Composition of cannabinoid extract of cw1as1 for the treatment of autism and associated symptoms

Abstract

The present disclosure provides botanical drug compositions and methods of their use for treating nervous system and / or mental diseases, conditions, disorders, and / or symptoms.

Description

Attorney Docket No.38383.0001P1 COMPOSITION OF CANNABINOID EXTRACT OF CW1AS1 FOR THE TREATMENT OF AUTISM AND ASSOCIATED SYMPTOMS

[0001] The present disclosure relates to a Cannabis sativa L.-derived composition and methods of their use for treating autism, epilepsy, and / or symptoms. BACKGROUND OF THE DISCLOSURE

[0002] Botanical cannabinoid extracts with cannabidiol (CBD) as the dominant cannabinoid have the potential to be effective in the treatment of nervous system, including central nervous system (CNS), and mental diseases, conditions, disorders, and / or symptoms. There is a long felt need for effective CBD-based botanical pharmaceuticals to use for treating one or more symptoms of autism and epilepsy. SUMMARY OF THE DISCLOSURE

[0003] The present disclosure provides pharmaceutical compositions comprising an oral suspension of a cannabinoid extract of Cannabis sativa L. and having a concentration of from beta- caryophyllene at an amount that is 2% to 10% percent of the amount of beta caryophyllene in the air dried plant material from which the extract is obtained, and / or α-bisabolol at an amount that is 2% to 20% percent of the amount of α-bisabolol ne in the air dried plant material from which the extract is obtained and / or α-humelene at an amount that is 2% to 20% percent of the amount of α- humelene in the air dried plant material from which the extract is obtained.

[0004] In some embodiments, the cannabinoid extract is of hemp variety ‘CW1AS1’, wherein representative seeds of the variety have been deposited under NCIMB No.43291.

[0005] In some embodiments, the pharmaceutical compositions of the present disclosure comprise the cannabinoid extract and glyceryl monolinoleate, such as unsaturated glycerol monolinoleate, and optionally a flavoring agent. In some embodiments, the composition is not an emulsion. The present disclosure provides methods of treating autism, epilepsy, or one or more symptoms thereof by administering an effective amount of the pharmaceutical compositions of the present disclosure.

[0006] In some embodiments, the methods of treating as disclosed herein are for treating a primary indication of a disease, disorder, condition, or symptom.Attorney Docket No.38383.0001P1

[0007] In some embodiments, the methods of treating as disclosed herein are for treating a secondary indication of a disease, disorder, condition, or symptom.

[0008] In some embodiments, the methods of treating as disclosed herein are for treating anxiety and / or irritability associated with autism.

[0009] The present disclosure provides methods of treating a disease, disorder, condition, and / or symptom, including symptoms associated with autism spectrum disorder, by administering the pharmaceutical composition with the cannabinoid extract of CW1AS1 being about 25 mg to about 300 mg for a <14 year old patient daily dose and about 50 mg to about 650 mg for an adult daily dose.

[0010] Current autism spectrum disorder (ASD) treatments are limited in efficacy and are associated with debilitating side effects. The botanical drug product of the present disclosure has the potential to have therapeutic effects in the treatment of irritability, repetitive behaviors, improved cognition, sociability, and quality of life for ASD patients. BRIEF DESCRIPTION OF THE DRAWINGS

[0011] FIG.1 provides an example study design for the clinical protocol of the present disclosure. DETAILED DESCRIPTION OF THE DISCLOSURE I. Definitions

[0012] Unless stated otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by those of ordinary skill in the art to which the disclosure belongs. While the following terms are believed to be well understood by one of ordinary skills in the art, the following definitions are set forth to facilitate explanation of the presently disclosed subject matter. Although any methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present disclosure, preferred methods and materials are described. The following terms are defined below. These definitions are for illustrative purposes and are not intended to limit the common meaning in the art of the defined terms.

[0013] The term “a” or “an” refers to one or more of that entity, i.e., can refer to a plural referent. As such, the terms “a” or “an”, “one or more” and “at least one” are used interchangeably herein. In addition, reference to “an element” by the indefinite article “a” or “an” does not exclude theAttorney Docket No.38383.0001P1 possibility that more than one of the elements is present, unless the context clearly requires that there is one and only one of the elements.

[0014] As used in this specification, the term “and / or” is used in this disclosure to mean either “and” or “or” unless indicated otherwise.

[0015] Throughout this specification, unless the context requires otherwise, the words “comprise”, or variations such as “comprises” or “comprising”, will be understood to imply the inclusion of a stated element or integer or group of elements or integers but not the exclusion of any other element or integer or group of elements or integers.

[0016] As used in this application, the terms “about” and “approximately” are used as equivalents. Any numerals used in this application with or without about / approximately are meant to cover any normal fluctuations appreciated by one of ordinary skill in the relevant art. In certain embodiments, the term “approximately” or “about” refers to a range of values that fall within 10%in either direction (greater than or less than) of the stated reference value unless otherwise stated or otherwise evident from the context (except where such number would exceed 100% of a possible value).

[0017] As used herein, “λz” refers to a terminal rate constant.

[0018] As used herein, “AE” refers to an adverse event.

[0019] As used herein, “Aer” refers to a cumulative amount excreted renally.

[0020] As used herein, “AESI” refers to an adverse event of special interest.

[0021] As used herein, “ALP” refers to alkaline phosphatase.

[0022] As used herein, “ALT” refers to alanine aminotransferase.

[0023] As used herein, “ANOVA” refers to analysis of variance.

[0024] As used herein, “ALT” refers to alanine aminotransferase.

[0025] As used herein, “API” refers to an active pharmaceutical ingredient.

[0026] As used herein, “ASM” refers to anti-seizure medication.

[0027] As used herein, “ASD” refers to autism spectrum disorder.

[0028] As used herein, “AST” refers to aspartate aminotransferase.Attorney Docket No.38383.0001P1

[0029] As used herein, “AUC0-inf”refers to the area under the concentration-time curve from time zero to infinity (extrapolated).

[0030] As used herein, “AUC0-last” refers to the area under the concentration-time curve from time zero until the last observed concentration.

[0031] As used herein, “AUC0-tau” refers to the area under the concentration-time curve from time zero to the end of dosing interval (tau) at steady state.

[0032] As used herein, “BDP” refers to a botanical drug product.

[0033] As used herein, “BDS” refers to a botanical drug substance.

[0034] As used herein, “BID” refers to twice a day.

[0035] As used herein, “BMI” refers to body mass index.

[0036] As used herein, “BP” refers to blood pressure.

[0037] As used herein, “BT” refers to body temperature.

[0038] As used herein, “CB” refers to G protein-coupled cannabinoid receptors.

[0039] As used herein, “CB1” refers to cannabinoid Type 1.

[0040] As used herein, “CB2” refers to cannabinoid Type 2.

[0041] As used herein, “CBC” refers to cannabichromene.

[0042] As used herein, “CBD” refers to cannabidiol.

[0043] As used herein, “CBDA” refers to cannabidiolic acid.

[0044] As used herein, “CBG” refers to cannabigerol.

[0045] As used herein, “CBN” refers to cannabinol.

[0046] As used herein, “CI” refers to the confidence interval.

[0047] As used herein, “CK” refers to creatine kinase.

[0048] As used herein, “Cl / F” refers to apparent clearance.

[0049] As used herein, “Cl / F,ss” refers to an apparent clearance at steady state.

[0050] As used herein, “ClR” refers to renal clearance.

[0051] As used herein, “Cmax” refers to maximal observed concentration.

[0052] As used herein, “Cmin” refers to minimal observed concentration.Attorney Docket No.38383.0001P1

[0053] As used herein, “CNS” refers to the central nervous system.

[0054] As used herein, “CRO” refers to a contract research organization.

[0055] As used herein, “CS” refers to clinically significant.

[0056] As used herein, “C-SSRS” refers to Columbia suicidality severity rating scale.

[0057] As used herein, “CSR” refers to clinical study report.

[0058] As used herein, “CTCAE” refers to Common Terminology Criteria for Adverse Events.

[0059] As used herein, “CTlast” refers to concentration at last time point.

[0060] As used herein, “CTU” refers to a Clinical Trial Unit.

[0061] As used herein, “CV” refers to the coefficient of variation.

[0062] As used herein, “CYP” refers to cytochrome P450.

[0063] As used herein, “DRF” refers to dose range finding.

[0064] As used herein, “DS” refers to Dravet Syndrome.

[0065] As used herein, “DSST” refers to Digit Symbol Substitution Test.

[0066] As used herein, “DEQ” refers to Drug Effects Questionnaire.

[0067] As used herein, “ECG” refers to electrocardiogram.

[0068] As used herein, “EC” refers to an ethics committee.

[0069] As used herein, “ECS” refers to the endogenous cannabinoid system.

[0070] As used herein, “eCRF” refers to an electronic case report form.

[0071] As used herein, “eGFR” refers to an estimated glomerular filtration rate.

[0072] As used herein, “EIU” refers to exposure in utero.

[0073] As used herein, “EMA” refers to the European Medicines Agency.

[0074] As used herein, “ENT” refers to an equilibrative nucleoside transporter.

[0075] As used herein, “EOS” refers to the end of study.

[0076] As used herein, “ET” refers to early termination.

[0077] As used herein, “FAAH” refers to fatty acid amide hydrolase.

[0078] As used herein, “fe%” refers to the fraction of unchanged drug excreted.

[0079] As used herein, “FE” refers to food-effect.Attorney Docket No.38383.0001P1

[0080] As used herein, “FIH” refers to First-in-Human.

[0081] As used herein, “FDA” refers to the Food and Drug Administration.

[0082] As used herein, “FSHE” refers to a full spectrum hemp extract.

[0083] As used herein, a “full-spectrum extract” refers to a CBD product that contains multiple cannabis plant extracts, including essential oils, terpenes, and other cannabinoids.

[0084] As used herein, “GACPs” refers to good agriculture and collection practices.

[0085] As used herein, “GCP” refers to Good Clinical Practice.

[0086] As used herein, “GGT” refers to gamma-glutamyl transferase.

[0087] As used herein, “GI” refers to gastrointestinal.

[0088] As used herein, “GLM” refers to a general linear model.

[0089] As used herein, “GLP” refers to Good Laboratory Practice.

[0090] As used herein, “GMP” refers to Good Manufacturing Practice.

[0091] As used herein, “GPR55” refers to G protein-coupled receptor 55.

[0092] As used herein, “5-HT1A” refers to a 5-hydroxytryptamine 1A receptor.

[0093] As used herein, “HBsAg” refers to a hepatitis B surface antigen.

[0094] As used herein, “HCV” refers to hepatitis C virus.

[0095] As used herein, “HED” refers to human equivalent doses.

[0096] As used herein, “HEENT” refers to the head, eyes, ears, nose, and throat.

[0097] As used herein, “hERG” refers to human Ether-à-go-go-Related Gene.

[0098] As used herein, “HIV” refers to the human immunodeficiency virus.

[0099] As used herein, “HR” refers to the heart rate.

[0100] As used herein, “HREC” refers to the Human Research Ethics Committee.

[0101] As used herein, “IB” refers to an Investigator’s Brochure.

[0102] As used herein, “ICF” refers to an informed consent form.

[0103] As used herein, “ICH” refers to the International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use.

[0104] As used herein, “ICR” refers to the Institute of Cancer Research.Attorney Docket No.38383.0001P1

[0105] As used herein, “IP” refers to an investigational product.

[0106] As used herein, “IUD” refers to an intrauterine device.

[0107] As used herein, “IUS” refers to an intrauterine system.

[0108] As used herein, “Kel” refers to a terminal elimination rate constant.

[0109] As used herein, “LGS” refers to Lennox-Gastaut Syndrome.

[0110] As used herein, “LLN” refers to a lower limit of normal.

[0111] As used herein, “MAD” refers to a multiple ascending dose.

[0112] As used herein, “MCH” refers to mean cell hemoglobin.

[0113] As used herein, “MCHC” refers to mean cell hemoglobin concentration.

[0114] As used herein, “MCV” refers to mean cell volume.

[0115] As used herein, “MDMA” refers to 3,4-methylenedioxymethamphetamine.

[0116] As used herein, “MedDRA” refers to Medical Dictionary for Regulatory Activities.

[0117] As used herein, “MTD” refers to maximal tolerated dose.

[0118] As used herein, “NF” or “(NF)” refers to National Formulary-compliant excipients. NFs are standard for the pharmaceutical industry. Traditionally, a formulary contains a collection of formulas for the compounding and testing of medication.

[0119] As used herein, “NCS” refers to not clinically significant.

[0120] As used herein, “NOAEL” refers to no observed adverse effect level.

[0121] As used herein, “Orphan Drug” refers to the orphan status given to drugs and biologics for rare diseases that meet certain criteria as set by FDA’s Orphan Drug Designation program.

[0122] As used herein, “OTC” refers to over-the-counter.

[0123] As used herein, “PASAT” refers to Paced Auditory Serial Addition Test.

[0124] As used herein, “PCP” refers to phencyclidine.

[0125] As used herein, “PICF” refers to a participant information and informed consent form.

[0126] As used herein, “PK” refers to pharmacokinetic(s).

[0127] As used herein, “PD” refers to pharmacodynamics.

[0128] As used herein, “PPND” refers to pre- and postnatal development.Attorney Docket No.38383.0001P1

[0129] As used herein, “PPARγ” refers to nuclear peroxisome proliferator-activated receptor-γ. As used herein, “po” refers to oral.

[0130] As used herein, “PR” refers to the PR interval.

[0131] As used herein, “QA” refers to quality assurance.

[0132] As used herein, “QC” refers to quality control.

[0133] As used herein, “QD” refers to quaque die (once a day).

[0134] As used herein, “QT” refers to the QT interval.

[0135] As used herein, “QTcF” refers to Fridericia’s corrected QT interval.

[0136] As used herein, “RBC” refers to a red blood cell.

[0137] As used herein, “RP2D” refers to Recommended Phase 2 Dose.

[0138] As used herein, “RR” refers to the respiratory rate.

[0139] As used herein, “SAE” refers to a serious adverse event.

[0140] As used herein, “SAD” refers to a single ascending dose.

[0141] As used herein, “SAP” refers to a statistical analysis plan.

[0142] As used herein, “SAS” refers to statistical analysis system.

[0143] As used herein, “SBA” refers to a Summary Basis of Approval (SBA) prepared by the FDA Center for Drugs and Biologics for many newly approved drugs. The SBA is used to evaluate and approve new drugs for marketing based on safety and effectiveness (efficacy), to assure that these drugs are properly labeled, and to share with the public the key facts on which approval is based.

[0144] As used herein, “SD” refers to the standard deviation.

[0145] As used herein, “SOC” refers to a system organ class.

[0146] As used herein, “SOP” refers to a standard operation procedure.

[0147] As used herein, “SPT” refers to a serum pregnancy test.

[0148] As used herein, “SRC” refers to a safety review committee.

[0149] As used herein, “SUSAR” refers to a suspected, unexpected, serious adverse reaction.Attorney Docket No.38383.0001P1

[0150] As used herein, “T½ el” refers to terminal elimination half-life.

[0151] As used herein, “TEAE” refers to a treatment-emergent adverse event.

[0152] As used herein, “TGA” refers to Therapeutic Goods Administration.

[0153] As used herein, “THC” refers to tetrahydrocannabinol.

[0154] As used herein, “THCA” refers to tetrahydrocannabinolic acid.

[0155] As used herein, “Tmax” refers to a time when the maximal concentration is observed.

[0156] As used herein, “TRPV1” refers to a transient receptor potential cation channel subfamily V member 1.

[0157] As used herein, “TRPV2” refers to a transient receptor potential cation channel subfamily V member 2.

[0158] As used herein, “UGT” refers to glucuronosyltransferase.

[0159] As used herein, “ULN” refers to the upper limit of normal.

[0160] As used herein, “UPT” refers to a urinary pregnancy test.

[0161] As used herein, “USP-NF” refers to a combination of two compendia, the United States Pharmacopeia (USP) and the NF.

[0162] As used herein, “Vd / F,ss” refers to an apparent volume of distribution at steady state.

[0163] As used herein, “VPA” refers to divalproex sodium.

[0164] As used herein, “Vz / F” refers to apparent volume of distribution.

[0165] As used herein, “V / F,ss” refers to volume of distribution at steady state.

[0166] As used herein, “WBC” refers to a white blood cell.

[0167] As used herein, “WOCBP” refers to women of childbearing potential.

[0168] As used herein, “treatment” “treat” or “treating” refers to a method for obtaining beneficial or desired results for a patient, including clinical results. For purposes of the present disclosure, beneficial or desired clinical results include, but are not limited to, one or more of the following: alleviating one or more symptoms resulting from the disease, condition, disorder, and / or symptom; reducing the severity of the disease, condition, disorder, and / or symptom; stabilizing the disease, condition, disorder, and / or symptom (e.g., preventing or delaying its worsening);Attorney Docket No.38383.0001P1 preventing or delaying the spread of the disease (e.g., metastasis), condition, disorder, and / or symptom; preventing or delaying the recurrence of the disease, condition, disorder, and / or symptom; delaying or slowing the progression of the disease, condition, disorder, and / or symptom; ameliorating the state of the disease, condition, disorder, and / or symptom; providing response (partial or total) to the disease, condition, disorder, and / or symptom; reducing the dose of one or more other drugs required to treat the disease, condition, disorder, and / or symptom; delaying the progression of the disease, condition, disorder, and / or symptom; improving the quality of life, and / or prolonging survival time. The compositions and methods of the present disclosure contemplate any one or more of these treatment aspects.

