Methods for treating childhood neurological disorders

Abstract

The present invention relates to compositions comprising cannabinoids together with additional active ingredients. The present invention also relates to pharmaceutical compositions, dosage forms, and methods for treating pediatric neurological disorders by administering the compositions to a patient in need thereof. In a first aspect, the present invention broadly relates to a method for treating pediatric neurological disorders, comprising administering to a patient in need thereof a therapeutically effective amount of a composition comprising about 50 wt% CBDA, and all other cannabinoids comprising about 15 wt% CBDA.

Description

[Technical Field]

[0001] FIELD OF THE INVENTION The present invention relates to compositions comprising cannabinoids together with additional active ingredients. The present invention also relates to pharmaceutical compositions, dosage forms, and methods of treating pediatric neurological disorders by administering the compositions to a patient in need thereof. [Background technology]

[0002] background The following background art discussion is intended only to facilitate an understanding of the present invention and is not an admission or acknowledgement that any of the material referred to is or was part of the common general knowledge as of the priority date of the application.

[0003] A. Neuroinflammation Neuroinflammation refers to the process by which the brain's innate immune system is triggered after an inflammatory challenge, such as that brought about by injury, infection, exposure to toxins, neurodegenerative disease, or aging. Neuroinflammation has been implicated in contributing to a variety of neurological and physical diseases, including Alzheimer's disease (AD), Parkinson's disease (PD), multiple sclerosis, amyotrophic lateral sclerosis, cerebral ischemia, traumatic brain injury, rheumatoid arthritis, chronic migraine, epilepsy, autism spectrum disorder (ASD), attention-deficit hyperactivity disorder (ADHD), cerebral palsy and related subtypes, neuropathic pain, and depression.

[0004] In the central nervous system (CNS), the innate immune response plays a significant role in both physiological and pathological conditions. CNS diseases, including traumatic brain injury, ischemic stroke, brain tumors, and cerebrovascular and neurodegenerative diseases, trigger a cascade of events broadly defined as neuroinflammation, which is characterized by the activation of microglial and astroglial populations. On the other hand, microglial and astroglial activation, T lymphocyte infiltration, and overproduction of inflammatory cytokines have been demonstrated in association with neuronal alterations in both animal and human tissues. Therefore, neuroinflammation is an important topic in modern neuroscience.

[0005] Inflammatory or pro-inflammatory cytokines / markers are a class of signaling molecules secreted by immune cells, such as helper T cells and macrophages, as well as certain other cell types, that promote neuroinflammatory and general inflammatory processes. These include interleukin-1 (IL-1), IL-12, and IL-18, tumor necrosis factor alpha (TNF-α), interferon gamma (IFNγ), and granulocyte-macrophage colony-stimulating factor (GM-CSF). These pro-inflammatory cytokines are primarily produced by and are involved in the upregulation of inflammatory responses and play an important role in mediating innate immune responses.

[0006] B. Neuropathy and Pediatric Neuropathy Examples of neurological disorders that are "neuroinflammation-based" include Alzheimer's disease (Alzheimer's disease is the most prevalent chronic, progressive neurodegenerative disease and cause of dementia), Parkinson's disease, multiple sclerosis, amyotrophic lateral sclerosis, cerebral ischemia, traumatic brain injury, rheumatoid arthritis, chronic migraine, epilepsy, autism spectrum disorder, attention-deficit hyperactivity disorder, cerebral palsy and related subtypes, neuropathic pain, and depression.

[0007] Examples of pediatric neurological disorders that are "neuroinflammation-based" include pediatric autoimmune neuropsychiatric syndromes (PANS) and subsets of PANS, including pediatric autoimmune neuropsychiatric disorders associated with streptococcal infection (PANDAS) and pediatric infection-induced neuropsychiatric disorders (PITAND). Children with PANS often exhibit neuropsychiatric symptoms and disorders, including obsessive-compulsive disorder (OCD), Tourette's syndrome, and tics (involuntary, purposeless movements).

