mg / kg daily for all indications, and increasing to maintenance doses of 10 mg / kg or 20 mg / kg for Lennox-Gestault Syndrome and Dravet Syndrome, and increasing to maintenance doses of 25 mg / kg per day for Tuberous Sclerosis Complex. When 1 gram of cannabis is smoked, it delivers CBD to the lungs in doses well below the therapeutic dose levels prescribed for Epidiolex.[OHl] The patient later was taking 2 mg THC and 19 mg CBD orally daily at bedtime. The label for the CBD drug Epidiolex includes dosages starting at 5 mg / kg daily (orally) for all indications, and increasing to maintenance doses of 10 mg / kg or 20 mg / kg for Lennox-Gestault Syndrome and Dravet Syndrome, and increasing to maintenance doses of 25 mg / kg per day for Tuberous Sclerosis Complex. The 19 mg CBD daily dose w as well below the therapeutic dosages for Epidiolex.

[0112] The patient had recurrent complex partial seizures while eaning down the PGB dose due to side effects. By the eighth follow-up visit, the patient had no complex partial seizures, no other types of non-convulsive seizures, for 18 months with the PGB dose reduced from 400 mg to 70 mg.EXAMPLE 11

[0113] In the year prior to the first visit, a 57-year old male patient was experiencing irregular, persistent absence seizures. Prior to the first visit, the patient was taking OXC, which treatment continued after the first visit. After the first visit, the patient was taking unknown amounts of THC by smoking cannabis, or inhaling 6.25mg THC daily. Because CBD is delivered at sub-therapeutic levels when marijuana is smoked, it is acceptable to attribute any therapeutic effect to THC. The label for the CBD drug Epidiolex includes dosages starting at 5 mg / kg daily for all indications, and increasing to maintenance doses of 10 mg / kg or 20 mg / kg for Lennox-Gestault Syndrome and Dravet Sy ndrome, and increasing to maintenance doses of 25 mg / kg per day for Tuberous Sclerosis Complex. When 1 gram of cannabis is smoked, itdelivers CBD to the lungs in doses well below the therapeutic dose levels prescribed for Epidiolex.

[0114] During the eleven years after commencing THC, the patient had no non- convulsive seizures of any type, including no absence seizures.EXAMPLE 12

[0115] In the year prior to the first visit, a 34-year old female patient was experiencing several myoclonic seizures per week. Prior to the first visit, the patient was taking LCM and LEV, which treatment continued after the first visit. After the first visit, the patient was taking 5 mg THC orally per day and 20 mg CBD orally per day.

[0116] The label for the CBD drug Epidiolex includes dosages starting at 5 mg / kg daily for all indications, and increasing to maintenance doses of 10 mg / kg or 20 mg / kg for Lennox-Gestault Syndrome and Dravet Syndrome, and increasing to maintenance doses of 25 mg / kg per day for Tuberous Sclerosis Complex. The 20 mg CBD daily dose was well below the therapeutic dosages for Epidiolex.

[0117] During the year after commencing THC, the patient had no non-convulsive seizures of any type, including no myoclonic seizures.EXAMPLE 13

[0118] In the year prior to the first visit, a 22 -year old male patient was experiencing two to three myoclonic seizures per week. Prior to the first visit, the patient was taking LEV and GBP, which treatment continued after the first visit. After the first visit, the patient was taking unknown amounts of THC by smoking cannabis, however switched to taking 10 mg THC orally daily and 10 mg CBD orally daily. Because CBD is delivered at sub-therapeutic levels when marijuana is smoked, it is acceptable to attribute any therapeutic effect to THC. The label for the CBD drug Epidiolex includes dosages starting at 5 mg / kg daily for all indications, and increasing to maintenance doses of 10 mg / kg or 20 mg / kg for Lennox-Gestault Syndrome and Dravet Syndrome, and increasing to maintenance doses of 25 mg / kg per day for Tuberous Sclerosis Complex. When 1 gram of cannabis is smoked, it delivers CBD to the lungs in doses well below7the therapeutic dose levels prescribed for Epidiolex. Also, the 10 mg CBD daily oral dose was well below the therapeutic dosages for Epidiolex.

[0119] During the two years after commencing THC, the patient had no non- convulsive seizures of any ty pe, including no myoclonic seizures.EXAMPLE 14

[0120] In the year prior to the first visit, a 52-year old male patient was experiencing three absence seizures per day. Prior to the first visit, the patient was taking LTG, whichtreatment continued after the first visit. After the first visit, the patient initially was taking 5 mg THC orally per day. The 5 mg daily dose of THC was increased over time to 20 mg THC orally per day.

[0121] The patient had persistent absence seizures and two GTC seizures while taking Lamictal XR irregularly and after stopping cannabinoid products during a job search. Restarting Lamictal and THC resulted in complete seizure remission.EXAMPLE 15

[0122] In the year prior to the first visit, a 4-year old female patient was experiencing frequent myoclonic seizures. Prior to the first visit, the patient was taking RFM, TPM, and CBD, which treatment continued after the first visit. After the first visit, the patient initially was taking 2 mg THC orally twice per day and 30mg CBD orally twice per day. The patient later was taking 3 mg THC and 30 mg CBD orally twice a day.

[0123] The label for the CBD drug Epidiolex includes dosages starting at 5 mg / kg daily for all indications, and increasing to maintenance doses of 10 mg / kg or 20 mg / kg for Lennox-Gestault Syndrome and Dravet Syndrome, and increasing to maintenance doses of 25 mg / kg per day for Tuberous Sclerosis Complex. The 30 mg CBD daily dose was well below the therapeutic dosages for Epidiolex.