[0169] As used herein, a “pharmaceutically effective amount” refers to an amount sufficient to ameliorate, reduce the rate of occurrence of, or prevent a symptom of a clinical indication II. Chemical Constituents of Cannabis

[0170] Cannabis sativa L. is a complex plant with over 400 chemical entities of which more than 60 of them are cannabinoid compounds. Atakan Z., Cannabis, a complex plant: different compounds and different effects on individuals, (Dec.2012) Ther Adv Psychopharmacol 2(6):241- 54.

[0171] Dried cannabis was found to contain a wide variety of compounds, including cannabinoids, terpenoids, flavonoids, hydrocarbons, fatty acids, phenols, and other miscellaneous classes of compounds and their metabolites. A comprehensive literature analyses and the chemical analyses of mass spectral signals identified up to 62 unique compounds in the cannabis extract attributable to 22 unique signals based on the corresponding molecular weights of the compounds or the corresponding fragments. Lewis et al., (2017) ACS Omega 2, 9, 6091–6103.

[0172] Cannabinoids in cannabis that have been confirmed include the following: Cannabicyclols (Cannabicyclolic acid (CBLA), Cannabicyclol (CBL), Cannabicyclovarin (CBLV)); Cannabichromenes (Cannabichromene (CBC), Cannabichromevarinic acid (CBCVA), Cannabichromenic acid (CBCA), Cannabichromevarin (CBCV)); Cannabielsoins (Cannabielsoin (CBE), Cannabielsoin acid A (CBEA-A), Cannabielsoic acid B (CBEA-B)); Cannabitriols (10-Attorney Docket No.38383.0001P1 Ethoxy-9-hydroxy-delta-6a-tetrahydrocannabinol, 8,9-Dihydroxy-delta-6a-tetrahydrocannabinol, Cannabitriol (CBT), Cannabitriolvarin (CBTV)); Cannabidiols (Cannabidiol (CBD), Cannabidiol monomethylether (CBDM), Cannabidiolic acid (CBDA), Cannabidivarinic acid (CBDVA), Cannabidiorcol (CBD-C1), Cannabidivarin (CBDV), Cannabidiphorol (CBDP)); Cannabigerols (Cannabigerol (CBG), Cannabigerovarin (CBGV), Cannabigerovarinic acid (CBGVA), Cannabigerol monomethylether (CBGM), Cannabigerolic acid monomethylether (CBGAM), Cannabigerolic acid (CBGA); Cannabinols and cannabinodiols (Cannabinolic acid (CBNA), Cannabinodiol (CBND), Cannabinodivarin (CBVD), Cannabinol (CBN), Cannabiorcool (CBN- C1), Cannabivarin (CBV), Cannabinol methylether (CBNM), Cannabinol-C2 (CBN-C2), Cannabinol-C4 (CBN-C4)); Delta-8-tetrahydrocannabinols (Delta-8-tetrahydrocannabinol (Δ8- THC), Delta-8-tetrahydrocannabinolic acid (Δ8-THCA)); Delta-9-tetrahydrocannabinols (Delta- 9-tetrahydrocannabinol (THC), Delta-9-tetrahydrocannabinol-C4 (THC-C4), Delta-9- tetrahydrocannabiorcol (THC-C1), Delta-9-tetrahydrocannabiorcolic acid (THCA-C1), Delta-9- tetrahydrocannabinolic acid-C4 (THCA-C4), Delta-9-tetrahydrocannabivarin (THCV), Delta-9- tetrahydrocannabivarinic acid (THCVA), Delta-9-tetrahydrocannabinolic acid A (THCA-A), Delta-9-tetrahydrocannabinolic acid B (THCA-B), Delta-9-tetrahydrocannabiphorol (THCP)); and Other Cannabinoids (10-Oxo-delta-6a-tetrahydrocannabinol (OTHC), Cannabichromanon (CBCF), Cannabifuran (CBF), Cannabiglendol, Delta-9-cis-tetrahydrocannabinol (cis-THC), Cannbicitran (CBT), Dehydrocannabifuran (DCBF), Tryhydroxy-delta-9-tetrahydrocannabinol (triOH-THC), Cannabiripsol (CBR)). See, e.g., Chief Botanicals, Complete List of Cannabinoids in Cannabis (2013). The 10 most common cannabinoids found in products today include Delta-9- Tetrahydrocannabinol (THC), Delta-8-Tetrahydrocannabinol (D8THC), Cannabidiol (CBD), Cannabinol (CBN), Cannabichromene (CBC), Cannabigerol (CBG), Tetrahydrocannabinolic acid (THCA), Cannabidiolic Acid (CBDA), Tetrahydrocannabivarin (THCV), and Cannabidivarin (CBDV).

[0173] Δ9- tetrahydrocannabinol (Δ9-THC or simply THC) is also known by its International Non-Proprietary Name (INN) as dronabinol. The unsaturated bond in the cyclohexene ring is located between C-9 and C-10 in the more common dibenzopyran ring numbering system. There are four stereoisomers of THC, but only the (–)-trans isomer occurs naturally (CAS-1972-08-03).Attorney Docket No.38383.0001P1 The fully systematic name for this THC isomer is (−)-(6aR,10aR)-6,6,9-trimethyl-3-pentyl- 6a,7,8,10a-tetrahydro-6H-benzo[c]chromen-1-ol. Two related substances, Δ9- tetrahydrocannabinol-2-oic acid and Δ9-tetrahydrocannabinol-4-oic acid (THCA), are also present in cannabis, sometimes in large amounts. The active isomer Δ8-THC, in which the unsaturated bond in the cyclohexene ring is located between C-8 and C-9, is found in much smaller amounts. Cannabis Drug Profile, European Monitoring Centre for Drugs and Drug Addiction (2023) online website.

[0174] The cannabis plant has more than 200 terpenes, many of which are only present in trace amounts. They are the chemical building blocks of essential oils in plants. Cannabis plants produce terpenes along with cannabinoids in glands called trichomes. Besides giving cannabis its taste and aroma, some terpenoids are believed to also have beneficial effects. Terpenes are simple hydrocarbons, while terpenoids are a modified class of terpenes with different functional groups and having an oxidized methyl group moved or removed at various positions. The most prominent terpenes in cannabis plants include but are not limited to myrcene, beta-caryophyllene, limonene, linalool, pinene, humulene, terpinolene, alpha-bisabolol, eucalyptol, geraniol, terpineol, farnesene, borneol, ocimene, nerolidol, guaiol, valencene, delta-3 carene, phytol, sabinene, phellandrene, fenchol, menthol, terpinene, isoborneol, and cymene. Other possible terpenes that might be present include but are not limited to octanol, isopulegol, cedrene, camphene, geranyl acetate, bergamotene, camphor, and pulegone. Liz G., The Complete List of Cannabis-Derived Terpenes (January 2, 2021) Cannabis Trends, Cannabinoids.

[0175] For additional information on the chemical constituents of cannabis see, e.g., Armentano, et al., Clinical Applications for Cannabis & Cannabinoids: A Review of the Recent Scientific Literature (October 31, 2021), NORML, 138 pages; Backes et al., Cannabis Pharmacy: The Practical Guide to Medical Marijuana – Revised and Updated (November 14, 2017) Black Dog & Leventhal, New Edition, 320 pages; Thomas et al., The Analytical Chemistry of Cannabis: Quality Assessment, Assurance, and Regulation of Medicinal Marijuana and Cannabinoid Preparations (Emerging Issues in Analytical Chemistry) Elsevier, 1stEdition, 132 pages; and Kinghorn, Phytocannabinoids: Unraveling the Complex Chemistry and Pharmacology of Cannabis sativa (Progress in the Chemistry of Organic Natural Products Book 103) Springer, 1stEdition, 140 pages.Attorney Docket No.38383.0001P1 III. Cannabidiol (CBD)

[0176] Botanical cannabinoids and purified CBD show relatively low toxicity and lack any dependence profile while having a broad spectrum of therapeutic properties, such as anticonvulsive, anxiolytic, neuroprotective, antidepressant, anti-inflammatory, and immunomodulating activities (Russo et al 2006).

[0177] The potential therapeutic effects of CBD have been attributed to multiple pharmacological mechanisms with researchers reporting more than 65 discrete molecular targets for CBD (Bih et al 2015, Lee et al 2017, Peng 2022). Cannabidiol is a highly lipophilic cannabinoid-receptor allosteric modulator that interacts with the CNS, resulting in modulation of the endogenous cannabinoid system (ECS), a widespread network of G protein-coupled cannabinoid receptors (CB), synthetic and degradative enzymes, and transporters including anandamide and 2-arachidonoylglycerol, cannabinoid (CB) Type 1 (CB1) or CB Type 2 (CB2) endogenous ligands (Di Marzo & Piscitelli 2015, Mouslech & Valla 2009, Cristino et al 2020). Physiologically, cannabinoid receptors of the ECS are present in brain regions involved in motor control, emotional responses, motivated behavior, and cognition. Peripherally these ECS receptors are involved in the modulation of the immune system, autonomic nervous system, and microcirculation (Bergamaschi et al 2011, Iffland & Grotenhermen 2017).

[0178] CBD is a blocker of the equilibrative nucleoside transporter (ENT) (Carrier et al 2006), the orphan G protein-coupled receptor (GPR)55 (Pertwee 2007), and the transient receptor potential cation channel subfamily M member (TRPM)8 channel (Muller 2019). Conversely, CBD enhances the activity of the 5-hydroxytryptamine (5-HT)1A receptor (Russo et al 2005), glycine receptors (Xiong et al 2011) and the transient receptor potential cation channel subfamily A member (TRPA)1 channel (Muller et al 2019). At high micromolar concentrations, CBD activates the nuclear peroxisome proliferator-activated receptor-γ (PPARγ) and the transient receptor potential cation channel subfamily V member (TRPV)1 and TRPV2 channels (Muller et al 2019, Pertwee 2008), also inhibiting cellular uptake and fatty acid amide hydrolase (FAAH)-catalyzed degradation of the endogenous cannabinoid anandamide (Bisogno et al 2001, De Petrocellis et al 2011). IV. Cannabis Hemp Extracts and CompositionsAttorney Docket No.38383.0001P1

[0179] The present disclosure provides for cannabinoid extracts of Cannabis sativa L. and pharmaceutical compositions comprising the same. The extracts of the present disclosure have a high ratio of CBD to THC, such as a ratio greater than 22:1.

[0180] Also described herein are methods of making a cannabinoid extract, comprising: a. providing a harvested plant material of Cannabis sativa L.; b. drying the plant material to a moisture content of the plant material of less than 10% or less than 8% in environmental conditions having an average temperature between 50 °F and 90 °F or 60 °F and 80 °F, c. contacting the dried plant material with a solvent to form a solvent extract comprising cannabinoids and terpenes and an undissolved portion; d. separating the undissolved portion from the solvent extract; e. removing a substantial portion of solvent from the solvent extract to a level of 5000 ppm in the cannabinoid extract; and f. subjecting the solvent extract to a decarboxylation process to form a cannabinoid extract. Thus, in some embodiments, the extract is a solvent reduced oil obtained from a process comprising isopropyl alcohol solvent extraction.

[0181] The cannabinoid extracts described herein are obtained from plant material of Cannabis sativa L. Suitable plant material includes the flowers and leaves of Cannabis sativa L. In some embodiments, the cannabinoid extract comprises at least 85% by weight of flowers and leaves of Cannabis sativa L.

[0182] In some embodiments, drying the plant material is in environmental conditions having a relative humidity between 0% and 65%. Drying the plant material can be in environmental conditions have a relative humidity, for example, between 0% and 60%, 0% and 50%, 0% and 40%, 0% and 30%, 0% and 20%, 0% and 10%, 10% and 65%, 10% and 50%, 10% and 40%, 10% and 30%, 10% and 20%, 20% and 65%, 20% and 50%, 20% and 40%, 20% and 30%, 30% and 65%, 30% and 50%, 30% and 40%, 40% and 65%, 40% and 50%, or 50% and 65%. The environmental conditions can have a relative humidity, for example, of about 0%, 10%, 20%, 30%, 40%, 50%, 60%, or about 65%.

[0183] In some embodiments, the dried plant material is stored for no more than 6 months at an average temperature below 80°F prior to contacting the plant material with solvent. In some embodiments, the dried plant material is stored for no more than 9 months at an average temperature below 80°F prior to contacting the plant material with solvent. In some embodiments,Attorney Docket No.38383.0001P1 the dried plant material is stored for no more than 12 months at an average temperature below 80°F prior to contacting the plant material with solvent. In some embodiments, the dried plant material is stored in a sealed container.

[0184] The solvent is one in which cannabinoids and terpenes are soluble, such an alcohol, such as isopropyl alcohol or ethanol. In some embodiments, the solvent comprises, consists of, or consists essentially of an alcohol with 2 to 5 carbons or an alcohol selected from isopropyl alcohol, ethanol, and butanol. In some embodiments, the alcohol consists of or consists essentially of isopropyl alcohol.

[0185] In some embodiments wherein the alcohol consists of or consists essentially of isopropyl alcohol, the substantial portion of the solvent is removed from the solvent extract by spraying the solvent extract onto a surface under vacuum, wherein the surface has a temperature of 170° F to 195°F or 180 °F and spraying the solvent extract in a chamber under vacuum, wherein the chamber is in fluid communication with a chiller such that vapor passes to the chiller thereby condensing vapor comprising isopropyl alcohol and separating vaporized isopropyl alcohol from the solvent extract, wherein the chiller is at a temperature of 0°C to 5°C.

[0186] In some embodiments, removing the undissolved portion from the extracted portion comprising cannabinoids comprises filtering the undissolved portion from the extraction portion.

[0187] Decarboxylation is the process of removing a carboxyl group from a carbon chain in cannabinoid acids thereby releasingCO2 released. This chemical process activates cannabinoids into more potent forms. Advantageously, the decarboxylation process detailed herein, which is performed in a vessel under vacuum, reduces the temperature required to achieve decarboxylation relative to conventional methods, such as decarboxylation in an oven.

[0188] In some embodiments, the decarboxylation process comprises heating and mixing the solvent extract in a vessel in fluid communication with a chiller to a temperature of from about 75° C to 85 °C until no evaporated solvent condensate is visually identified in the chiller.

[0189] In some embodiments, the decarboxylation process further comprises maintaining heat and lowering and holding pressure in the vessel to 600 torr until no evaporated solvent condensate is visually identified in the chiller, wherein the chiller temperature is -7°C to 0°C or about -5°C.Attorney Docket No.38383.0001P1 In some embodiments, the decarboxylation process is performed over a timespan of about 12 hours to about 16 hours.

[0190] In some embodiments, the decarboxylation process comprises heating and mixing the solvent extract in a vessel in fluid communication with a condenser to a temperature of from about 75°C to 85°C until no evaporated solvent condensate is visible in the condenser and incrementally reducing the pressure one or more times while heating, wherein between each pressure reduction no evaporated solvent condensate is visible in the condenser.

[0191]

[0192] In some embodiments, at least a portion of decarboxylation occurs during removing the solvent from the solvent extract.

[0193] In some embodiments, the vessel comprises a heat jacket configured to heat the solvent extract contained within the vessel. The above described handling and extraction process ensure an extract comprising bothcannabinoid and terpenes.

[0194] The extraction method is used to extract the cannabinoids and terpenes from hemp variety ‘CW1AS1’ strain. In other embodiments, said methods can be used with any cannabis plants.

[0195] The extracts of the present disclosure are designed to produce products for human or animal consumption via inhalation (via combustion, vaporization and nebulization), buccal absorption within the mouth, oral administration (e.g., eating / drinking), and topical application delivery methods. In embodiments, the administration is oral.

[0196] The extracts of the present disclosure may also be combined with pure compounds of interest to the extractions, e.g. cannabinoids or terpenes to further enhance or modify the resulting formulation's fragrance, flavor, or pharmacology. Thus, in some embodiments, the present disclosure teaches compositions comprising at least one ingredient extracted from the ‘CW1AS1’ plant. In some embodiments, extracts from the hemp lines of the present disclosure are combined with one or more additional compounds. In some embodiments, extracts of the present disclosure, such as whole hemp extracts, or a purified cannabinoid from said hemp plant, can be combined with another cannabinoid or terpene to produce a composition.Attorney Docket No.38383.0001P1

[0197] The compositions of the present disclosure encompass many forms. In some embodiments, the present disclosure provides CBD oils and tinctures. In some embodiments, the present disclosure provides CBD capsules. In some embodiments, the CBD oils comprise extracts from ‘CW1AS1’, such as solvent extracted oils, heat extracted oils. In some embodiments, the capsules comprise extracts from ‘CW1AS1.’ V. Pharmaceutical Composition

[0198] In some embodiments, the pharmaceutical composition of the present disclosure is a botanical drug product (BDP) comprising a cannabinoid extract of the Cannabis sativa L. plant comprising cannabinoids and terpenes. The extract can be obtained according to the process described herein.

[0199] In some embodiments, the pharmaceutical composition of the present disclosure is a botanical drug product (BDP) comprising a cannabinoid extract of the Cannabis sativa L. proprietary ‘CW1AS1’ hemp cultivar, which is disclosed and claimed in U.S. Patent No. 10,653,085 and U.S. Patent No.10,736,295, both of which are herein incorporated by reference in their entireties. Representative seed of ‘CW1AS1’ has been deposited under NCIMB 43291.