[0008] The symptoms of OCD and Tourette's syndrome in these PANS and PANDAS cases are hypothesized to result from the development of autoantibodies that cross-react with proteins normally expressed in the brain, a mechanism known as molecular homology. The link between immune dysregulation and the symptoms of OCD and Tourette's syndrome in this subset of pediatric patients is becoming increasingly clear.

[0009] TSPO / PK PET imaging studies of microglial activation have examined both non-infectious Tourette's syndrome and PANDAS (Kurlan R. Tourette's syndrome. New England Journal of Medicine. 2010;363(24):2332-2338; Leckman JF Tourette's syndrome. The Lancet. 2002;360(9345):1577-1586. doi: 10.1016 / s0140-6736(02)11526-1). Children with PANDAS have increased PK binding in the striatum compared with healthy adult controls, which corresponds to the previously described increase in striatal volume during acute illness in PANDAS patients (Leckman JF Tourette's syndrome. The Lancet. 2002;360(9345):1577-1586. doi: 10.1016 / s0140-6736(02)11526-1; Williams K., Bloch MH, State MW, Pittenger C. Tourette syndrome. In: Charney DS, editor. Neurobiology of Mental Illness. 4th. New York, NY, USA: Oxford University Press; 2013).

[0010] Considerable evidence suggests that immune dysregulation may contribute to the pathophysiology of Tourette's syndrome and PANS / PANDAS (Leckman JF Tourette's syndrome. The Lancet. 2002;360(9345):1577-1586. doi: 10.1016 / s0140-6736(02)11526-1; Williams K., Bloch MH, State MW, Pittenger C. Tourette syndrome. In: Charney DS, editor. Neurobiology of Mental Illness. 4th. New York, NY, USA: Oxford University Press; 2013; Swedo SE Pediatric autoimmune neuropsychiatric disorders associated with streptococcal infections (PANDAS) Molecular Psychiatry. 2002;7(supplement 2):S24-S25). However, two recent studies using different methodologies suggest abnormalities in microglial activation in patients with Tourette syndrome and PANS / PANDAS. Both studies focused on the basal ganglia.

[0011] Recent studies have demonstrated that TSPO is a ligand that binds to a transporter protein (TSPO) expressed by activated microglia ( 11Using in vivo positron emission tomography (PET) imaging with C-[R]-PK11195 (PK), increased PK binding, indicative of inflammatory microglial activation, was observed in the bilateral caudate nuclei of children with Tourette's syndrome and PANS / PANDAS (Williams KA, Swedo SE. Post-infectious autoimmune disorders: Sydenham's chorea, PANDAS, and beyond. Brain Research. 2015;1617:144-154; Frick LR, Williams K., Pittenger C. Microglial dysregulation in psychiatric disease. Clinical and Developmental Immunology. 2013;2013:10; Ji K., Miyauchi J., Tsirka SE. Microglia: an active player in the regulation of synaptic activity. Neural Plasticity. 2013;2013:9).

[0012] Although there is growing evidence for microglial dysregulation in OCD, Tourette's syndrome, and PANS / PANDAS, the case for microglial dysregulation is strongest in these neurological disorders, with recent postmortem and PET imaging studies providing converging evidence for increased microglial activation in the striatum of patients with complex neuroinflammatory disorders (Paolicelli RC, Bolasco G., Pagani F., et al. Synaptic pruning by microglia is necessary for normal brain development. Science. 2011;333(6048):1456-1458; Schafer DP, Lehrman EK, Kautzman AG, et al. Microglia sculpt postnatal neural circuits in an activity- and complement-dependent manner. Neuron. 2012;74(4):691-705). This is complemented by studies in the Hdc-KO mouse model of Tourette's syndrome. C. Microglial Activation | Neurodegeneration