[0124] During the year after commencing THC, the patient had infrequent myoclonic seizures and no other types of non-convulsive seizures.EXAMPLE 16

[0125] In the year prior to the first visit, a 3-year old male patient was experiencing frequent myoclonic seizures. Prior to the first visit, the patient was taking CEV and GBP, which treatment continued after the first visit. After the first visit, the patient initially was taking a total daily dose of 4 mg THC orally. The patient's daily dose was increased over time to a total daily dose of 12 mg THC orally.

[0126] During the five years after commencing THC, the patient had infrequent myoclonic seizures and no other types of non-convulsive seizures. No non-convulsive or convulsive seizures were reported on the total daily dose of 12 mg THC orally.EXAMPLE 17

[0127] In the year prior to the first visit, a 13-year old male patient was experiencing frequent absence seizures. Prior to the first visit and after the first visit, the patient was taking no other anti-seizure medications. After the first visit, the patient initially was taking a total daily dose of 5 mg THC orally. The patient's daily dose was increased over time to a total daily dose of 12 mg THC orally.

[0128] When taking a total daily dose of 12 mg THC, the patient had infrequent myoclonic seizures and no other types of non-convulsive seizures.EXAMPLE 18

[0129] In the year prior to the first visit, a 12-year old male patient was experiencing infrequent absence seizures. Prior to the first visit, the patient was taking LTG and TPM, which treatment continued after the first visit. After the first visit, the patient initially was taking CBD at an unknown dose without taking THC. Without THC, the CBD resulted in worsening seizures and a drug interaction with other antiseizure medication. The CBD was stopped, and THC was added to regimen with THC only for rescue as needed. The rescue medication was lOmg / mL oral liquid, with 1-3 mg THC per rescue administration.

[0130] When THC was added as a rescue medication, the frequency of absence seizures was reduced.EXAMPLE 19

[0131] In the year prior to the first visit, a 5-year old female patient was experiencing frequent atonic seizures (at least one per day). Prior to the first visit, the patient was taking VP A and Benzo, which treatment continued after the first visit. After the first visit, the patient was taking a total daily dose of 5 mg THC orally and a 1.875 mg THC-A patch was applied daily.

[0132] During the two years after commencing THC, the patient's atonic seizures were largely resolved, and the patient had no other types of non-convulsive seizures.

[0133] Tables 1 and 2 for patients in Examples 1 to 19Table 1Table 2

[0134] Those having ordinary skill in the art will appreciate that the disclosure can be modified in ways not specifically described herein. The disclosure is not to be limited in scope by the specific embodiments described herein, which are for illustrative purposes only. The disclosure includes any modifications and variations, including all functionally equivalent productions, compositions, and methods.

Claims

CLAIMS1. A method of treating non-convulsive seizures in a patient in need thereof, comprising administering to the patient a THC compound in a therapeutically effective dose.

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

3. A method of treating non-convulsive seizures in a patient in need thereof, comprising administering to the patient dronabinol in a therapeutically effective dose.

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

5. A method of treating non-convulsive seizures in a patient in need thereof, comprising administering to the patient delta-9-tetrahydrocannabinol in a therapeutically effective dose.

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

7. The method of any of claims 1-6, wherein the dose is at a level that results in minimal or no untoward psychotropic effects in the patient.

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

9. The method of any of claims 1-8, wherein the dose is 2.5 to 150 mg daily.

10. The method of any of claims 1-8, wherein the dose is 2.5 to 70 mg daily.

10. The method of any of claims 1-8, wherein the dose is 2.5 to 50 mg daily.

11. The method of any of claims 1-8, wherein the dose is 5 to 70 mg daily.

12. The method of any of claims 1-8, wherein the dose is 2.5 to 50 mg daily.

13. The method of any of claims 1-8, wherein the dose is 2.5 to 5 mg daily.

14. The method of any of claims 1-8, wherein the dose is 2.5 to 25 mg daily.

15. The method of any of claims 1-8, wherein the dose is 2.5 to 12.5 mg daily.

16. The method of any of claims 1-8, wherein the dose is 5 to 50 mg daily.

17. The method of any of claims 1-8, wherein the dose is 5 to 25 mg daily.

18. The method of any of claims 1-8, wherein the dose is 5 to 12.5 mg daily.

19. .The method of any of claims 1-8, wherein the dose is 2.5 to 20 mg daily.

20. The method of any of claims 1-8, wherein the dose is 5 to 20 mg daily.

21. The method of any of claims 1-8, wherein the dose is 12.5 to 20 mg daily.

22. The method of any of claims 1-8, wherein the dose is 12.5 to 25 mg daily.

23. The method of any of claims 1-8, wherein the dose is 12.5 to 50 mg daily.

24. The method of any of claims 1-8, wherein the dose is 12.5 to 70 mg daily.

25. The method of any of claims 1-8, wherein the dose is 0.02 to 4.0 mg / kg daily.

26. The method of any of claims 1-8, wherein the dose is 0.02 to 4.0 mg / kg daily.

27. The method of any of claims 1-8, wherein the dose is 0. 112 to 0.56 mg / kg daily.

28. The method of any of claims 1-8, wherein the dose is 0.32 to 0.56 mg / kg daily.

29. The method of any of claims 1-8, wherein the dose is 0. 112 to 0.32 mg / kg daily.

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