[0200] The botanical drug substance (BDS) of the present disclosure is a cannabinoid extract containing cannabinoids, carbohydrates, non-cannabinoid / terpene lipids, terpenes, and proteins. The primary cannabinoid is cannabidiol (CBD), along with other minor cannabinoids components including but not limited to cannabichromene (CBC), Δ9-tetrahydrocannabinol (THC), cannabigerol (CBG), cannabidiolic acid (CBDA), cannabidivarin (CBDV), cannabigerolic acid (CBGA) and cannabinol (CBN). Total tetrahydrocannabinnoids (i.e., THC and tetrahydrocannabinolic acid [THCA]) are controlled in the FSHE dried biomass to ≤0.3% (per regulatory requirements for CBD products), and THC is controlled to ≤2% in the BDS and ≤0.3% w / w in the drug product. In some embodiments, the BDS comprises from about 45% to about 65% CBD, from about 1% to about 5% CBC, and from about 0.5% to about 2.5% THC weight / weight% of the BDS. The BDS can comprise, for example, from about 45% to about 60%, about 45% to about 55%, about 45% to about 50%, about 50% to about 65%, about 50% to about 55%, about 55% to about 65%, or about 55% to about 60% CBD weight / weight% of the BDS. The BDS can comprise, for example, from about 1% to about 4%, about 1% to about 3%, about 1% to about 2%,Attorney Docket No.38383.0001P1 about 2% to about 4%, about 2% to about 3%, or about 3% to about 4% CBC weight / weight% of the BDS. The BDS can comprise, for example, from about 0.5% to about 2%, about 0.5% to about 1%, about 1% to about 2.5%, about 1% to about 2%, or about 2% to about 2.5% THC weight / weight% of the BDS. In some embodiments, the BDS comprises about 55% CBD, 2% CBC, and about 1% to about 2% THC weight / weight% of the BDS. The BDS is a nonaqueous dark green to black semi-solid obtained via extraction of a proprietary strain (i.e., ‘CW1AS1’) of Cannabis sativa L. biomass. The biomass is cultivated and harvested in compliance with good agriculture and collection practices (GACPs). The BDS is primarily composed of cannabinoids, followed by carbohydrates, non-cannabinoid / terpene lipids, terpenes, and proteins. Each of the molecule classes may possess activity and is expected to contribute to the overall pharmacological activity of the BDS. The BDS has low aqueous solubility.

[0201] In some embodiments, the botanical drug product (BDP) Oral Suspension of the present disclosure comprises the cannabinoid extract in one or more oils and / or oil-like substances. Examples of suitable oils include but are not limited to glyceryl monolinoleate, corn oil, olive oil, sesame oil, soybean oil (e.g., hydrogenated soybean oil), rapeseed oil, coconut oil, sunflower oil, and combinations thereof. In some embodiments, the BDP oral suspension comprises a lipid-based formulation or lipid-surfactant based formulation comprising glyceryl monolinoleate. In some embodiments, the BDP oral suspension comprises the botanical extract in glyceryl monolinoleate. The glyceryl monolinoleate is a blend of long chain mono, di, and triglycerides. In embodiments, the glyceryl monolinoleate is winterised. An example of suitable glyceryl monolinoleate is Maisine CC®, manufactured by Gattefosse. In some embodiments, the glyceryl monolinoleate is a winterized oil composed of mono-, di- and triglycerides of oleic and linoleic acids (C18:1 / C18:2).

[0202] In some embodiments, the composition comprises a carrier, wherein the carrier comprises, consists of, or consists essentially of a mono, di, or tri glyceride or any combination thereof, wherein the fatty acids of the glycerides have a saturated or unsaturated carbon chain length ranging from 8 to 20 carbons. In some embodiments, the carbon chain length is 12 to 20. In some embodiments, the glyceride is sesame oil, corn oil, or modified corn oil.

[0203] In some embodiments, the BDP of the present disclosure comprises one or more flavoring agents including but not limited to orange flavoring, citric acid flavoring, cherry flavoring,Attorney Docket No.38383.0001P1 strawberry flavoring, chocolate flavoring, mint flavoring, and combinations thereof. In some embodiments, the BDP comprises organic chocolate mint flavoring. In some embodiments, the BDP of the present disclosure can be formulated in many different forms and finished formats including but not limited to emulsifications, particle encapsulations, powders, liquids, solids, etc.

[0204] In some embodiments, the BDP of the present disclosure is administered orally, wherein such oral administration may be in a form including but not limited to capsules, tinctures, sprays, etc.

[0205] In one embodiment, the oral drug product (i.e., BDP) of the present disclosure consists of BDS of 103 mg / mL in glyceryl monolinoleate, National Formulary (NF), and an organic chocolate mint flavoring agent. The manufacturing process involves mixing BDS with excipients to yield a fully homogeneous suspension.

[0206] Glycerol monolinoleate (C21H38O4; MW 354.5 g / mol; PubChem CID 5283469; CAS RN®: 26545-74-4) is a 1-monoglyceride that has octadecadienoyl (linoleoyl) as the acyl group. It is functionally related to linoleic acid. Glycerol monolinoleate is a mixture of monoglycerides, mainly glyceryl monooleate and glyceryl monolinoleate, together with variable quantities of diglycerides and triglycerides. Synonyms include 1-linoleoyl-fac-glycerol, monolinolein, 1- monolinolein, and glycerol 1-monolinolate. Glyceryl monolinoleate is a natural product found in Saposhnikovia divaricate, Hycoscyamus niger, and other organisms. It can be used to enhance absorption of the drug substance, thereby enhancing bioavailability for systemic exposure. For additional information see USPNF Docid: GUID-B60F2346-5660-41F4-97FE- 7721AECF2902_2_en-US.

[0207] In some embodiments of the present disclosure, the route of administration for the compositions of the present disclosure is oral without further dilution or reconstitution.

[0208] In some embodiments of the present disclosure, the compositions of the present disclosure, including the BDP disclosed herein, can be stored under US Pharmacopeia (USP) controlled room temperature conditions of about 20°C to about 25°C (about 68°F to about 77°F) with excursions permitted between about 15°C to about 30°C (about 59°F to about 86°F).Attorney Docket No.38383.0001P1

[0209] The BDS and as such, the BDP of the present disclosure contain numerous pharmacologically active compounds also found in cannabis, including THC, CBD and terpenoids. Cannabidiol is the primary naturally occurring cannabinoid in the BDS of the present disclosure along with minor cannabinoid components including cannabichromene (CBC), tetrahydrocannabinol (THC), cannabigerol (CBG), cannabigerolic acid (CBGA), cannabidiolic acid (CBDA), cannabidivarin (CBDV), and cannabinol (CBN). In some embodiments, the composition comprises a CBD concentration of from about 5% to about 8% w / w%, a THC concentration of from about 0% to about 0.3% w / w%, a CBC concentration of from about 0 to about 0.5% w / w%, and a CBG concentration of from about 0% to about 0.3% w / w% of the BDP. In some embodiments, the composition comprises a concentration of delta 9-THC is 0-0.3% w / w / of the pharmaceutical composition, a concentration of cannabichromene is 0-0.5% w / w of the pharmaceutical composition, a concentration of cannabigerol is 0 to 0.3% w / w of the pharmaceutical composition and / or wherein a concentration of total cannibinoids is 5.6-8.4% w / w of the pharmaceutical composition.

[0210] The anticipated dosing regimen is a starting dose of 25 mg of BDS (equivalent to approximately 13.75 mg of CBD or 0.2 mg / kg assuming a 70kg person) with maximum expected dose level up to 618 mg of BDS (equivalent to 340 mg of CBD or 4.85 mg / kg assuming a 70kg person).

[0211] The dosing regimens of the present disclosure includes dosages of BDS of about 25 mg, 50 mg, 100 mg, 150 mg, 200 mg, 250 mg, 300 mg, 350 mg, 400 mg, 450 mg, 500 mg, 550 mg, 600 mg, 650 mg, 700 mg, 750 mg, and 800 mg.

[0212] In some embodiments, the BDS dosing regimens of the present disclosure range between about 25 mg to about 50 mg, about 50 mg to about 100 mg, about 75 mg to about 125 mg, about 100 mg to about 150 mg, about 125 mg to about 175 mg, about 150 mg to about 200 mg, about 175 mg to about 225 mg, about 200 mg to about 250 mg, about 225 mg to about 275 mg, about 250 mg to about 300 mg, about 275 mg to about 325 mg, about 300 mg to about 350 mg, about 325 mg to about 375 mg, about 350 mg to about 400 mg, about 375 mg to about 425 mg, about 400 mg to about 450 mg, about 425 mg to about 475 mg, about 450 mg to about 500 mg, about 475 mg to about 525 mg, about 500 mg to about 550 mg, about 525 mg to about 575 mg, aboutAttorney Docket No.38383.0001P1 550 mg to about 600 mg, about 575 mg to about 625 mg, about 600 mg to about 650 mg, about 625 mg to about 675 mg, about 650 mg to about 700 mg, about 675 mg to about 725 mg, about 700 mg to about 750 mg, about 725 mg to about 775 mg, about 750 mg to about 800 mg..

[0213] In embodiments for treating autism in a pediatric, the administered dosage of the BDS is from about 20 mg to about 400 mg per day. The administered dosage can be, for example, from about 20 mg to about 350 mg, about 20 mg to about 300 mg, about 20 mg to about 200 mg, about 20 mg to about 100 mg, about 20 mg to about 50 mg, about 50 mg to about 400 mg, about 50 mg to about 350 mg, about 50 mg to about 300 mg, about 50 mg to about 200 mg, about 50 mg to about 100 mg, about 100 mg to about 400 mg, about 100 mg to about 350 mg, about 100 mg to about 300 mg, about 100 mg to about 200 mg, about 200 mg to about 400 mg, about 200 mg to about 300 mg, or about 300 mg to about 400 mg. In some embodiments, the administered dosage of the BDS is about 25 mg, 50 mg, 100 mg, 150 mg, 200 mg, or about 300 mg per day.

[0214] In some embodiments, the pharmaceutical composition is administered to provide BDS at an amount from about 40 mg to about 700 mg per day. The administered dosage can be, for example, from about 40 mg to about 650 mg, about 40 mg to about 600 mg, about 40 mg to about 500 mg, about 40 mg to about 400 mg, about 40 mg to about 300 mg, about 40 mg to about 200 mg, about 40 mg to about 100 mg, about 40 mg to about 80 mg, about 80 mg to about 700 mg, about 80 mg to about 650 mg, about 80 mg to about 600 mg, about 80 mg to about 500 mg, about 100 mg to about 500 mg, about 100 mg to about 400 mg, about 100 mg to about 300 mg, about 100 mg to about 200 mg, about 200 mg to about 650 mg, about 200 mg to about 600 mg, about 200 mg to about 500 mg, about 200 mg to about 400 mg, about 200 mg to about 300 mg, about 300 mg to about 650 mg, about 300 mg to about 600 mg, about 300 mg to about 500 mg, about 300 mg to about 400 mg, about 400 mg to about 650 mg, about 400 mg to about 600 mg, about 400 mg to about 500 mg, or about 500 mg to about 700 mg per day. In some embodiments, the administered dosage of the BDS is from about 100 mg to about 700 mg per day. In some embodiments, the administered dosage of the BDS is about 50 mg, about 100 mg, about 175 mg, about 250 mg, about 300 mg, about 350 mg, about 500 mg, about 600 mg, or about 700 mg per day.Attorney Docket No.38383.0001P1

[0215] In some embodiments, the BDS is administered as a titrating dose, wherein the initial dose is increased every 3, 4, or 5 days until a maintenance phase. In such embodiments, the effects and tolerability of the titrating dose are observed to determine a maintenance dose.

[0216] In some embodiments wherein the BDS is administered as a titrating dose, the treatment comprises administering a first daily dose of the composition that is equivalent to about 103 mg of the extract to the subject for 4 to 7 days and administering a second daily dose of about 206 mg for 4 to 7 days after the 4 to 7 days of administering the first daily dose, and optionally continuing administration the second daily dose as a maintenance dose after the 4 to 7 days of administering the second daily dose or resuming administration of the first daily dose after the 4 to 7 days of the second daily dose and optionally wherein a daily dose is administered twice daily.

[0217] In some embodiments wherein the BDS is administered as a titrating dose, the treatment comprises administering a third daily dose of the composition that is equivalent to about 360 mg of the extract to the subject for 4 to 7 days after the 4 to 7 days of administering the second daily dose, and optionally continuing administration of the third daily dose as a maintenance dose after the 4 to 7 days of administering the third daily dose or resuming administration of the second daily dose as a maintenance dose after the 4 to 7 days of administering the third daily dose.

[0218] In some embodiments wherein the BDS is administered as a titrating dose, the treatment comprises administering a fourth daily dose of the composition that is equivalent to about 515 mg of the extract to the subject for 4 to 7 days after the 4 to 7 days of administering the third daily dose, and optionally continuing administration of the fourth daily dose as a maintenance dose after the 4 to 7 days of administering the fourth daily dose or resuming administration of the third daily dose as a maintenance dose after the 4 to 7 days of administering the fourth daily dose.

[0219] In some embodiments wherein the BDS is administered as a titrating dose, the treatment comprises administering a fifth daily dose of the composition that is equivalent to about 618 mg of the extract to the subject for 4 to 7 days after the 4 to 7 days of administering the fourth daily dose, and optionally continuing administration of the fifth daily dose as a maintenance dose after the 4 to 7 days of administering the fifth daily dose or resuming administration of the fourth daily dose as a maintenance dose after the 4 to 7 days of administering the fifth daily dose.Attorney Docket No.38383.0001P1

[0220] In some embodiments wherein the BDS is administered as a titrating dose, the treatment comprises administering a first daily dose of the composition that is equivalent to about 53 mg of the extract to the subject for 4 to 7 days and administering a second daily dose of about 103 mg for 4 to 7 days after the 4 to 7 days of administering the first daily dose, and optionally continuing administration the second daily dose as a maintenance dose after the 4 to 7 days of administering the second daily dose or resuming administration of the first daily dose after the 4 to 7 days of the second daily dose and optionally wherein a daily dose is administered twice daily.

[0221] In some embodiments wherein the BDS is administered as a titrating dose, the treatment comprises administering a third daily dose of the composition that is equivalent to about 180 mg of the extract to the subject for 4 to 7 days after the 4 to 7 days of administering the second daily dose, and optionally continuing administration of the third daily dose as a maintenance dose after the 4 to 7 days of administering the third daily dose or resuming administration of the second daily dose as a maintenance dose after the 4 to 7 days of administering the third daily dose.

[0222] In some embodiments wherein the BDS is administered as a titrating dose, the treatment comprises administering a fourth daily dose of the composition that is equivalent to about 263 mg of the extract to the subject for 4 to 7 days after the 4 to 7 days of administering the third daily dose, and optionally continuing administration of the fourth daily dose as a maintenance dose after the 4 to 7 days of administering the fourth daily dose or resuming administration of the third daily dose as a maintenance dose after the 4 to 7 days of administering the fourth daily dose.

[0223] In some embodiments wherein the BDS is administered as a titrating dose, the treatment comprises administering a fifth daily dose of the composition that is equivalent to about 314 mg of the extract to the subject for 4 to 7 days after the 4 to 7 days of administering the fourth daily dose, and optionally continuing administration of the fifth daily dose as a maintenance dose after the 4 to 7 days of administering the fifth daily dose or resuming administration of the fourth daily dose as a maintenance dose after the 4 to 7 days of administering the fifth daily dose.

[0224] The dosing regimens of the present disclosure includes dosages of CBD of about 25 mg, about 50 mg, about 100 mg, 150 mg, 200 mg, 250 mg, 300 mg, 350 mg, 400 mg, 450 mg, 500 mg, 550 mg, 600 mg, 650 mg, 700 mg, 750 mg, 800 mg, 850 mg, 900 mg, 950 mg, 1000 mg, 1050 mg, 1100 mg, 1150 mg, 1200 mg, and 1250 mg.Attorney Docket No.38383.0001P1

[0225] In some embodiments, the CDB dosing regimens of the present disclosure range between about 25 mg to about 50 mg, about 50 mg to about 100 mg, about 75 mg to about 125 mg, about 100 mg to about 150 mg, about 125 mg to about 175 mg, about 150 mg to about 200 mg, about 175 mg to about 225 mg, about 200 mg to about 250 mg, about 225 mg to about 275 mg, about 250 mg to about 300 mg, about 275 mg to about 325 mg, about 300 mg to about 350 mg, about 325 mg to about 375 mg, about 350 mg to about 400 mg, about 375 mg to about 425 mg, about 400 mg to about 450 mg, about 425 mg to about 475 mg, about 450 mg to about 500 mg, about 475 mg to about 525 mg, about 500 mg to about 550 mg, about 525 mg to about 575 mg, about 550 mg to about 600 mg, about 575 mg to about 625 mg, about 600 mg to about 650 mg, about 625 mg to about 675 mg, about 650 mg to about 700 mg, about 675 mg to about 725 mg, about 700 mg to about 750 mg, about 725 mg to about 775 mg, about 750 mg to about 800 mg, about 775 mg to about 825 mg, about 800 mg to about 850 mg, about 825 mg to about 875 mg, about 850 mg to about 900 mg, about 875 mg to about 925 mg, about 900 mg to about 950 mg, about 925 mg to about 975 mg, about 950 mg to about 1000 mg, about 975 mg to about 1025 mg, about 1000 mg to about 1050 mg, about 1025 mg to about 1075 mg, about 1050 mg to about 1100 mg, about 1075 mg to about 1125 mg, about 1100 mg to about 1150 mg, about 1125 mg to about 1175 mg, about 1150 mg to about 1200 mg, about 1175 mg to about 1225 mg, about 1200 mg to about 1250 mg, about 1225 mg to about 1275 mg, and about 1250 mg to about 1300 mg.In some embodiments, the pharmaceutical composition is dosed at an amount to provide for CBD dosing of about 0.5 mg / kg, about 0.75 mg / kg, about 1.0 mg / kg, 1.5 mg / kg, 2.0 mg / kg, 2.5 mg / kg, 3.0 mg / kg, 3.5 mg / kg, 4.0 mg / kg, 4.5 mg / kg, 5.0 mg / kg, 5.5 mg / kg, 6.0 mg / kg, 6.5 mg / kg, 7.0 mg / kg, 7.5 mg / kg, 8.0 mg / kg, 8.5 mg / kg, 9.0 mg / kg, 9.5 mg / kg, 10.0 mg / kg, 10.5 mg / kg, 11.0 mg / kg, 11.5 mg / kg, 12.0 mg / kg, 12.5 mg / kg, 13.0 mg / kg, 13.5 mg / kg, 14.0 mg / kg, 14.5 mg / kg, 15.0 mg / kg, 15.5 mg / kg, and 16.0 mg / kg.