[0013] Microglial cells are resident macrophages unique to the central nervous system (CNS). They play important roles during CNS development and adult homeostasis. They contribute significantly to adult neurogenesis and neuroinflammation (Zhan Y., Paolicelli RC, Sforazzini F., et al. Deficient neuron-microglia signaling results in impaired functional brain connectivity and social behavior. Nature Neuroscience. 2014;17(3):400-406; Guruswamy R, ElAli A. Complex Roles of Microglial Cells in Ischemic Stroke Pathobiology: New Insights and Future Directions. Int J Mol Sci. 2017;18:18). Thus, they are involved in the pathogenesis of neurodegenerative diseases and contribute to aging. They play an important role in the maintenance and breakdown of the blood-brain barrier. As innate immune cells, they contribute substantially to the immune response against infectious pathogens that invade the CNS (Xiong XY, Liu L, Yang QW. Functions and mechanisms of microglia / macrophages in neuroinflammation and neurogenesis after stroke. Prog Neurobiol. 2016;142:23-44). They also play a major role in the growth of CNS tumors. Microglia are, therefore, the primary cell population connecting the nervous and immune systems (Xiong XY, Liu L, Yang QW. Functions and mechanisms of microglia / macrophages in neuroinflammation and neurogenesis after stroke. Prog Neurobiol. 2016;142:23-44).

[0014] Under physiological conditions, ramified, resting microglia provide a neuroprotective environment (David S, Greenhalgh AD, Kroner A. Macrophage and microglial plasticity in the injured spinal cord. Neuroscience. 2015;307:311-18; Bieber K, Autenrieth SE. Insights how monocytes and dendritic cells contribute and regulate immune defense against microbial pathogens. Immunobiology. 2015;220:215-26). However, most CNS pathologies and regenerative approaches involve microglial activation with corresponding inflammatory events (Hoogland IC, Houbolt C, van Westerloo DJ, van Gool WA, van de Beek D. Systemic inflammation and microglial activation: systematic review of animal experiments. J Neuroinflammation. 2015;12:114; Ascoli BM, Gea LP, Colombo R, Barbe-Tuana FM, Kapczinski F, Rosa AR. The role of macrophage polarization on bipolar disorder: identifying new therapeutic targets. Aust NZJ Psychiatry. 2016;50:618-30; Cherry JD, Olschowka JA, O'Banion MK. Neuroinflammation and M2 microglia: the good, the bad, and the inflamed. J Neuroinflammation. 2014;11:98).Thus, activated inflammatory microglia are neurotoxic and kill neurons by engulfing them or by releasing a variety of neurotoxic molecules and factors, including reactive oxygen species (ROS), glutamate, Fas ligand, tumor necrosis factor alpha (TNFα), and others (Loane DJ, Kumar A. Microglia in the TBI brain: the good, the bad, and the dysregulated. Exp Neurol. 2016;275:316-27; Nakagawa Y, Chiba K. Diversity and plasticity of microglial cells in psychiatric and neurological disorders. Pharmacol Ther. 2015;154:21-35).

[0015] Activated microglia, which drive chronic neuroinflammation, are associated with CNS aging (Loane DJ, Kumar A. Microglia in the TBI brain: the good, the bad, and the dysregulated. Exp Neurol. 2016;275:316-27), chronic neuropathic pain (Orihuela R, McPherson CA, Harry GJ. Microglial M1 / M2 polarization and metabolic states. Br J Pharmacol. 2016;173:649-65), and psychiatric disorders (Orihuela R, McPherson CA, Harry GJ. Microglial M1 / M2 polarization and metabolic states. Br J Pharmacol. 2016;173:649-65), as well as Alzheimer's disease (Nakagawa Y, Chiba K. Diversity and plasticity of microglial cells in psychiatric and neurological disorders. Pharmacol Ther. Microglial M1 / M2 polarization and metabolic states. Br J Pharmacol. 2016;173:649-65), amyotrophic lateral sclerosis (ALS), and multiple sclerosis have also been shown to contribute substantially to neurodegenerative diseases. Aging parallels systemic chronic activation and polarization of the immune system toward a low-level inflammatory state. (Ransohoff RM. A polarizing question: do M1 and M2 microglia exist? Nat Neurosci. 2016;19:987-91; Tang Y, Le W. Differential Roles of M1 and M2 Microglia in Neurodegenerative Diseases. Mol Neurobiol. 2016;53:1181-94).