[0226] In some embodiments, the pharmaceutical composition is dosed at an amount to provide for a CBD dose about 0.75 mg / kg to about 1.25 mg / kg, about 1.0 mg / kg to about 1.5 mg / kg, about 1.25 mg / kg to about 1.75 mg / kg, about 1.5 mg / kg to about 2.0 mg / kg, about 1.75 mg / kg to about 2.25 mg / kg, about 2.0 mg / kg to about 2.5 mg / kg, about 2.25 mg / kg to about 2.75 mg / kg, about 2.5 mg / kg to about 3.0 mg / kg, about 2.75 mg / kg to about 3.25 mg / kg, about 3.0 mg / kg to about 3.5Attorney Docket No.38383.0001P1 mg / kg, about 3.25 mg / kg to about 3.75 mg / kg, about 3.5 mg / kg to about 4.0 mg / kg, about 3.75 mg / kg to about 4.25 mg / kg, about 4.0 mg / kg to about 4.5 mg / kg, about 4.25 mg / kg to about 4.75 mg / kg, about 4.5 mg / kg to about 5.0 mg / kg, about 4.75 mg / kg to about 5.25 mg / kg, about 5.0 mg / kg to about 5.5 mg / kg, about 5.25 mg / kg to about 5.75 mg / kg, about 5.5 mg / kg to about 6.0 mg / kg, about 5.75 mg / kg to about 6.25 mg / kg, about 6.0 mg / kg to about 6.5 mg / kg, about 6.25 mg / kg to about 6.75 mg / kg, about 6.5 mg / kg to about 7.0 mg / kg, about 6.75 mg / kg to about 7.25 mg / kg, about 7.0 mg / kg to about 7.5 mg / kg, about 7.25 mg / kg to about 7.75 mg / kg, about 7.5 mg / kg to about 8.0 mg / kg, about 7.75 mg / kg to about 8.25 mg / kg, about 8.0 mg / kg to about 8.5 mg / kg, about 8.25 mg / kg to about 8.75 mg / kg, about 8.5 mg / kg to about 9.0 mg / kg, about 8.75 mg / kg to about 9.25 mg / kg, about 9.0 mg / kg to about 9.5 mg / kg, about 9.25 mg / kg to about 9.75 mg / kg, about 9.5 mg / kg to about 10.0 mg / kg, about 9.75 mg / kg to about 10.25 mg / kg, about 10.0 mg / kg to about 10.5 mg / kg, about 10.25 mg / kg to about 10.75 mg / kg, about 10.5 mg / kg to about 11.0 mg / kg, about 10.75 mg / kg to about 11.25 mg / kg, about 11.0 mg / kg to about 11.5 mg / kg, about 11.25 mg / kg to about 11.75 mg / kg, and about 11.5 mg / kg to about 12.0 mg / kg. The foregoing doses are administered twice daily. In some embodiments, the dose is titrated. For example, a patient starts at a dose of 2.5 mg / kg and after 4 to 7 days increases the dose to 5 mg / kg and so on until a dose is reached that ameliorates the symptoms..

[0227] In some embodiments, the volume of BDP oral suspension per dose is from about 0.1 mL to about 6 mL. The volume of BDS oral suspension per dose can be, for example, from about 0.1 mL to about 3 mL, about 0.1 mL to about 2 mL, about 0.1 mL to about 1 mL, about 0.25 mL to about 5 mL, about 0.25 mL to about 3 mL, about 0.25 mL to about 3 mL, about 0.25 mL to about 2 mL, about 0.25 mL to about 1 mL, about 0.5 mL to about 5 mL, about 0.5 mL to about 3 mL, about 0.5 mL to about 2 mL, about 0.5 mL to about 1 mL, about 1 mL to about 5 mL, about 1 mL to about 3 mL, or about 3 mL to about 5 mL. In some embodiments, the volume of BDS oral suspension per dose is about 0.25 mL, about 0.5 mL, about 1.0 mL, about 1.5 mL, about 2 mL, or about 3 mL.

[0228] In some embodiments, the volume of BDS oral suspension per dose is from about 0.5 mL to about 8 mL. The volume of BDS oral suspension per dose can be, for example, from about 0.5 mL to about 6 mL, about 0.5 mL to about 3 mL, about 0.5 mL to about 1 mL, about 1 mL to aboutAttorney Docket No.38383.0001P1 8 mL, about 1 mL to about 6 mL, about 1 mL to about 3 mL, about 3 mL to about 8 mL, or about 3 mL to about 6 mL. In some embodiments, the volume of BDS oral suspension per dose is about 0.5 mL, 1 mL, 1.75 mL, 2.5 mL, 3 mL, 2.5 mL, 5 mL, or about 6 mL.

[0229] In some embodiments, the BDS oral suspension is administered 1, 2, or 3 times a day. In a further embodiment, the BDS oral suspension is administered 2 times a day. Each administration is near the time of a meal.

[0230] In some embodiments, the amount of BDS in the BDP ranges from between about about 95 mg / mL to about 110 mg / mL, about 100 mg / mL to about 105 mg / mL, about 105 mg / mL to about 110 mg / mL, or about 110 mg / mL to about 115 mg / mL.

[0231] In some embodiments, the composition comprises a concentration of beta-caryophyllene at an amount that is 2% to 10% percent of the amount of beta caryophyllene in the air dried plant material from which the extract is obtained.

[0232] In some embodiments, the composition comprises a concentration of cannabidiol of at least 45 mg / mL to 75 mg / mL. The composition can comprise a concentration, for example, of cannabidiol of 50 mg / mL to 70 mg / mL, 50 mg / mL to 65 mg / mL of cannabidiol.

[0233] In some embodiments, the composition comprises a ratio of cannabidiol:tetrahydrocannabinol of from about 20:1 to about 60:1. The composition can comprise a ratio, for example, of cannabidiol:tetrahydrocannabidiol of from about 20:1 to about 55:1, about 20:1 to about 50:1, about 20:1 to about 45:1, about 20:1 to about 40:1, about 20:1 to about 35:1, about 20:1 to about 30:1, about 30:1 to about 60:1, about 30:1 to about 50:1, about 30:1 to about 40:1, about 40:1 to about 60:1, about 40:1 to about 50:1, or about 50:1 to about 60:1. In some embodiments, the composition comprises a ratio of cannabidiol:tetrahydrocannabidiol of from about 25:1 to about 40:1.

[0234] In some embodiments, the composition comprises a ratio of cannabidiol: tetrahydrocannabinol of from about 22:1 to about 30:1. The composition can comprise a ratio, for example, of cannabidiol:tetrahydrocannabinol of from about 22:1 to about 29:1, about 22:1 to about 28:1, about 22:1 to about 27:1, about 22:1 to about 26:1, about 22:1 to about 25:1, about 23:1 to about 30:1, about 23:1 to about 28:1, about 23:1 to about 26:1, about 23:1 to about 25:1,Attorney Docket No.38383.0001P1 or about 25:1 to about 30:1. In some embodiments, the composition comprises a ratio of cannabidiol:tetrahydrocannabinol of from about 23:1 to about 26:1. In some embodiments, the composition comprises a ratio of cannabidiol:tetrahydrocannabinol of about 25:1.

[0235] In some embodiments, the composition comprises a tetrahydrocannabinol concentration of less than about 3 mg / mL. The composition can comprise, for example, a tetrahydrocannabinol concentration of less than about 2.8 mg / mL, 2.7 mg / mL, 2.5 mg / mL, 2.3 mg / mL, 2.0 mg / mL, 1.8 mg / mL, 1.7 mg / mL, 1.5 mg / mL, 1.3 mg / mL, 1.0 mg / mL, 0.8 mg / mL, 0.6 mg / mL, 0.3 mg / mL, 0.1 mg / mL, or less than about 0.05 mg / mL. In some embodiments, the composition comprises a tetrahydrocannabinol concentration of from about 1 mg / mL to about 3 mg / mL.

[0236] In some embodiments, the composition comprises a concentration of α-bisabolol at an amount that is 2% to 20% percent of the amount of α-bisabolol ne in the air dried plant material from which the extract is obtained.

[0237] In some embodiments, the composition comprises a concentration of α-humelene at an amount that is 2% to 20% percent of the amount of α-humelene in the air dried plant material from which the extract is obtained.

[0238] In some embodiments, the composition consists of or consists essentially of a cannabinoid extract of Cannabis sativa L. plant of the variety ‘CW1AS1’ strain, glyceryl monolinoleate, and a flavoring agent. VI. Representative Nervous System and Mental Diseases, Conditions, Disorders and / or Symptoms Treated by the Present Disclosure

[0239] In some embodiments, the BDS and BDP of the present disclosure can be used to treat a wide range of nervous, nervous-associated, pain, pain-associated, inflammation, inflammation- associated, mental, and mental -associated diseases, conditions, disorders and / or symptoms.

[0240] Nervous system diseases, also known as nervous system or neurological disorders, refer to over 600 medical conditions affecting the nervous system. Examples of nervous system diseases, disorders, conditions, and / or symptoms that can be treated according to the present disclosure include but are not limited to Acute Spinal Cord Injury, Alzheimer's Disease, Amyotrophic Lateral Sclerosis (ALS), Ataxia, Bell's Palsy Brain Tumors, Cerebral Palsy, CerebralAttorney Docket No.38383.0001P1 Aneurysm, Epilepsy, Seizures, Lennox-Gastaut syndrome (LGS), Dravet syndrome, and Tuberous Sclerosis Complex (TSC), Guillain-Barré Syndrome, Headache Head Injury, Hydrocephalus, Lumbar Disk Disease (Herniated Disk), Meningitis, Motor Neurone Disease (MND), Multiple Sclerosis, Muscular Dystrophy, Seizure Disorder, Neurofibromatosis, Neurocutaneous Syndromes, Parkinson's Disease, Stroke (Brain Attack), Cluster Headaches, Tension Headaches, Migraine Headaches, Encephalitis, Sciatica, Shingles, Septicemia, Types of Muscular Dystrophy and Neuromuscular Diseases, Myasthenia Gravis, Huntington’s Disease, Charcot-Marie-Tooth Disease, Polyneuropathy, Moyamoya Disease, Multiple System Atrophy, Neoplasm, Chronic Inflammatory, Acute Motor Axonal Neuropathy, Angelman Syndrome, Progressive multifocal leukoencephalopathy (PML), Canavan Disease, Medical Medullary Syndrome, Demyelinating Polyradiculoneuropathy, Spina Bifida, Autism Spectrum Disorder, Strokes, 16P11.2 Deletion Syndrome, Prader-Willi Syndrome, Sotos Syndrome, 22q11 Deletion Syndrome, Rett Syndrome, 1P36 Deletion Syndrome, and Sturge-Weber Syndrome.

[0241] Autoimmune and inflammatory diseases that can be treated according to the present disclosure include but are not limited to Ankylosing Spondylitis, Antiphospholipid Antibody Syndrome, Autoimmune Encephalitis, Chronic Recurrent Multifocal Osteomyelitis, Gout, Henoch-Schonlein Purpura, Juvenile Dermatomyositis, Juvenile Idiopathic Arthritis, Juvenile Lupus (SLE), Juvenile Scleroderma, Juvenile Vasculitis, Kawasaki Disease, Lupus (Systemic Lupus Erythematosus), Mixed Connective Tissue Disease, Myositis, Poststreptococcal Inflammatory Syndromes, Psoriatic Arthritis, Reactive Arthritis, Rheumatoid Arthritis, Scleroderma, Sjogren's Syndrome, Spondyloarthritis / Spondyloarthropathy, Systemic Juvenile Idiopathic Arthritis, Undifferentiated Connective Tissue Disease, Uveitis, and Vasculitis.

[0242] The compositions and treatments of the present disclosure can also be used to treat pain, including but not limited to temporary, acute, chronic, or permanent pain. Acute pain is pain that may come from inflammation, tissue damage, injury, illness, or recent surgery. It usually lasts less than a week or two. The pain usually ends after the underlying cause is treated or has been resolved. Chronic pain is pain that persists for months or even years. The pain may come from inflammation, tissue damage, injury, illness, or recent surgery. The pain may be associated with headaches including but not limited to the most common types of chronic headaches such as migraines, clusterAttorney Docket No.38383.0001P1 headaches, and tension headaches. The pain may be low back pain. Other pain disorders that can be treated according to the present disclosure include but are not limited to neuralgias and neuropathies that affect nerves throughout the body, pain due to damage to the central nervous system (the brain and spinal cord), as well as pain where no physical cause can be found-- psychogenic pain. Common types of pain that can be treated according to the present disclosure include but are not limited to arthritis (.e.g., osteoarthritis, rheumatoid arthritis), muscle pain, bone pain, joint pain, back pain, neck pain, musculoskeletal pain, cancer pain (e.g., near a tumor), headaches, including migraines, testicular pain (orchialgia), lasting pain in scar tissue, muscle pain all over (such as with fibromyalgia), multiple sclerosis, neurogenic pain (e.g., from damage or pressure to the nerves or other parts of the nervous system), AIDS, gall bladder disease, problems with the CNS (e.g., diabetes, shingles, sciatica), and organ pain because of injuries, infections, or health problems such as inflammatory bowel disease, irritable bowel syndrome, pelvic pain, and stomach ulcers. Many of these types of pain can be chronic and a person can have more than one kind of pain at the same time (e.g., fibromyalgia can cause pain in muscles and nerves).

[0243] Mental illness is a general term for a group of illnesses that may include symptoms that can affect a person’s thinking, perceptions, mood, and / or behavior. Mental illness can make it difficult for someone to cope with work, relationships, and other demands. Examples of mental and / or psychiatric diseases, disorders, conditions and / or symptoms that can be treated according to the present disclosure include but are not limited to Schizophrenia, Bipolar Affective Disorder, Psychosis, Depression, Dissociation and Dissociative Disorders, Personality Disorder, Paranoia, Anxiety Disorders, Eating Disorders, Mood Disorders, Obsessive-Compulsive Disorders, Post- Traumatic Stress (PTS) Disorders, Dissociative Disorders, Panic Disorders, Substance Use Disorders, behavioral and emotional disorders in children and adults, and Schizoaffective disorder. In some embodiments, the compositions and treatments of the present disclosure can be used to treat schizophreniform disorder (acute schizophrenic episode); schizoaffective disorder; bipolar I disorder (mania, manic disorder, manic-depressive psychosis); bipolar II disorder; major depressive disorder with psychotic feature (psychotic depression); delusional disorders (paranoia); shared psychotic disorder (shared paranoia disorder); brief psychotic disorder (other and unspecified reactive psychosis); psychotic disorder not otherwise specified (unspecifiedAttorney Docket No.38383.0001P1 psychosis); paranoid personality disorder; schizoid personality disorder; and schizotypal personality disorder. See, e.g., US Patent No.9,017,737.

[0244] Disorders that can be treated according to the present disclosure include but are not limited to antisocial personality disorder, anxiety disorder, Asperger symptom / disorder, attention deficit disorder, autistic disorder, bipolar disorder, body dysmorphic disorder, borderline personality disorder, central auditory processing disorder, chromosome disorder, compulsive personality disorder, conversion disorder, cruise-associated diarrheal disorder, cumulative trauma disorder, delusional disorder, dependent personality disorder, depersonalization disorder, depressive disorder, developmental disorder, dissociative identity disorder, dysthymic disorder, eating disorder, anorexia nervosa, bulimia nervosa, binge-eating disorder, EBV-associated lymphoproliferative disorder, endometrial disorder, expressive disorder, expressive language disorder, factitious disorder, functional disorder, gender identify disorder, generalized anxiety disorder, genetic disorders, hearing disorder, histrionic personality disorder, identity disorder, internet addiction disorder, iodine deficiency disorder, language disorder, late luteal phase dysphoric disorder, lymphoproliferative disorder, major depressive disorder, Matha Stewart disorder, Mendelian disorder, mental disorder, motor speech disorder, movement disorder, multiple autoimmune disorder, multiple personality disorder, musculoskeletal disorder, myeloproliferative disorder, narcissistic personality disorder, neurodegenerative disorder, neurogenic communication disorder, neurotic disorder, non-Mendelian disorder, obsessive- compulsive disorder (OCD), obsessive-compulsive personality disorder, Pan-ethnic disorder, panic disorder, partial syndrome eating disorder, passive-aggressive personality disorder, post- translation lymphoproliferative disorder, post-traumatic stress disorder (PTSD), Prader-Willi syndrome, premenstrual dysphoric disorder, psychotic disorder, reactive attachment disorder of infancy or early childhood, reading disorder, S-100-positive T-cell lymphoproliferative disorder, schizoid personality disorder, seasonal affective disorder, seizure disorder, sexual pain disorder, shared psychotic disorder, silicone-reactive disorder, single gene disorder, sleep disorder, sleep terror disorder, smell disorder, social anxiety disorder, somatization disorder, speech disorder, swallowing disorder, taste disorder, thought disorder, throat disorder, thyroid disorder, urea cycle disorder, urologic disorder, voice disorder, treatment-resistant depression, and X-linked disorder.Attorney Docket No.38383.0001P1 This list is adapted from McGraw-Hill Concise Dictionary of Modern Medicine (2002) The McGraw Hill Companies, Inc.

[0245] Autism spectrum disorder (ASD) is a neurological and developmental disorder that affects how people interact with others, communicate, learn, and behave. Although autism can be diagnosed at any age, it is described as a “developmental disorder” because symptoms generally appear in the first 2 years of life. According to the Diagnostic and Statistical Manual of Mental Disorders (DSM-5), a guide created by the American Psychiatric Association that health care providers use to diagnose mental disorders, people with ASD often have difficulty with communication and interaction with other people; restricted interests and repetitive behaviors; and symptoms that affect their ability to function in school, work, and other areas of life. Autism is known as a “spectrum” disorder because there is wide variation in the type and severity of symptoms people experience. People of all genders, races, ethnicities, and economic backgrounds can be diagnosed with ASD. Although ASD can be a lifelong disorder, treatments and services can improve a person’s symptoms and daily functioning. The American Academy of Pediatrics recommends that all children receive screening for autism. The compositions of the present disclosure can be used to treat or ameliorate one or more symptoms associated with autism and orphan conditions that share similar symptomatology. Examples of such symptoms include but are not limited to the following: stereotypic behavior, irritability, social anxiety, social withdrawal, inappropriate speech, hyperactivity / non-compliance, seizures, lethargy, depressive symptoms / depression. Adapted from a list provided by the National Institute of Mental Health (February 2023).

[0246] Thus, cannabinoid extract containing pharmaceutical compositions described herein can be used to treat autism spectrum disorder (ASD) or one or more symptoms associated therewith. It is estimated that 1 in 36 children may have ASD (Maenner et al., 2020). ASD is characterized by deficits in social communication, irritability, repetitive behaviors, impulsivity, temper tantrums, and high caregiver burden (Lecavalier et al., 2006).

[0247] Currently, the only Food and Drug Administration (FDA)-approved therapeutics used for the treatment of ASD symptoms are aripiprazole and risperidone, both of which are indicated for irritability in pediatric ASD (Abilify®Package Insert, Risperdal®Package Insert). TheseAttorney Docket No.38383.0001P1 therapeutics for this chronic developmental disorder are effective but are associated with considerable adverse effects (AEs) as a result of long-term use, such as weight gain, metabolic syndrome, risk of the onset of type 2 diabetes, prolactin elevation, development of breast tissue, and extrapyramidal / movement-related side effects (Abilify®Package Insert, Risperdal®Package Insert). The anticonvulsant divalproex sodium (VPA), although not approved for the treatment of ASD, significantly reduces irritability and repetitive behaviors in individuals with ASD (Hollander et al 2006, Hollander et al 2010, King et al 2013). Although VPA is efficacious for pediatric epilepsy and some ASD symptoms, it also has significant AEs, including weight gain, sedation, and nausea (Depakote®Package Insert).

[0248] Thus, described herein are methods of treating autism spectrum disorder (ASD) in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of the pharmaceutical composition described herein. In some embodiments, treating ASD in a subject comprises treating one or more symptoms of ASD selected from anxiety, irritability, lethargy / social withdrawal, stereotypic behavior, hyperactivity / noncompliance, inappropriate speech, social avoidance, and sleep disturbances. In some embodiments, treating ASD in a subject comprises improving one or more deficits associated with ASD selected from cognition deficits, sensory sensitivity, social deficits, and speech and language deficits.

[0249] In some embodiments, the subject is a human. In some embodiments, the human is less than 18 years of age or 5 to 17 years of age. In some embodiments, the human is at least 13 years of age or 13 to 30 years of age.

[0250] Also described herein are methods of treating epilepsy in a subject in need thereof, the method comprising administering to a subject a therapeutically effective amount of the pharmaceutical composition described herein. In some embodiments, the subject is a human.

[0251] These AE profiles of currently approved and off-label therapeutics affect patient compliance in maintaining therapy and suggest that there is a large, unmet medical need for additional treatment options that do not have a significant AE profile. EXAMPLESAttorney Docket No.38383.0001P1

[0252] The present disclosure is further illustrated by the following examples that should not be construed as limiting. The contents of all references, patents, and published patent applications cited throughout this application, as well as the Figures, are incorporated herein by reference in their entirety for all purposes. Example 1: Drying and Extraction of Cannabis sativa L. plants to form Botanical Drug Substance (BDS)

[0253] After manual harvesting of Cannabis sativa L. plants, the plants are handled gently to reduce trichome loss and transported to a drying facility. The plants are dried using natural drying without additional heat applied. The moisture level is ensured to be 10% or lower as measured using Ohaus MB90 or a MB120 Moisture Analyzer.

[0254] The plants are spaced evenly to provide adequate airflow. Large plants may be cut into smaller pieces to hang dry. Fans and vents are ensured to exchange wet and dry air in and out of the facility, and the plant materials are kept clean and isolated from contaminants.

[0255] The plants are dried to 7% moisture or below. The stems should snap cleanly before removal of flowers from stalks, or more drying is required. Following drying to 7% moisture or below, the hemp plants are hand processed to separate the flowers and leaves from the stalks, branches, and other undesired plant material. The hemp is then ran through a brush separator to remove stem material and to particle size hemp and homogenize the hemp biomass.

[0256] Extraction

[0257] The extraction process extracts CBD and other cannabinoids from hemp cultivars of Cannabis sativa L. using isopropyl alcohol. Flower and leaves of a hemp plant of the variety ‘CW1AS1’ strain is mixed with isopropyl alcohol using a CUP-15 (Delta Separations / Prospiant) centrifuge. The cannabinoids are extracted from the physical biomass and brought into the solution. After centrifugation, the solution or miscella retrieved from the centrifuge is filtered with a 50-micron bag and a 25-micron bag through a filtration system. The miscella is then pumped into a storage drum, and the alcohol is substantially evaporated from the extract with spray evaporation. Alcohol recovered from the evaporation system can be used for further solvent extractions. The extract isolated from the alcohol is collected.Attorney Docket No.38383.0001P1

[0258] Decarboxylation - Reactor Method

[0259] Decarboxylation can be performed using a decarboxylation reactor. As many cannabinoids contain a carboxyl group, decarboxylation activates these cannabinoids to more effective forms after removal of the carboxyl group. The extract placed into a 20 L vessel that is heat jacketed and heated to a temperature 180 to 190°F. Chiller columns are in fluid communication with the reactor configured to receive evaporated products from the reactor, and the vessel is placed under vacuum. A mixer is applied to the extract solution. Further evaporation of remaining alcohol solvent occurs, and application of heat converts the cannabinoids into decarboxylated cannabinoids.

[0260] A representative chemical analysis of the extract is shown in Table 1. Table 1: Chemical Analysis Component Amount Cannabidiol 6.49% by weight Δ9-Tetrahydrocannabinol 0.24% by weight Cannabichromene 0.37% by weight Cannabigerol 0.20% by weight (-)-α-bisabolol 5700 ppm Camphene < 50 ppm (1S)-(+)-3-Carene < 50 ppm β-Caryophyllene 5100 ppm p-Cymene < 50 ppm Eucalyptol 140 ppm α-Humulene 2300 ppm (-)-Isopulegol < 50 ppm (R)-(+)Limonene 67 ppm Linalool 72 ppm beta-Myrcene < 50 ppm (E)-b-Ocimene < 50 ppm (Z)-b-Ocimene < 50 ppm α-Pinene < 50 ppm β-Pinene < 50 ppm α-Terpinene < 50 ppm β-Terpinene < 50 ppm γ-Terpinene < 50 ppm Terpinolene < 50 ppm Example 2: Formulation of BDS Oral Suspension (BDP)Attorney Docket No.38383.0001P1

[0261] The BDP manufacturing process consists of compounding a solution of a cannabinoid extract of CW1AS1, Glycerol Monolinoleate, NF, and flavoring agent in a large mixing kettle. The mixture is heated to 45-75 °C followed by mixing for 30 minutes. The homogenized solution is filled into bottles followed by capping and secondary packaging.

[0262] A summary of the manufacturing process operating parameters is provided in Table 2. Table 2: Process Operating Parameters Process Step Operating Parameter Range Compounding Temperature 45-75 ℃ Time No more than 30 minutes Homogenization Mixing speed 700-800 rpms Temperature 45-75 °C Time No more than 30 minutes Filling Frequency 400 bottles / hour Example 3: Summary of Nonclinical Pharmacokinetics

[0263] CBD exposure following oral dosing was assessed in two in vivo genetic toxicity studies (i.e., comet assay and mouse micronucleus) to confirm exposure. In Study 842-489-5825 (comet assay), male rats administered a single oral dose of the BDS of the present disclosure at 2000 mg / kg body weight (corresponding to approximately 145 mg / kg total cannabinoids) resulted in mean CBD plasma concentration of 1177 ng / mL at 2 hours, 1487 ng / mL at 4 hours, and 1795 ng / mL at 6 hours. In Study 842-474-5814 (mouse micronucleus), male mice administered single oral dose of the BDS of the present disclosure of 2000 mg / kg body weight (corresponding to approximately 145 mg / kg total cannabinoids) resulted in mean CBD plasma concentration of 602.3 ng / mL at 2 hours, 408.6 ng / mL at 4 hours, 350.7 ng / mL at 6 hours, and 32.2 ng / mL at 24 hours after treatment. Example 4: Summary of Nonclinical ToxicologyAttorney Docket No.38383.0001P1

[0264] Four good laboratory practice (GLP) toxicology studies and one non-GLP dose range finding (DRF) were performed to assess repeat-dose toxicity (i.e., 14-day repeat-dose rat and 90- day repeat-dose rat) and genotoxicity (i.e., Ames, comet assay, and mouse micronucleus), which have been reported in literature (Dziwenka et al 2020). The BDS contained ~55% CBD, ~2% CBC, and 1 to 2%THC.

[0265] A non-GLP 14-day DRF oral toxicity study was conducted in 40 Sprague-Dawley CD®IGS rats (20 males and 20 females) at dose levels of 0 (vehicle control [olive oil]), 1000, 2000, and 4000 mg / kg / day of botanical extract (i.e., corresponding to the BDS of the present disclosure) via oral gavage, corresponding to ~63, ~125 and ~251 mg total cannabinoids / kg body weight (Study 48149). Clinical signs directly attributable to test article administration were observed in the 4000 mg / kg / day group: hypoactivity, hyperactivity, reduced food consumption, and piloerection. Test article-related changes in serum chemistry values on Day 15 were observed in this dose group and consisted of increased blood urea nitrogen and creatinine. Test article-related decreases in mean weekly body weights, daily body weight gain, food consumption, and food efficiency were observed in the 1000, 2000, and 4000 mg / kg / day groups. Test article-related microscopic observations consisted of hepatocyte hypertrophy in the 2000 and 4000 mg / kg / day groups that correlated with an increase in liver weights, and vacuolation of the adrenal cortex in 1000, 2000, and 4000 mg / kg / day groups that correlated with dose-dependent increased adrenal weights. Based on these data, an oral dose <1000 mg / kg / day is expected to be tolerated in a rat study of longer duration.

[0266] A 90-day GLP repeat-dose toxicology study was performed with male and female Sprague-Dawley rats divided into four main test and four recovery groups (i.e., 10 and 5 / sex / group for the main and recovery study, respectively) (Study 48150). Dose levels of 200 (low-dose), 400 (mid-dose), and 800 mg / kg / day (high-dose) of botanical extract of the present disclosure in olive oil and vehicle control (olive oil) were administered by oral gavage once a day for 93 and 94 days to males and females, respectively, with a weekly dose adjustment based on the body weight changes. The same study design was applied for the recovery groups, followed by a recovery period (i.e., 31 days for the male rats and 30 days for the female rats). Dose-dependent decreases in mean weekly body weights were observed in the male main test groups (low-, mid-, and high-Attorney Docket No.38383.0001P1 dose) and test article recovery groups, correlating with significant decreases in mean daily body weight gain and food consumption. A significant decline in food efficiency (measured as food consumption measurements coincidence with body weight changes) occurred in the high-dose recovery group. Body weight decrements of less than 10%, with evidence of a faster recovery considered non-adverse, occurred in the low and mid-doses (main and recovery groups), while declines greater than 10% considered adverse were observed in high doses treated groups. Based on these results, the no observed adverse effect level (NOAEL) was determined to be 800 mg / kg / day (app. ~ 55 mg / kg / day total cannabinoids) for females and 400 mg / kg / day (~ 27 mg / kg / day total cannabinoids) for males.

[0267] The BDS of the present disclosure did not show evidence of bacterial mutagenicity in a bacterial reverse mutation test (Ames) up to 5000 µg (Study 51956). The BDP did not show genotoxicity activity up to a dose of 2000 mg / kg in a mouse micronucleus test (Study 842-474- 5814) or in the examined rat stomach or liver tissues in an in vivo alkaline comet assay (Study 843- 489-5825). Example 5: Non-Interventional PK Study A non-interventional PK study was conducted with Farm Bill 2018-compliant product containing the same cannabinoid extract of the present disclosure and a similar drug product composition to the BDP of the present disclosure. There were no serious adverse events (SAEs) or withdrawals due to safety during the study, and overall data showed CBD absorption, which correlated with patterns observed in other human CBD PK studies. Example 6: A Phase 1, Double-Blind, Randomized, Placebo-Controlled, Single and Multiple Ascending Dose Study

[0268] The present study is a double-blind, randomized, placebo-controlled, single ascending dose (SAD) and multiple ascending dose (MAD) study to evaluate the safety, tolerability, pharmacokinetics (PK), and pharmacodynamics (PD) of the BDP of the present disclosure (i.e., an oral suspension of the BDS of the present disclosure) in fasting and fed healthy participants. See Fig.1 for an example of the study design (i.e., schematic) for the clinical protocol.

[0269] The BDP of the present disclosure is a botanical cannabinoid drug substance in a suspension intended for oral delivery. The BDS of the present disclosure is an oral suspension ofAttorney Docket No.38383.0001P1 103 mg / mL of the BDS in glyceryl monolinoleate, National Formulary (NF), and an organic chocolate mint flavoring agent. The placebo is the suspension vehicle with no drug substance and is identical in appearance to the BDP of the present disclosure.

[0270] Food effect will be evaluated in one cross-over SAD fasting dose cohort after a minimum 14-day washout period. Approximately 64 participants will be enrolled.

[0271] Participants will undergo study-specific screening within 28 days prior to dose administration. Prior to any screening procedures being performed, participants will sign the study- specific consent form in the presence of a suitably trained study site staff member.

[0272] The study is comprised of two parts, Part A (SAD) and Part B (MAD). Up to 8 participants will be randomized (6 participants receiving the active drug and 2 participants receiving the placebo) in each cohort of Parts A and B. Participants in Part A will receive a single dose of the BDP of the present disclosure or placebo on Day 1 while those in Part B will receive a split dose of the BDP of the present disclosure or placebo, where one dose will be administered as two equal doses taken twice daily, (BID; administered approximately every 12 hours [± 30 minutes]) for 6 consecutive days (Day 1-Day 6), and 1 morning dose on Day 7.

[0273] Cohorts will be dosed sequentially in an ascending fashion. Safety Review Committee (SRC) meetings will be held after safety and tolerability data up to at least Day 7 (Part A) and up to at least Day 9 (Part B) are available for all participants from a single cohort and remainder of timepoints of the preceding cohort (when applicable), in order to make decisions whether to escalate to the next dose level, decrease the next dose level, repeat a dose level, or to not evaluate any additional dose. A new cohort will not be dosed until the clinical portion of the preceding dose level has been completed, appropriate data has been reviewed by the SRC and authorization to proceed with the next dose level has been given by the SRC.

[0274] Part A and Part B each have four planned dose level cohorts (A1-A4 and B1-B4). Part A will include 1 cohort (A-X), which will enter a cross-over dosing scheme, where the participants will return to the clinical site on Day 14 to receive the BDP of the present disclosure or placebo following a high-fat, high-calorie breakfast on the morning on Day 15 after overnight fasting period. There will be an additional +2-day window between treatments allowed. In addition, based on the safety data accumulated from previous cohorts, optional Cohorts A5 / B5 and A6 / B6 may beAttorney Docket No.38383.0001P1 employed if maximum tolerated dose (MTD) or maximum planned dose level has not been achieved in A4 / 5 and B4 / 54 for each study Part A and B, respectively.

[0275] Parts A and B of the study will be completed sequentially but with partial overlapping. Part B may be initiated when safety and tolerability are known and deemed acceptable for the first two cohorts in Part A (Cohorts A1-A2) at least.

[0276] A staggered dosing schedule will be used for dosing each cohort in Part A and will include 2 sentinel participants (1 active and 1 placebo). The 2 sentinel participants will be dosed initially, and the remaining 6 participants will be dosed at least 24 hours later, contingent on the resulting safety profile and once deemed safe to move forward in the opinion of Investigator in consultation with the SRC (if required).

[0277] All participants will fast overnight, and no food will be allowed from at least 10 hours before dosing until at least 4 hours post-dose on Day 1 (Part A and Part B) and Day 7 (Part B). Additionally, no fluids (except for water given with the study drugs) will be allowed for 1 hour before dosing until 1-hour post-dose. No food will be allowed from at least 2 hours before until at least 1 hour after dosing for all other doses (Part B).

[0278] In the fed cross-over period for one cohort in Part A (A-X), after a fasting period of at least 10 hours, participants will be administered the BDP of the present disclosure 30 minutes after starting a Food and Drug Administration (FA)-compliant high-fat, high-calorie breakfast (approximately 50% calories from fat, approximately 800-1000 kcals). Participants will be required to consume entire meal in 30 minutes or less. No food will be allowed at least 4 hours post-dose. Except for water given with the study drug and fluids provided with the high-fat, high- calorie meal, no liquids will be allowed for 1 hour before dosing until 1-hour post-dose.

[0279] The anticipated dosing regimen is a starting dose of 226.6 mg BDS (equivalent to 125 mg CBD) with maximum expected dose level up to 1823.1 mg BDS (equivalent to 1000 mg CBD).