[0016] Medicinal applications of cannabis

[0017] Cannabis sativa L. has a long history of medical use. Medicinal cannabis has attracted considerable interest due to its anti-inflammatory, antioxidant, and anti-necrotic protective effects, as well as its favorable safety and tolerability profile in humans, making it a promising candidate for many therapeutic approaches. However, clinical use has been limited due to adverse effects on the central nervous system and the potential for abuse and addiction. The plant exudes a resin containing a mixture of cannabinoids, with two main components, Δ9-tetrahydrocannabinol (THC) and cannabidiol (CBD). The structure of CBD was described in the 1960s and has attracted attention due to its lack of psychoactive activity. Due to its excellent tolerability in humans, lack of psychoactive effects, and low abuse potential, it appears ideal for clinical trials.

[0018] C. Cannabinoids In addition to its favorable safety profile and lack of psychoactive effects, CBD also offers a wide range of therapeutic benefits. Several experimental in vitro and in vivo studies have demonstrated anti-inflammatory and immunomodulatory, antipsychotic, analgesic, and antiepileptic properties. For these reasons, CBD is currently one of the most studied cannabinoids. Compared to Δ9-THC, CBD exhibits lower affinity for cannabinoid receptors type 1 (CB1) and type 2 (CB2). CB1 receptors are found primarily in the terminals of central and peripheral neurons, while CB2 receptors are primarily found in immune cells. Several in vitro studies have shown that CBD, at low concentrations, has weak CB1 and CB2 antagonistic effects.

[0019] Research suggests that CBD behaves as a negative allosteric modulator of CB1, meaning that it does not directly activate the receptor but alters the potency and efficacy of its orthosteric ligands: Δ9-THC and 2-arachidonoylglycerol (2-AG). These preliminary results, while requiring further validation, may explain CBD's ability to antagonize some of the effects of Δ9-THC reported in vitro, in vivo, and human clinical studies. It has also been suggested that CBD's role as an allosteric modulator of CB1 may explain its therapeutic role in treating central and peripheral nervous system disorders. CBD has also been shown to inhibit neutrophil chemotaxis and proliferation. CBD can also induce arachidonic acid release and reduce prostaglandin E2 (PGE2) and nitric oxide (NO) production.

[0020] However, not all of CBD's physiological effects are mediated by cannabinoid receptors. CBD has numerous targets outside the endocannabinoid system, and its actions independent of cannabinoid receptors are the subject of recent pharmacological research. Some effects, such as anti-inflammatory and immunosuppressive effects, are mediated by more than one target. The anti-inflammatory and immunosuppressive effects are likely due to adenosine receptor A activation. 1A and A 2A CBD's activity is mediated by activation of strychnine-sensitive α1 and α1β glycine receptors and inhibition of equilibrative nucleoside transporters. Furthermore, CBD's activity may derive different physiological effects from the same target. For example, the same glycine receptor is involved in both anti-inflammatory and neuropathic pain suppression. While its effects on the serotonin 5HT1A receptor can produce anxiolytic, panic-resolving, and antidepressant effects, research has provided a thorough overview of CBD's molecular pharmacology. Despite advances in CBD's molecular pharmacology, many of its pharmacological mechanisms remain uncharacterized.

[0021] Published studies in animals have demonstrated that the oral bioavailability of cannabidiol is approximately between 13 and 19%. Plasma and brain concentrations are dose-dependent in animals, and bioavailability is increased with various oil formulations. Cannabinoids undergo extensive first-pass metabolism, with metabolites mostly excreted via the kidneys.

[0022] Cannabinoids are extensively metabolized by the liver, where they are hydroxylated by P450 enzymes, primarily the CYP3A (2 / 4) and CYP2C (8 / 9 / 19) families of isoenzymes, to 7-OH-CBD, which then undergoes extensive further metabolism in the liver and the resulting metabolites are excreted in the feces and, to a much lesser extent, in the urine.

[0023] Cannabidiol is known to act on cannabinoid (CB) receptors (CB1 and CB2) of the endocannabinoid system, which is found in many areas of the body, including the peripheral and central nervous systems, including the brain. The endocannabinoid system regulates many physiological responses in the body, including pain, memory, appetite, and mood. More specifically, CB1 receptors can be found in pain pathways in the brain and spinal cord, where they can affect cannabidiol-induced analgesia and anxiolysis, and CB2 receptors have effects on immune cells, where they can affect cannabidiol-induced anti-inflammatory processes.