[0280] The role of the BDP of the present disclosure as adjuvant therapy is being evaluated in conditions where the available treatments are clinically insufficient or have a significant AE profile. Thus, the BDP of the present disclosure is being developed for the treatment of symptoms of CNS-associated diseases, with the first indication being ASD.Attorney Docket No.38383.0001P1

[0281] An adaptive design based on safety data will be used. The planned dose range of the BDS of the present disclosure is anticipated to be 226.6 mg (equivalent to 125 mg CBD) to 1823.1 mg (equivalent to 1000 mg CBD). See Table . Table 3: Clinical Dosing and Equivalent Levels of Total Cannabinoids, Cannabidiol and Δ9- Tetrahydrocannabinol Dose Cannabinoid Equivalents (mg) Volume BDS (mg BDS)Total CannabinoidsaCBDbΔ9-THCc Oral Suspension (mL)226.6 145.51254.8 2.2 1823.1 1163.6100038.5 17.7 Δ9-THC: Δ9-Tetrahydrocannabinol; CBD: cannabidiolaBased-on target concentration of 62% total cannabinoidsbBased on target concentration of 60% cannabidiol

[0282] cBased on potential maximum concentration of 2.7% Δ9-tetrahydrocannabinolInclusion criteria. Participants to be included in this study must meet the following inclusion criteria: (1) Provide signed ethics committee (EC)-approved consent form prior to any study procedures, can understand and comply with the requirements of the study, and are able to communicate with the Investigator; (2) Males and females, aged 18 and 65 years (inclusive), with body mass index (BMI) of 18-32.0 kg / m2and body weight ≥50.0 kg at screening; (3) No known allergic reaction to cannabis products and formulation components (glyceryl monolinoleate (NF), and organic chocolate mint flavoring agent); (4) Medically healthy with no clinically significant medical history (fully resolved childhood asthma and mild asthma that does not require a reliever more than once per month, and does not require a preventer or any additional therapies is not considered clinically significant and permissible), physical examination, laboratory profiles, vital signs, or ECG, as deemed by the Investigator; (5) Must have hepatic and renal clinical laboratory test results (ALT, AST, total bilirubin [including direct and indirect bilirubin results], and estimated glomerular filtration rate [eGFR]) within a laboratory defined normal range; Example 7: A Maximum Tolerated Dose and 7-Day Dose Range Finding Study

[0283] The objectives of this study were to determine the maximum tolerated dose (MTD) and to evaluate and characterize the toxicokinetics and toxicity of the test article, the BDP of theAttorney Docket No.38383.0001P1 present disclosure, when administered via oral (gavage) once or for up to 7 consecutive days to dogs.

[0284] The study design are shown in Table 4 and Table 5: Table 4: Study Design for MTD and 7-Day Dose Range Finding Dose Level Dose Dose Main Study Group Test (mg / kg / ), Volume Concentration No. Article No. of No. of BDSa(mL / kg) (mg / mL) Males Females 1 BDP105 2 2BDP 30 5 61b 1b3 BDP 50 5 10 4 BDP 100 5 20aThe first day of dosing for each dose level was designated as Day 1.bthe same animals were administered up to 3 additional doses of the BDS (CBD), with a 5-day washout period between each dose level, as warranted. The proposed dose levels were increased or decreased based on the responses to the preceding dose level(s) until the dose-limiting toxicity was observed (MTD). Doses did not exceed 100 mg / kg (limit dose). Table 5: Study Design for MTD and 7-Day Dose Range Finding Dose Level Dose Dose Main Study Group Test (mg / kg / day), Volume Concentration No. Article No. of No. of BDS (mL / kg) (mg / mL) Males Females 5 Vehicle 10 5 0 2 2 6 BDP 30 5 2 2 2 7 BDP 50 5 6 2 2 8 BDP 100 5 10 2 2

[0285] The following parameters and endpoints were evaluated in this study: mortality, clinical signs, body weights, food consumption, clinical pathology parameters (hematology, coagulation, and clinical chemistry), toxicokinetic (TK) parameters of cannabidiol (CBD) and other analytes, (±)-cannabichromene (CBC), 7-hydroxy-cannabidiol (7OHCBD), 7-carboxy-cannabidiol (7COOHCBD), delta-9-tetrahydrocannabinol (THC), 11-hydroxy-THC (11OHTHC), and 11- carboxy-THC (11COOHTHC) on Day 1 and Day 7, and macroscopic examination.

[0286] Following a single or repeated once daily oral gavage dosing to beagle dogs at dose levels 10, 30, 50 or 100 mg / kg, the BDP was well tolerated at all dose levels and all animals survived to study completion.

[0287] In both the Maximum Tolerated Dose (MTD) and Dose Range Finding (DRF) phases at >10 mg / kg, all animals exhibited transient clinical observations of decreased activity starting 2Attorney Docket No.38383.0001P1 hours post dose. At >30 mg / kg all animals exhibited transient clinical observations of incoordination, salivation, abnormal pupils and / or eye color and / or vomitus starting 4 hours post dose. All clinical observations resolved prior to the start of the next dose.

[0288] In the 7-day DRF phase, administration of the BDP at 0 (control), 10, 30, or 50 mg / kg / day to male and female beagle dogs for 7 days was associated with alterations in clinical chemistry parameters in males at 50 mg / kg / day (decreases in sodium) and females at >30 mg / kg / day (increases in alkaline phosphatase [ALP], decreases in globulin, total protein, calcium, glucose, and sodium).

[0289] For all other parameters (body weights, food consumption, additional clinical pathology parameters, and macroscopic examination), there were no toxicologically significant changes considered to be related to administration of the BDP.

[0290] Following once daily oral administration of the BDP to male dogs, mean Cmax, AUCtlast and AUC0-24hr values of CBD and other analytes (CBC, 7OHCBD, 7COOHCBD, delta-9-THC, 110HTHC, and 11COOHTHC) increased with increasing dose in a generally dose-proportional manner from 10 to 30 mg / kg / day, with no apparent increase from 30 to 50 mg / kg / day on Days 1 and 7. In females, mean Cmax, AUCtlast and AUC0-24hr values of CBD and the other analytes displayed minimal to no increase with increasing dose on Day 1, but appeared to increase with increasing dose in a less than dose-proportional manner on Day 7. Systemic exposure (Cmaxand AUC values) to CBD in male and female dogs did not appear to change consistently following repeated administration of the BDP. Systemic exposure to all analytes in males and females were lower than CBD with changes not being dose proportional with the BDP.

[0291] In conclusion, oral administration of the BDP up to 100 mg / kg was generally well tolerated. The single dose MTD was considered to be 100 mg / kg based on the occurrence of clinical observations. Also, dose levels of 10, 30 or 50 mg / kg / day administered daily to dogs for 7 days was well tolerated. Example 8: A 4-Week Study by Oral Gavage Administration in Beagle Dogs with a 2-Week Recovery Period

[0292] The objectives of this study were to determine potential toxicity of the BDP of the present disclosure (i.e., an oral suspension of the BDS of the present disclosure), when given via oralAttorney Docket No.38383.0001P1 (gavage) daily for up to 4 weeks to dogs and to evaluate the potential reversibility of any findings following a 2-week recovery period. The doses and concentrations were based on the content of cannabidiol (CBD) present. In addition, the toxicokinetic (TK) characteristics were determined. The study design was as shown in Table 6: Table 6: Study Design Dose Level Dose Dose Main Study Recovery Study Group Test (mg / kg / day), Volume Concentration No. Article No. of No. of No. of No. of BDSa(mL / kg) (mg / mL) Males Females Males Females 1 Vehicle 0 5 0 4 4 2 2 2 BDP 10 5 2 4 4 - - 3 BDP 30 5 6 4 4 - - 4 BDP 50 5 10 4 4 2 2 - = Not Applicable a Dose based on the content of CBD in BDS

[0293] The following parameters and endpoints were evaluated in this study: mortality, clinical signs, body weights, body weight gains, food consumption, ophthalmology, electrocardiographic

[0294] examinations (ECGs), clinical pathology parameters (hematology, coagulation, clinical

[0295] chemistry, and urinalysis), organ weights, and macroscopic and microscopic examinations. In addition, TK parameters were determined on Days 1 and 28 for CBD, (±)- cannabichromene (CBC), 7-hydroxy-cannabidiol (7OHCBD), 7-carboxy-cannabidiol (7COOHCBD), delta-9-tetrahydrocannabinol (THC), 11-hydroxy-THC (11OHTHC), and 11- carboxy-THC (11COOHTHC).

[0296] All dose formulation results were within approximately 4% of the target BDS concentration as measured by the primary CBD component. The analytical data demonstrated acceptable performance of the method for all reported results and that dose formulations were prepared at the intended target concentration and were homogeneous. Vehicle control samples were below the limit of quantitation (<0.2000 mg / mL). Following a repeated once daily oral gavage dosing to beagle dogs at dose levels 10, 30, or 50 mg / kg / day, the BDS was well tolerated at < 50 mg / kg / day for up to 4 Weeks.

[0297] There was no test article-related mortality. A single control male at 0 mg / kg / day was euthanized early on Day 6 based on clinical observations (severely increased lung sounds, audible breathing (wheezing), severe pallor, severely decreased activity, salivation, low heart rate, andAttorney Docket No.38383.0001P1 cold to touch) post dose. Clinical pathology changes were consistent with an acute phase response and supportive of microscopic findings of mixed cell inflammation and foreign material within the lungs. The cause of moribundity leading to early euthanasia of this dog was gavage injury / aspiration and was not considered BDP related.

[0298] At > 10 mg / kg / day, animals exhibited non-adverse, BDS-related, transient clinical observations of salivation (including controls), decreased activity, incoordination, abnormal pupils, vomitus, and / or hunched posture starting 4 to 6 hours post dose. All clinical observations resolved prior to the start of the next dose.

[0299] Abnormal feces (liquid / soft / mucoid), decreased appetite, and / or thin body conditions were observed in most males and females across all dose groups (> 10 mg / kg / day), including control animals. Veterinary intervention was required (food enrichment, gastrointestinal (GI) blend canned food) each day of the study until the feces and / or body conditions of the animal normalized. Thin body condition and loss of body weight (up to approximately -23.5% in males and up to -12.0% in females compared to controls) were likely secondary to fecal changes and decreased appetite (up to -91.1% in males and up to -96.1% in females compared to controls).

[0300] The magnitude and timing of the observations varied throughout the dosing period. However, these observations fully resolved or trended toward resolution during the recovery period and were therefore not considered adverse.

[0301] BDP-related changes were observed in hematology parameters in males and / or females and included mildly lower mean reticulocyte counts at > 30 mg / kg / day accompanied by minimally to mildly lower erythrocyte mass (red blood cell count [RBC], hemoglobin concentration, and / or hematocrit) at 50 mg / kg / day. Minimally to mildly lower mean lymphocyte, eosinophil, basophil, and total white blood cell counts were noted at 50 mg / kg / day. Minimally to mildly higher mean platelet (PLT) counts were observed at > 10 mg / kg / day. BDP-related minimally shortened mean activated partial thromboplastin times (APTT) were observed in males at > 10 mg / kg / day and females at 50 mg / kg / day. BDP-related changes in chemistry parameters were observed in males and / or females as mildly to moderately higher mean alkaline phosphatase (ALP) at ≥ 10 mg / kg / day and minimally higher gamma glutamyl-transferase (GGT) at ≥ 30 mg / kg / day.Attorney Docket No.38383.0001P1

[0302] Minimally lower mean total calcium at > 30 mg / kg / day, minimally to mildly lower mean albumin and resultant total protein concentrations at 50 mg / kg / day were evident. Following a 2- week recovery interval, lower albumin and total protein concentrations persisted in females at 50 mg / kg / day. All remaining BDP-related alterations in clinical pathology parameters had partially to fully resolved at 50 mg / kg / day.

[0303] Non-adverse BDP-related microscopic findings were noted in the liver and thymus. In the liver, minimal to mild hepatocellular hypertrophy was present in all BDP dose groups in both sexes. Hepatocellular hypertrophy correlated with higher mean liver / gallbladder weights and higher hepatobiliary clinical chemistry parameters at > 10 mg / kg / day. BDP-related decreased lymphoid cellularity of thymus in all dose groups of both sexes was considered an indirect effect secondary to stress. This correlated with lower mean thymus weights at > 30 mg / kg / day in males and all dose groups in females and lower mean lymphocyte counts in females at 50 mg / kg / day.

[0304] Mean prostate gland weights in males at > 10 mg / kg / day and mean spleen weights in males at > 30 mg / kg / day and females at 50 mg / kg / day were lower than controls and considered BDS-related. Prostate gland and spleen weight differences lacked microscopic correlates. At the end of the recovery phase, minimal hepatocellular hypertrophy was observed in one male and both females at 50 mg / kg / day and there were no organ weight differences, indicative of partial recovery. Decreased lymphoid cellularity in the thymus was also reduced in incidence and severity, supportive of partial recovery.

[0305] Following once daily oral administration of the BDP to male and female dogs, mean Cmax, AUCtlast, and AUC0-24hrvalues of CBD increased with increasing dose in a generally dose proportional manner from 10 to 50 mg / kg / day. TK values for other analytes (CBC, 7OHCBD, 7COOHCBD, THC, 110HTHC, and 11COOHTHC) increased with increasing dose in a generally dose proportional manner from 10 to 30 mg / kg / day, with no apparent increase from 30 to 50 mg / kg / day on Days 1 and 28. Systemic exposure (Cmaxand AUC values) to CBD in male and female dogs did not appear to change consistently following repeated administration of the BDS. Systemic exposure (Cmaxand AUC values) to the metabolites of both CBD and THC was less than the corresponding parent substance on Days 1 and 28 and ranged from < LLOQ (lower limit ofAttorney Docket No.38383.0001P1 quantitation) to up to approximately 41% lower than the parent compound. Systemic exposure to the analytes appeared to be independent of sex.

[0306] For all other parameters (ophthalmology, electrocardiographic examinations (ECGs), clinical pathology parameters (urinalysis), and macroscopic examinations), there were no toxicologically significant changes considered to be related to administration of the BDP.

[0307] In conclusion, following repeated once daily oral gavage dosing to beagle dogs at dose levels of 10, 30 or 50 mg / kg / day, the disclosed BDS was tolerated at < 50 mg / kg / day for up to 4 weeks, and there were no test article-related deaths. Transient clinical observations of salivation (including controls), decreased activity, incoordination, abnormal pupils, vomitus, and / or hunched posture were noted at > 10 mg / kg / day. BDP-related changes in hematology and clinical chemistry parameters in males and / or females starting at > 10 mg / kg / day (increases in ALP, GGT and / or

[0308] PLT, decreases in albumin, total protein, calcium, reticulocytes, RBC mass and lymphocyte counts). Non-adverse BDS-related microscopic findings were present in the liver and thymus were observed in males and females and correlated with clinical pathology findings.

[0309] The no-observed-adverse-effect-level (NOAEL) for males and females for the BDS was considered to be 50 mg / kg / day based on the CBD content, the highest dose level tested, and was associated with a mean plasma CBD Cmaxof 3850 ±1470 ng / mL and AUC0-24h, of

[0310] 47700 ±18900 hr•ng / mL in males and females combined on Day 28. Example 9: A Phase 2 Study to Investigate the Safety, Tolerability, and Effectiveness of the BDP in Adolescents and Adults with Autism Spectrum Disorder

[0311] This is a multicenter open-label study to investigate the safety, tolerability, and effectiveness of the BDP disclosed herein in adolescents and adults with ASD. Subjects will be enrolled to receive the BDP. This study will utilize a flexible-dose design, with doses individualized to each subject based on safety and tolerability. Doses will be titrated up from the starting dose over an approximately 3-week Titration Period, with dose adjustments taking place approximately every 4 days.

[0312] Subjects will begin dosing with 0.5 mL of the BDP (51.5 mg BDS; equivalent to 28.4 mg CBD and 1.1 mg THC) administered twice daily for a total daily dose of 1.0 mL (equivalent toAttorney Docket No.38383.0001P1 56.8 mg CBD and 2.2 mg THC) and titrated up to a maximum dose of 3.0 mL (309 mg BDS; equivalent to 170.4 mg CBD and 6.5 mg THC) twice daily for a total daily dose of 6.0 mL (equivalent to 340.8 mg CBD and 13.1 mg THC).

[0313] The Titration Period will be followed by one more week of dosing (Maintenance Period) for a total Treatment Period of 4 weeks, and a 2-week Safety Follow-up Period. Safety and efficacy assessments will take place during each clinic visit. Assessments made during the Titration Period will be conducted by telephone or videoconference.

[0314] Dose Titration Guideline. All subjects will receive the BDP beginning with a 3-week Titration Period to reach a safe and tolerable dose according to the following schedule in Table 7: Table 7: Dose Titration Amount of Titration Period Study Medication Day 1 Day 5 Day 9 Day 13 Day 17 Day 21 Day 22-29 Per dose 0.5 mL 1.0 mL 1.75 2.5 mL 3.0 mL Check-in to confirm Maintenance mL maintenance dose Per day 1.0 mL 2.0 mL 3.5 mL 5.0 mL 6.0 mL Check-in to confirm Maintenance maintenance dose

[0315] This table is a guideline only for the Investigator; the actual titration will depend on the individual subject’s response to treatment, i.e., decisions to increase each subject’s dose will be based on tolerability and safety.

[0316] The BDP should be taken twice per day (BID), in the morning and evening (approximately every 12 ± 2 hours) within one hour after eating a meal (e.g., breakfast and dinner).

[0317] The Titration Period is expected to take up to 3 weeks, with dose adjustments to be made approximately every 4 days. Some subjects may reach a dose limit based on safety and tolerability (based on Investigator judgment) in less than 3 weeks at which point they would remain at that dose through Week 4 of the study.