[0024] Cannabidiol has been shown to act as a negative allosteric modulator of the cannabinoid CB1 receptor, the most abundant G protein-coupled receptor (GPCR) in the body. Receptor allosteric modulation is achieved by modulating the activity of the receptor at a site functionally distinct from the agonist or antagonist binding site. The negative allosteric modulatory effects of cannabidiol are therapeutically important because direct agonists are limited by their psychomimetic effects, whereas direct antagonists are limited by their inhibitory effects.

[0025] There has been some progress in regulatory approval of CBD. Epidiolex® is a plant-derived, pharmaceutical-grade cannabidiol (CBD) medication that received FDA approval for use in the United States in 2018. Epidiolex® contains 100 mg of cannabidiol per milliliter (mL) of solution and is taken orally twice daily. The Australian Therapeutic Goods Administration (TGA) approved Epidiolex in September 2020 for the treatment of seizures associated with Lennox-Gastaut syndrome (LGS) or Dravet syndrome in patients aged 2 years or older. There is a need in the art for improved cannabinoid compositions and effective treatments for childhood neurological disorders. It is an object of the present invention to overcome one or more of the problems foreseen by the prior art. [Prior art documents] [Non-patent literature]

[0026] [Non-Patent Document 1] Kurlan R. Tourette's syndrome. New England Journal of Medicine. 2010;363(24):2332-2338 [Non-patent document 2] Leckman JF Tourette's syndrome. The Lancet. 2002;360(9345):1577-1586. doi: 10.1016 / s0140-6736(02)11526-1 [Non-patent document 3] Leckman JF Tourette's syndrome. The Lancet. 2002;360(9345):1577-1586. doi: 10.1016 / s0140-6736(02)11526-1 [Non-patent document 4] Williams K., Bloch MH, State MW, Pittenger C. Tourette syndrome. In: Charney DS, editor. Neurobiology of Mental Illness. 4th. New York, NY, USA: Oxford University Press; 2013 Summary of the Invention [Means for solving the problem]

[0027] Summary of the Invention In a first aspect, the present invention broadly relates to a method of treating a pediatric neurological disorder, comprising administering to a patient in need thereof a therapeutically effective amount of a composition comprising about 50% CBDA w / w, and all other cannabinoids at about 15% w / w.

[0028] In a preferred embodiment, the present invention provides a method for treating a pediatric neurological disorder, comprising administering to a patient in need thereof a therapeutically effective amount of one of the following cannabinoids: w / w% CBDA 40-60%; CBD 1-5%; CBG 1-10%; CBDP 1-5%; CBDB 1~5%; CBGA 1-10%; CBN 1-3%; and THC<1% The method includes administering a composition comprising:

[0029] In another preferred embodiment, the composition comprises one of the following cannabinoids: w / w% CBDA 50%; CBD 2%; CBG 5%; CBDP 2%; CBDB 2%; CBGA 5%; CBN 1-3%; THC<0.3% and additional active ingredients Includes.

[0030] In another preferred embodiment, the composition comprises one of the following cannabinoids: w / w% CBDA 49%; CBD 2%; CBG 5%; CBDP 2%; CBDB 2%; CBGA 5%; CBN 3%; THC<0.3% and additional active ingredients Includes.

[0031] In another preferred embodiment, the composition comprises one of the following cannabinoids: w / w% CBDA 45%; CBD 1%; CBG 4%; CBDP 1%; CBDB 2%; CBGA 4%; CBN 2%; THC<0.2% and additional active ingredients Includes.

[0032] In another preferred embodiment, the composition comprises one of the following cannabinoids: w / w% CBDA 45%; CBD 1%; CBG 4%; CBDP 1%; CBDB 2%; CBGA 4%; CBN 1%; THC<0.2% and additional active ingredients Includes.

[0033] In another preferred embodiment, the composition comprises THC (alpha and delta 8) selected from the group consisting of the following cannabinoids (w / w%): THC<1%, THC<0.3%, THC<0.2%, THC>1%, THC>1% up to 10%, THC>1% up to 15%, THC>1% up to 30%.

[0034] In another preferred embodiment, the composition further comprises a cannabinoid selected from the group consisting of CBC, CBN, CBDV, plant terpenes, and THC (alpha and delta 8).

[0035] In another preferred embodiment, the composition comprises one of the following cannabinoids: CBC, CBN, CBDV, Plant terpenes, and THC (alpha and delta 8) Further includes:

[0036] In a preferred embodiment, the composition comprises the following cannabinoids: w / w% CBC (1-3%) CBN (1-3%) CBDV (1-3%) Plant terpenes (2-5%) THC (Alpha and Delta 8) >1% to up to 30% Further includes:

[0037] In a preferred embodiment, the composition comprises the following cannabinoids: w / w% CBDA 40-60%; CBD 1-5%; CBG 1-10%; CBDP 1-5%; CBDB 1~5%; CBGA 1-10%; CBN 1-3%; CBC 1-3%; CBN 1-3%; CBDV 1-3%; plant terpenes (2–5%), and THC<1% Includes.

[0038] In a preferred embodiment, the composition comprises the following cannabinoids: w / w% CBDA 40-60%; CBD 1-5%; CBG 1-10%; CBDP 1-5%; CBDB 1~5%; CBGA 1-10%; CBN 1-3%; CBC 1-3%; CBN 1-3%; CBDV 1-3%; plant terpenes (2–5%), and THC (Alpha and Delta 8) >1% to up to 30% Includes.

[0039] In a preferred embodiment, the composition comprises: w / w% CBDA 40-60%; CBD 1-5%; CBG 1-10%; CBDP 1-5%; CBDB 1~5%; CBGA 1-10%; CBN 1-3%; CBC 1-3%; CBN 1-3%; CBDV 1-3%; plant terpenes (2–5%), and THC<1% The composition comprises one or more cannabinoids selected from the group consisting of:

[0040] In a preferred embodiment, the composition comprises: w / w% CBDA 40-60%; CBD 1-5%; CBG 1-10%; CBDP 1-5%; CBDB 1~5%; CBGA 1-10%; CBN 1-3%; CBC 1-3%; CBN 1-3%; CBDV 1-3%; plant terpenes (2–5%), and THC (Alpha and Delta 8) >1% to up to 30% The composition comprises one or more cannabinoids selected from the group consisting of:

[0041] In a preferred embodiment, the composition comprises a cannabinoid in an amount selected from the group consisting of any one of the above embodiments.

[0042] In preferred embodiments, the pediatric neurological disorder is selected from the group consisting of PANS / PANDAS, Tourette's syndrome, cerebral palsy, ataxia, attention deficit hyperactivity disorder (ADHD), Lennox-Gastaut, Dravet syndrome, leukodystrophies and subtypes, Reye's syndrome, Rett syndrome, Fragile X syndrome, Phelan-McDermid syndrome, Angelman syndrome, Pitt-Hopkins syndrome, Prader-Willi syndrome, metabolic disorders, and glycosylation disorders.

[0043] In a preferred embodiment, the PANS are selected from the group consisting of PANDAS and PITANDS.

[0044] In preferred embodiments, the metabolic disorder is selected from the group consisting of Hurler syndrome, Niemann-Pick disease, Tay-Sachs disease, Gaucher disease, Fabry disease and Krabbe disease, galactosemia, maple syrup urine disease, phenylketonuria, glycogen storage diseases, mitochondrial disorders, Friedreich's ataxia, peroxisomal disorders, metal metabolism disorders, organic acidemias, and urea cycle disorders.

[0045] In preferred embodiments, the glycosylation disorder is selected from the group consisting of N-glycosylation disorders, O-glycosylation disorders, glycosylphosphatidylinositol (GPI) anchor and glycolipid anchor disorders, and glycosylation pathway disorders.

[0046] In a preferred embodiment, the childhood neurological disorder is associated with neuroinflammation.