[0318] During titration, if a subject is unable to tolerate an increased dose, they should be reverted to the previous tolerable dose and remain at that dose until AEs subside, in consultation with the Investigator. Subjects can attempt to increase the dose again during the Titration Period in consultation with the Investigator.Attorney Docket No.38383.0001P1

[0319] Subjects should titrate until they achieve at least one of the following: experience unacceptable / intolerable side effects, as judged by the Investigator, or reach the maximum allowed daily dose.

[0320] If at any point after reaching a stable tolerable dose a subject experiences intolerable AEs, the Investigator may decrease the dose or temporarily pause dosing until tolerability is achieved. Subjects whose dose has been decreased can have their dose increased again in consultation with the Investigator provided there is adequate tolerance. Subjects who fail to tolerate dose adjustments may be withdrawn from the study by the Investigator in consultation with the Sponsor.

[0321] Inclusion Criteria. To be eligible for the study, subjects must meet ALL of the following inclusion criteria prior to enrollment: Males or females 13-30 years of age at Screening, Diagnosis of ASD confirmed by Mini International Neuropsychiatric Interview (MINI), ABC-I score of ≥18 at Screening and Baseline, CGI-S of irritability associated with ASD score of >4 at Screening and Baseline.

[0322] Description of Investigational Product. The IP is a BDP containing FSHE-derived from Cannabis sativa L. proprietary CW1AS1 hemp cultivar in an oral solution consisting of Glyceryl Monolinoleate, NF and a mint chocolate flavoring agent. The BDS is primarily composed of cannabinoids (~48%) followed by carbohydrates (~40%), non-cannabinoid / terpene lipids (~6%), terpenes (~5%), and proteins (~1%). While efficacy is expected to be derived from the cannabinoids, each of the molecule classes may possess activity and is expected to contribute to the overall pharmacological activity of the BDS. The BDP is a brown oil-based solution consisting of 103 mg / mL BDS in Glyceryl Monolinoleate, NF and a chocolate mint flavoring. Example 10: An Open-Label, Safety, Tolerability, and Effectiveness Study of the BDP disclosed herein in Children and Adolescents with Autism Spectrum Disorder (ASD)

[0323] This open-label Phase 2 study is being conducted to evaluate the safety, tolerability, and effectiveness of the BDP disclosed herein in pediatric patients with ASD. Current ASD treatments are limited in efficacy benefit and are associated with serious side effects that could significantly impair health. The BDP has the potential to treat irritability, repetitive behaviors, and improve cognition, sociability, and quality of life for ASD patients.Attorney Docket No.38383.0001P1

[0324] Dose Titration Guideline. Approximately 20 subjects will be enrolled to receive one of two different doses (N = 10 per dose group) of open-label BDP for a total of up to 12 weeks. Within each dose group, enrolled subjects will include 5 subjects <12 years old and 5 subjects ≥12 years old. Group 1 will be enrolled and completed prior to enrolling any subjects in Group 2 to ensure that a maximum daily dose of up to 3.0 mL is safe and well tolerated. Safety and tolerability data from Group 1 to be reviewed before deciding to proceed to Group 2. Subjects will be dosed BID, approximately 12 ± 2 hours apart within one hour after eating a meal (e.g., breakfast and dinner), and will begin with a 3-week Titration Period according to the following schedule: Table 8: Dose Titration Titration Period Dose Day Day Day 22-85 Group Day 1 Day 5 Day 9 13 17 Day 21 (9 weeks) Group 1 (N = 10) Per Dose 0.25 0.5 mL 0.75 1.0 mL 1.5 mL Check-in to confirm Maintenance mL mL maintenance dose Per Day 0.5 mL 1.0 mL 1.5 mL 2.0 mL 3.0 mL Check-in to confirm Maintenance maintenance dose Group 2 (N = 10) Per Dose 0.5 mL 1.0 mL 1.75 2.5 mL 3.0 mL Check-in to confirm Maintenance mL maintenance dose Per Day 1.0 mL 2.0 mL 3.5 mL 5.0 mL 6.0 mL Check-in to confirm Maintenance maintenance dose

[0325] Overall Design. This is a single-site, open-label study to evaluate the safety, tolerability, and effectiveness of the BDP disclosed herein in children and adolescents aged 5-17 years old with ASD. Approximately 20 subjects will be enrolled to receive one of two different doses of the BDPAttorney Docket No.38383.0001P1 (N = 10 per dose group). Each dose group will be comprised of 5 subjects <12 years old and 5 subjects ≥12 years old. The BDP will be administered with food.

[0326] The following dose levels will be evaluated:

[0327] The first 10 subjects (Group 1) will begin with 0.25 mL (i.e., 25.75 mg BDS; equivalent to 14.2 mg CBD and 0.55 mg THC) administered BID for a total daily dose of 0.5 mL and will titrate up to a maximum dose of 1.5 mL (i.e., 154.5 mg BDS; equivalent to 85.2 mg CBD and 3.25 mg THC) BID for a total daily dose of 3.0 mL.

[0328] The subsequent 10 subjects (Group 2) will begin with 0.5 mL (i.e., 51.5 mg BDS; equivalent to 28.4 mg CBD and 1.1 mg THC) administered BID for a total daily dose of 1.0 mL, and will titrate up to a maximum dose of 3.0 mL (i.e., 309 mg BDS; equivalent to 170.4 mg CBD and 6.5 mg THC) BID for a total daily dose of 6.0 mL.

[0329] Doses will be titrated up from the starting dose over an approximately 3-week Titration Period, with upward dose adjustments to take place approximately every 4 days, based on assessments of safety and tolerability and in the judgment of the Investigator. Assessments made during the Titration Period will be conducted by telephone or videoconference.

[0330] The Titration Period will be followed by an approximately 9-week Maintenance Period (for a total Treatment Period of 12 weeks), and a 2-week Follow-up Period. If at any point during the Maintenance Period a subject experiences intolerable adverse effects, the Investigator may decrease the dose until tolerability is achieved. In-person clinic visits are scheduled to take place on Days 29 ± 3 days, 57 ± 3 days, and 85 ± 3 days and the final safety follow-up visit will take place on Day 99 ± 3 days by telephone or videoconference.

[0331] Inclusion Criteria. To be eligible for the study, subjects must meet ALL of the following inclusion criteria prior to enrollment:

[0332] Male or female pediatric outpatients aged between 5 to 1 years inclusive at Screening.Attorney Docket No.38383.0001P1

[0333] Diagnosis of ASD confirmed by the Autism Diagnostic Observation Schedule™, Second Edition (ADOS-2).

[0334] ABC-I score of ≥ 18 at Screening and Baseline.

[0335] CGI-S of irritability associated with ASD score of > 4 at Screening and Baseline. INCORPORATION BY REFERENCE

[0336] All references, articles, publications, patents, patent publications, and patent applications cited herein within the above text and / or cited below are incorporated by reference in their entireties for all purposes. However, mention of any reference, article, publication, patent, patent publication, and patent application cited herein is not, and should not be taken as acknowledgment or any form of suggestion that they constitute valid prior art or form part of the common general knowledge in any country in the world. U.S. PATENT DOCUMENTS

[0337] 10,653,085 Joel Stanley and Keri Reel

[0338] 10,736,295 Joel Stanley and Keri Reel OTHER PUBLICATIONS

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[0370] Pertwee RG. The diverse CB1 and CB2 receptor pharmacology of three plant cannabinoids: D9-tetrahydrocannabinol, cannabidiol and D9-tetrahydrocannabivarin. Br J Pharmacol.2008;153:199-215.

[0371] Risperdal®Package Insert, August 2022

[0372] Russo EB, Burnett A, Hall B, Parker KK. Agonistic properties of cannabidiol at 5-HT1a receptors. Neurochem Res.2005;30(8):1037-1043.

[0373] Russo EB. Taming THC: potential cannabis synergy and phytocannabinoid-terpenoid entourage effects. Br J Pharmacol.2011;163(7):1344-64.

[0374] Russo, E. and G.W. Guy, A tale of two cannabinoids: the therapeutic rationale for combining tetrahydrocannabinol and cannabidiol. Med Hypotheses, 2006.66(2): p.234-46.

[0375] Stout SM, Cimino NM. Exogenous cannabinoids as substrates, inhibitors, and inducers of human drug metabolizing enzymes: a systematic review. Drug Metab Rev.2014;46(1):86-95.

[0376] Velayudhan L, McGoohan K, Bhattacharyya S. Safety and tolerability of natural and synthetic cannabinoids in adults aged over 50 years: A systematic review and meta-analysis. PLoS Med.20210329th ed.2021;18(3):e1003524

[0377] Xiong W, Cheng K, Cui T, et al. Cannabinoid potentiation of glycine receptors contributes to cannabis-induced analgesia. Nat Chem Biol.2011;7(5):296-303.Attorney Docket No.38383.0001P1

[0378] Yamaori S, Ebisawa J, Okushima Y, Yamamoto I, Watanabe K. Potent inhibition of human cytochrome P450 3A isoforms by cannabidiol: role of phenolic hydroxyl groups in the resorcinol moiety. Life Sci.2011;88(15-16):730-6.

Claims

Attorney Docket No.38383.0001P1 CLAIMS What is claimed is:

1. A method of treating one or more symptoms of autism spectrum disorder (ASD) or a seizure disorder in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a pharmaceutical composition comprising a cannabinoid and terpene extract of Cannabis sativa L. of the variety ‘CW1AS1’ strain, wherein a representative seed of the variety has been deposited under NCIMB No.43291, and a carrier, wherein the carrier comprises, consists of, or consists essentially of a mono, di, or tri glyceride or any combination thereof, wherein the fatty acids of the glycerides have a saturated or unsaturated carbon chain length ranging from 8 to 20 carbons.

2. The method of claim 1, wherein the extract is a solvent reduced oil obtained from a process comprising isopropyl alcohol solvent extraction.

3. The method of claim 1 or 2, wherein the carbon chain length is 12 to 20.

4. The method of claim 1 or 2, wherein the glyceride is sesame oil, corn oil, modified corn oil, 5. The method of claim 1 or 3, wherein the composition comprises: a. beta-caryophyllene at an amount that is 2% to 10% percent of the amount of beta caryophyllene in the air dried plant material from which the extract is obtained, and / or b. α-bisabolol at an amount that is 2% to 20% percent of the amount of α-bisabolol ne in the air dried plant material from which the extract is obtained and / or c. α-humelene at an amount that is 2% to 20% percent of the amount of α-humelene in the air dried plant material from which the extract is obtained, and / or d. a concentration of cannabidiol of 5 to 8% w / w of the composition.Attorney Docket No.38383.0001P1 6. The method of any one of claims 1 to 5, wherein the composition comprises a ratio of cannabidiol:tetrahydrocannabinol of from 20:1 to 60:1 or from about 25:1 to about 40:

1.

7. The method of any one of claim 1 to 6, wherein a concentration of delta 9-THC is 0-0.3% w / w / of the pharmaceutical composition, a concentration of cannabichromene is 0-0.5% w / w of the pharmaceutical composition, a concentration of cannabigerol is 0 to 0.3% w / w of the pharmaceutical composition and / or wherein a concentration of total cannabinoids is 5.6-8.4% w / w of the pharmaceutical composition.

8. The method of any of claims 1-7, wherein the composition is not an emulsion.

9. The method of any of claims 1-8, wherein the Cannabis sativa plant is of the variety ‘CW1AS1’ strain, wherein a representative seed of the variety has been deposited under NCIMB No.43291.

10. The method of any of claims 1-9, wherein the cannabinoid composition comprises a tetrahydrocannabinol concentration of 1 to 3 mg / mL.

11. The method of any of claims 1-10, wherein the pharmaceutical composition consists of or consists essentially of a cannabinoid extract of Cannabis sativa plant, the carrier, and a flavoring agent.

12. The method of any one of claims 1 to 11, wherein the carrier is a winterized oil composed of mono-, di- and triglycerides of oleic and linoleic acids.

13. The method of any one of claims 1 to 12, wherein one or more symptoms of ASD is treated 14. The method of any one of claims 1 to 13, wherein the symptom of ASD is selected from irritability, anxiety, lethargy / social withdrawal, stereotypic behavior, hyperactivity / noncompliance, inappropriate speech, or social avoidance or wherein the symptom is irritability.Attorney Docket No.38383.0001P1 15. The method of any one of claims 1 to 14, wherein the subject is a human.

16. The method of any one of claims 15, wherein the human subject is less than 18 years of age or 5 to 17 years of age.

17. The method of any one of claims 15 wherein the human subject is at least 13 years of age or 13 to 30 years of age.

18. The method of claim 16, wherein a daily dose of the pharmaceutical composition comprises from 20 mg to 400 mg of the cannabinoid extract.

19. The method of claim 16 or 17, wherein a daily dose of the pharmaceutical composition comprises from about 100 mg to about 700 mg of the cannabinoid extract.

20. The method of claims 16 or 17, comprising administering a first daily dose of the composition that is equivalent to about 103 mg of the extract to the subject for 4 to 7 days and administering a second daily dose of about 206 mg for 4 to 7 days after the 4 to 7 days of administering the first daily dose, and optionally continuing administration the second daily dose as a maintenance dose after the 4 to 7 days of administering the second daily dose or resuming administration of the first daily dose after the 4 to 7 days of the second daily dose and optionally wherein a daily dose is administered twice daily.

21. The method of claim 20, comprising administering a third daily dose of the composition that is equivalent to about 360 mg of the extract to the subject for 4 to 7 days after the 4 to 7 days of administering the second daily dose, and optionally continuing administration of the third daily dose as a maintenance dose after the 4 to 7 days of administering the third daily dose or resuming administration of the second daily dose as a maintenance dose after the 4 to 7 days of administering the third daily dose.

22. The method of claim 21, comprising administering a fourth daily dose of the composition that is equivalent to about 515 mg of the extract to the subject for 4 to 7 days after the 4 to 7 days of administering the third daily dose, and optionally continuing administration ofAttorney Docket No.38383.0001P1 the fourth daily dose as a maintenance dose after the 4 to 7 days of administering the fourth daily dose or resuming administration of the third daily dose as a maintenance dose after the 4 to 7 days of administering the fourth daily dose.

23. The method of claim 22, comprising administering a fifth daily dose of the composition that is equivalent to about 618 mg of the extract to the subject for 4 to 7 days after the 4 to 7 days of administering the fourth daily dose, and optionally continuing administration of the fifth daily dose as a maintenance dose after the 4 to 7 days of administering the fifth daily dose or resuming administration of the fourth daily dose as a maintenance dose after the 4 to 7 days of administering the fifth daily dose.

24. The method of claim 16, comprising administering a first daily dose of the composition that is equivalent to about 53 mg of the extract to the subject for 4 to 7 days and administering a second daily dose of about 103 mg for 4 to 7 days after the 4 to 7 days of administering the first daily dose, and optionally continuing administration the second daily dose as a maintenance dose after the 4 to 7 days of administering the second daily dose or resuming administration of the first daily dose after the 4 to 7 days of the second daily dose and optionally wherein a daily dose is administered twice daily.

25. The method of any of claims 24, comprising administering a third daily dose of the composition that is equivalent to about 180 mg of the extract to the subject for 4 to 7 days after the 4 to 7 days of administering the second daily dose, and optionally continuing administration of the third daily dose as a maintenance dose after the 4 to 7 days of administering the third daily dose or resuming administration of the second daily dose as a maintenance dose after the 4 to 7 days of administering the third daily dose.

26. The method of any of claims 25, comprising administering a fourth daily dose of the composition that is equivalent to about 263 mg of the extract to the subject for 4 to 7 days after the 4 to 7 days of administering the third daily dose, and optionally continuing administration of the fourth daily dose as a maintenance dose after the 4 to 7 days ofAttorney Docket No.38383.0001P1 administering the fourth daily dose or resuming administration of the third daily dose as a maintenance dose after the 4 to 7 days of administering the fourth daily dose.

27. The method of any of claims 26, comprising administering a fifth daily dose of the composition that is equivalent to about 314 mg of the extract to the subject for 4 to 7 days after the 4 to 7 days of administering the fourth daily dose, and optionally continuing administration of the fifth daily dose as a maintenance dose after the 4 to 7 days of administering the fifth daily dose or resuming administration of the fourth daily dose as a maintenance dose after the 4 to 7 days of administering the fifth daily dose.

28. The method of claims 16 or 17, comprising administering a first daily dose of the composition that is between 100 to 700 mg of the extract to the subject for 7 to 60 days and administering a second daily dose for 7 to 60 days that is more than or less than the first daily dose after the 7 to 60 days of administering the first daily dose, and optionally continuing administration the second daily dose as a maintenance dose after the 760 days of administering the second daily dose, resuming administration of the first daily dose after the 7 to 60 days of the second daily dose and optionally wherein a daily dose is administered twice daily, or administering a third daily dose that is more or less than the second daily dose after the 7- 60 days of the second daily dose, optionally wherein the first, second or third daily dose is a maintenance dose.

29. The method of any one of claims 1 to 28, wherein the seizure disorder is treated.

30. A method of making a cannabinoid extract, comprising: a. providing a harvested plant material of Cannabis sativa; b. drying the plant material to a moisture content of the plant material of less than 10% or less than 8% in environmental conditions having an average temperature between 50°F and 90°F or 60°F and 80°F,Attorney Docket No.38383.0001P1 c. contacting the dried plant material with a solvent to form a solvent extract comprising cannabinoids and terpenes and an undissolved portion; d. separating the undissolved portion from the solvent extract; and e. removing a substantial portion of solvent from the solvent extract and subjecting the solvent extract to a decarboxylation process to form a cannabinoid extract to obtain a level of 5000 ppm in the cannabinoid extract.

31. The method of claim 30, wherein drying the plant material is in environment conditions having average relative humidity between 0% and 65%.

32. The method of claim 30 or 31, wherein the solvent comprises, consists of, or consists essentially of an alcohol with 2 to 5 carbons or an alcohol selected from isopropyl alcohol and ethanol.

33. The method of claim 32, wherein the solvent consists of or consists essentially of isopropyl alcohol.

34. The method of any one of claim 30 to 33, wherein the solvent is isopropyl alcohol and the substantial portion of the solvent is removed from the solvent extract by heating to solvent extract to a temperature of 170° to 195° F or 180 to 190 F and spraying the solvent extract in a chamber under a vacuum, wherein the chamber is in fluid communication with a condenser (e.g, a chiller) such that vapor passes to the condenser thereby condensing vapor comprising isopropyl alcohol and separating vaporized isopropyl alcohol from the solvent extract, wherein the condenser is at a temperature of 0°C to 5°C.

35. The method of any one of claims 30 to 34, wherein the decarboxylation process comprises heating and mixing the solvent extract in a vessel in fluid communication with a condenser, wherein the solvent extract is heated to a temperature of from about 75°C to 85°C until no evaporated solvent condensate is visible in the condenser and incrementally reducing theAttorney Docket No.38383.0001P1 pressure one or more times while heating, wherein before each pressure reduction, no evaporated solvent condensate is visible in the condenser.

36. The method of claim 35, wherein the pressure is incrementally reduced to 5-15 torr and held until no solvent is visible in the condenser and / or held for 1-2 hours, thereby obtaining the cannabinoid extract.

37. The method of claim 35 or 36, wherein the condenser temperature is -7°C to 0°C or about -5°C.

38. The method of any one of claims 30 to 37, wherein at least a portion of decarboxylation occurs during removing the solvent from the solvent extract.

39. The method of any one of claim 35 to 38, wherein the vessel comprises a heat jacket configured to heat the solvent extract contained within the vessel.

40. The method of any of claims 30 to 39, wherein removing the undissolved portion from the solvent extract comprises filtering the undissolved portion from the extraction portion.

41. The method of any one of claims 30 to 40, wherein the dried plant material that is contacted with the solvent comprises at least 85% by weight of flowers and leaves of the dried plant material.

42. The method of any one of claims 30 to 41, wherein the dried plant material is stored for no more than 12 months at an average temperature not to exceed 80°F prior to contacting the plant material with solvent.

43. The method of any one of claims 30 to 42, wherein the dried plant material is stored for no more than 9 months at an average temperature not to exceed 80°F prior to contacting the plant material with solvent.Attorney Docket No.38383.0001P1 44. The method of any one of claims 30 to 43, wherein the dried plant material is stored for no more than 6 months at an average temperature not to exceed 80°F prior to contacting the plant material with solvent.

45. The method of any one of claims 30 to 44, wherein the dried plant material is stored in a sealed container.

46. The method of any one of claims 30 to 45, wherein the Cannabis sativa plant material is of the variety ‘CW1AS1’ strain, wherein a representative seed of the variety has been deposited under NCIMB No.43291.

47. An extract obtained from a method according to any one of claims 30 to 46.

48. A pharmaceutical composition comprising an extract according to claim 47.

49. The pharmaceutical composition according to claim 48, wherein the composition comprises a carrier, wherein the carrier comprises, consists of, or consists essentially of a mono, di, or tri glyceride or any combination thereof, wherein the fatty acids of the glycerides have a saturated or unsaturated carbon chain length ranging from 8 to 20 carbons, optionally, wherein the carbon chain length is 12 to 20, optionally wherein the glyceride is sesame oil, corn oil, modified corn oil, 50. The pharmaceutical composition according to claim 48 or 49, wherein the composition is not an emulsion.

51. The pharmaceutical composition according to any one of claims 48 to 50, wherein the composition consists of or consists essentially of the extract, the carrier, and a flavoring agent.

52. The pharmaceutical composition according to claim any one of claims 48 to 51, wherein a concentration of cannabidiol is 5-8% w / w of the composition.Attorney Docket No.38383.0001P1 53. The pharmaceutical composition according to any one of claims 48 to 52, wherein a concentration of delta 9-THC is 0-0.3% w / w / of the pharmaceutical composition, a concentration of cannabichromene is 0-0.5% w / w of the pharmaceutical composition, and a concentration of cannabigerol is 0 to 0.3% w / w of the pharmaceutical composition and / or wherein a concentration of total cannabinoids is 5.6-8.4% w / w of the pharmaceutical composition.

54. The pharmaceutical composition according to any one of claims 48 to 53, wherein the carrier is a winterized oil composed of mono-, di- and triglycerides of oleic and linoleic acids and / or wherein the oil is obtained from corn.

55. The pharmaceutical composition according to any one of claims 48 to 54, wherein the composition comprises: a. beta-caryophyllene at an amount that is 2% to 10% percent of the amount of beta caryophyllene in the air dried plant material from which the extract is obtained, and / or b. α-bisabolol at an amount that is 2% to 20% percent of the amount of α-bisabolol ne in the air dried plant material from which the extract is obtained and / or c. α-humelene at an amount that is 2% to 20% percent of the amount of α-humelene in the air dried plant material from which the extract is obtained, and / or d. a concentration of cannabidiol of 5 to 8% w / w of the composition..

56. The pharmaceutical composition according to any one of claims 48 to 55,, wherein the composition comprises a ratio of cannabidiol:tetrahydrocannabinol of from 20:1 to 60:1 or from about 25:1 to about 40:

1.

57. A method of treating one or more symptoms of autism spectrum disorder (ASD) in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of the pharmaceutical composition according to any one of claims 48 to 56.Attorney Docket No.38383.0001P1 58. The method of claim 57, wherein the symptom of ASD is anxiety and / or irritability.

59. The method of claim 57 or 58, wherein the subject is a human.

60. The method of any one of claims 59, wherein the human subject is less than 18 years of age or 5 to 17 years of age.

61. The method of any one of claims 59, wherein the human subject is at least 13 years of age or 13 to 30 years of age.

62. The method of claim 60, wherein a daily dose of the pharmaceutical composition comprises from 20 mg to 400 mg of the cannabinoid extract.

63. The method of claim 60 or 61, wherein a daily dose of the pharmaceutical composition comprises from about 100 mg to about 700 mg of the cannabinoid extract.

64. The method of claims 60 or 61, comprising administering a first daily dose of the composition that is equivalent to about 103 mg of the extract to the subject for 4 to 7 days and administering a second daily dose of about 206 mg for 4 to 7 days after the 4 to 7 days of administering the first daily dose, and optionally continuing administration the second daily dose as a maintenance dose after the 4 to 7 days of administering the second daily dose or resuming administration of the first daily dose after the 4 to 7 days of the second daily dose and optionally wherein a daily dose is administered twice daily.

65. The method of claim 64, comprising administering a third daily dose of the composition that is equivalent to about 360 mg of the extract to the subject for 4 to 7 days after the 4 to 7 days of administering the second daily dose, and optionally continuing administration of the third daily dose as a maintenance dose after the 4 to 7 days of administering the third daily dose or resuming administration of the second daily dose as a maintenance dose after the 4 to 7 days of administering the third daily dose.Attorney Docket No.38383.0001P1 66. The method of claim 65, comprising administering a fourth daily dose of the composition that is equivalent to about 515 mg of the extract to the subject for 4 to 7 days after the 4 to 7 days of administering the third daily dose, and optionally continuing administration of the fourth daily dose as a maintenance dose after the 4 to 7 days of administering the fourth daily dose or resuming administration of the third daily dose as a maintenance dose after the 4 to 7 days of administering the fourth daily dose.

67. The method of claim 66, comprising administering a fifth daily dose of the composition that is equivalent to about 618 mg of the extract to the subject for 4 to 7 days after the 4 to 7 days of administering the fourth daily dose, and optionally continuing administration of the fifth daily dose as a maintenance dose after the 4 to 7 days of administering the fifth daily dose or resuming administration of the fourth daily dose as a maintenance dose after the 4 to 7 days of administering the fifth daily dose.

68. The method of claim 60, comprising administering a first daily dose of the composition that is equivalent to about 53 mg of the extract to the subject for 4 to 7 days and administering a second daily dose of about 103 mg for 4 to 7 days after the 4 to 7 days of administering the first daily dose, and optionally continuing administration the second daily dose as a maintenance dose after the 4 to 7 days of administering the second daily dose or resuming administration of the first daily dose after the 4 to 7 days of the second daily dose and optionally wherein a daily dose is administered twice daily.

69. The method of any of claims 68, comprising administering a third daily dose of the composition that is equivalent to about 180 mg of the extract to the subject for 4 to 7 days after the 4 to 7 days of administering the second daily dose, and optionally continuing administration of the third daily dose as a maintenance dose after the 4 to 7 days of administering the third daily dose or resuming administration of the second daily dose as a maintenance dose after the 4 to 7 days of administering the third daily dose.

70. The method of any of claims 69, comprising administering a fourth daily dose of the composition that is equivalent to about 263 mg of the extract to the subject for 4 to 7 daysAttorney Docket No.38383.0001P1 after the 4 to 7 days of administering the third daily dose, and optionally continuing administration of the fourth daily dose as a maintenance dose after the 4 to 7 days of administering the fourth daily dose or resuming administration of the third daily dose as a maintenance dose after the 4 to 7 days of administering the fourth daily dose.

71. The method of any of claims 70, comprising administering a fifth daily dose of the composition that is equivalent to about 314 mg of the extract to the subject for 4 to 7 days after the 4 to 7 days of administering the fourth daily dose, and optionally continuing administration of the fifth daily dose as a maintenance dose after the 4 to 7 days of administering the fifth daily dose or resuming administration of the fourth daily dose as a maintenance dose after the 4 to 7 days of administering the fifth daily dose.

72. A method of treating epilepsy in a subject in need thereof, the method comprising administering to a subject a therapeutically effective amount of the pharmaceutical composition comprising an extract obtained from the method according to any of claims 48 to 56.

73. The method of claim 72, wherein the subject is a human.

74. A pharmaceutical composition is a lipid-based formulation or lipid-surfactant based formulation, wherein the formulation comprises a cannabinoid extract of Cannabis sativa and a carrier, wherein the carrier comprises, consists of, or consists essentially of a mono, di, or tri glyceride or any combination thereof, wherein the fatty acids of the glycerides have a saturated or unsaturated carbon chain length ranging from 8 to 20 carbons, wherein the composition comprises: a. beta-caryophyllene at an amount that is 2% to 10% percent of the amount of beta caryophyllene in the air dried plant material from which the extract is obtained, and / or b. α-bisabolol at an amount that is 2% to 20% percent of the amount of α-bisabolol ne in the air dried plant material from which the extract is obtained and / orAttorney Docket No.38383.0001P1 c. α-humelene at an amount that is 2% to 20% percent of the amount of α-humelene in the air dried plant material from which the extract is obtained, and / or d. a concentration of cannabidiol of 5 to 8% w / w of the composition.

75. The pharmaceutical composition of claim 74, wherein the composition comprises the concentration of α-bisabolol of from 4 mg / mL to 8 mg / mL or the ratio of cannabidiol to α- bisabolol of 10:1 to 23:

1.

76. The pharmaceutical composition of claim 74 or 75, wherein the composition comprises the concentration of beta-caryophyllene is from 4 mg / mL to 15 mg / mL or the ratio of cannabidiol to beta-caryophyllene of 5:1 to 11:

1.

77. The pharmaceutical composition of any one of claims 74 to 76, wherein the composition comprises a ratio of cannabidiol:tetrahydrocannabinol of from 20:1 to 60:1 or from about 25:1 to about 40:

1.

78. The pharmaceutical composition of any one of claim 74 to 77, wherein a concentration of delta 9-THC is 0-0.3% w / w / of the pharmaceutical composition, a concentration of cannabichromene is 0-0.5% w / w of the pharmaceutical composition, a concentration of cannabigerol is 0 to 0.3% w / w of the pharmaceutical composition and / or wherein a concentration of total cannabinoids is 5.6-8.4% w / w of the pharmaceutical composition.

79. The pharmaceutical composition of any of claims 74 to 78, wherein the composition is not an emulsion.

80. The pharmaceutical composition of any of claims 74 to79, wherein the Cannabis sativa L. is of the variety ‘CW1AS1’ strain, wherein a representative seed of the variety has been deposited under NCIMB No.43291.

81. The pharmaceutical composition of any of claims 74 to 80, wherein the cannabinoid composition comprises a tetrahydrocannabinol concentration of 1 to 3 mg / mL.Attorney Docket No.38383.0001P1 82. The pharmaceutical composition of any of claims 74 to 81, wherein the composition comprises a concentration of α-humelene of from about 2 mg / mL to about 3.5 mg / mL.

83. The pharmaceutical composition of any of claims 74 to 82, wherein the pharmaceutical composition consists of or consists essentially of a cannabinoid extract of Cannabis sativa L., the carrier, and a flavoring agent.

84. The pharmaceutical composition of any one of claims 74 to 83, wherein the carbon chain length of the glyceride is 12 to 20 or wherein the glyceride is sesame oil, corn oil, modified corn oil, or combination thereof, or wherein the carrier comprises, consists or consists essentially of a winterized oil composed of mono-, di- and triglycerides of oleic and linoleic acids.

85. A method of treating one or more symptoms of autism spectrum disorder (ASD) in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of the pharmaceutical composition of any of claims 74 to 84.

86. The method of claim 85, wherein the symptom of ASD is anxiety and / or irritability.

87. The method of claim 85 or 86, wherein the subject is a human.

88. The method of claim 87, wherein the human subject is less than 18 years of age or 5 to 17 years of age.

89. The method of claim 87, wherein the human subject is at least 13 years of age or 13 to 30 years of age.

90. The method of any of claims 88, wherein a daily dose of the pharmaceutical composition comprises from 20 mg to 400 mg of the cannabinoid extract.Attorney Docket No.38383.0001P1 91. The method of any of claims 88 or 89, wherein a daily dose of the pharmaceutical composition comprises from about 100 mg to about 700 mg of the cannabinoid extract.

92. The method of claims 88 or 89, comprising administering a first daily dose of the composition that is equivalent to about 103 mg of the extract to the subject for 4 to 7 days and administering a second daily dose of about 206 mg for 4 to 7 days after the 4 to 7 days of administering the first daily dose, and optionally continuing administration the second daily dose as a maintenance dose after the 4 to 7 days of administering the second daily dose or resuming administration of the first daily dose after the 4 to 7 days of the second daily dose and optionally wherein a daily dose is administered twice daily.

93. The method of claim 92, comprising administering a third daily dose of the composition that is equivalent to about 360 mg of the extract to the subject for 4 to 7 days after the 4 to 7 days of administering the second daily dose, and optionally continuing administration of the third daily dose as a maintenance dose after the 4 to 7 days of administering the third daily dose or resuming administration of the second daily dose as a maintenance dose after the 4 to 7 days of administering the third daily dose.

94. The method of claim 93, comprising administering a fourth daily dose of the composition that is equivalent to about 515 mg of the extract to the subject for 4 to 7 days after the 4 to 7 days of administering the third daily dose, and optionally continuing administration of the fourth daily dose as a maintenance dose after the 4 to 7 days of administering the fourth daily dose or resuming administration of the third daily dose as a maintenance dose after the 4 to 7 days of administering the fourth daily dose.

95. The method of claim 94, comprising administering a fifth daily dose of the composition that is equivalent to about 618 mg of the extract to the subject for 4 to 7 days after the 4 to 7 days of administering the fourth daily dose, and optionally continuing administration of the fifth daily dose as a maintenance dose after the 4 to 7 days of administering the fifth daily dose or resuming administration of the fourth daily dose as a maintenance dose after the 4 to 7 days of administering the fifth daily dose.Attorney Docket No.38383.0001P1 96. The method of claim 87, comprising administering a first daily dose of the composition that is equivalent to about 53 mg of the extract to the subject for 4 to 7 days and administering a second daily dose of about 103 mg for 4 to 7 days after the 4 to 7 days of administering the first daily dose, and optionally continuing administration the second daily dose as a maintenance dose after the 4 to 7 days of administering the second daily dose or resuming administration of the first daily dose after the 4 to 7 days of the second daily dose and optionally wherein a daily dose is administered twice daily.

97. The method of any of claims 96, comprising administering a third daily dose of the composition that is equivalent to about 180 mg of the extract to the subject for 4 to 7 days after the 4 to 7 days of administering the second daily dose, and optionally continuing administration of the third daily dose as a maintenance dose after the 4 to 7 days of administering the third daily dose or resuming administration of the second daily dose as a maintenance dose after the 4 to 7 days of administering the third daily dose.

98. The method of any of claims 97, comprising administering a fourth daily dose of the composition that is equivalent to about 263 mg of the extract to the subject for 4 to 7 days after the 4 to 7 days of administering the third daily dose, and optionally continuing administration of the fourth daily dose as a maintenance dose after the 4 to 7 days of administering the fourth daily dose or resuming administration of the third daily dose as a maintenance dose after the 4 to 7 days of administering the fourth daily dose.

99. The method of any of claims 98, comprising administering a fifth daily dose of the composition that is equivalent to about 314 mg of the extract to the subject for 4 to 7 days after the 4 to 7 days of administering the fourth daily dose, and optionally continuing administration of the fifth daily dose as a maintenance dose after the 4 to 7 days of administering the fifth daily dose or resuming administration of the fourth daily dose as a maintenance dose after the 4 to 7 days of administering the fifth daily dose.Attorney Docket No.38383.0001P1 100. A method of treating a seizure disorder in a subject in need thereof, the method comprising administering to a subject a therapeutically effective amount of the pharmaceutical composition of any of claims 74 to 84.

101. The method of claim 100, wherein the subject is a human.

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