[0047] In a preferred embodiment, the composition further comprises an oil selected from the group consisting of synthetic oils, vegetable-based oils, mineral oils, canola oil, and olive oil.

[0048] In a preferred embodiment, the composition comprises less than 5% w / w terpenes.

[0049] In a preferred embodiment, the composition comprises less than 2% w / w organic plant material.

[0050] In a preferred embodiment, the composition comprises less than 2% w / w plant phenolics.

[0051] In preferred embodiments, the cannabinoid component of the composition is selected from the group consisting of those in a concentration of between 1 and 500 mg / ml, between 10 and 100 mg / ml, and 50 mg / ml.

[0052] In preferred embodiments, the CBDA component of the composition is selected from the group consisting of those in a concentration of between 1 and 500 mg / ml, between 10 and 100 mg / ml, and 50 mg / ml.

[0053] In a preferred embodiment, the composition has a UPLC mass chromatogram corresponding to FIG. 3 utilizing the conditions described in Example 1.

[0054] In a preferred embodiment, the composition further comprises an additional active ingredient.

[0055] In a preferred embodiment, the additional active ingredient is selected from the group consisting of diclofenac, prednisone, celecoxib, and psylocibin.

[0056] In a second aspect, the present invention is a pharmaceutical composition adapted for treating childhood neurological disorders comprising a composition as discussed in the first aspect of the invention, together with a pharmaceutically acceptable carrier.

[0057] In a third aspect, the present invention is a dosage form adapted for treating childhood neurological disorders, comprising a composition as discussed in the first aspect of the invention.

[0058] In a preferred embodiment, the dosage form adapted to treat childhood neurological disorders comprises the following composition: w / w% CBDA 40-60%; CBD 1-5%; CBG 1-10%; CBDP 1-5%; CBDB 1~5%; CBGA 1-10%; CBN 1-3% THC<1% Including, The CBDA component of the composition is selected from the group consisting of between 1 mg and 1000 mg, between 1 mg and 500 mg, between 1 and 100 mg, less than 400 mg, less than 300 mg, less than 200 mg, and less than 100 mg.

[0059] In a preferred embodiment, the dosage form adapted to treat childhood neurological disorders comprises the following composition: w / w% CBDA 40-60%; CBD 1-5%; CBG 1-10%; CBDP 1-5%; CBDB 1~5%; CBGA 1-10%; CBN 1-3% THC<1% Including, The CBDA component of the composition is selected from the group consisting of 600 mg, 400 mg, 300 mg, 200 mg, 100 mg, 50 mg, 10 mg, 5 mg, 2 mg, and 1 mg.

[0060] In a fourth aspect, the present invention provides a kit adapted for treating a childhood neurological disorder, comprising the following composition: w / w% CBDA 40-60%; CBD 1-5%; CBG 1-10%; CBDP 1-5%; CBDB 1~5%; CBGA 1-10%; CBN 1-3% THC<1% together with instructions.

[0061] In a fifth aspect, the present invention provides the use of a composition in the manufacture of a medicament for the treatment of a childhood neurological disorder, wherein the composition comprises one of the following cannabinoids: w / w% CBDA 40-60%; CBD 1-5%; CBG 1-10%; CBDP 1-5%; CBDB 1~5%; CBGA 1-10%; CBN 1-3%, and THC<1% It is a use including.

[0062] In a preferred embodiment, the cannabinoid is w / w% CBDA 50%; CBD 2%; CBG 5%; CBDP 2%; CBDB 2%; CBGA 5%; CBN 3% and THC<0.3% Composition 1, comprising: and w / w% CBDA 45%; CBD 1%; CBG 4%; CBDP 1%; CBDB 2%; CBGA 4%; CBN 2% and THC<0.2% Composition 2, comprising is present in an amount selected from the group consisting of:

[0063] In preferred embodiments, the pediatric neurological disorder is selected from the group consisting of PANS / PANDAS, Tourette's syndrome, cerebral palsy, ataxia, attention deficit hyperactivity disorder (ADHD), Lennox-Gastaut, Dravet syndrome, leukodystrophies and subtypes, Reye's syndrome, Rett syndrome, Fragile X syndrome, Phelan-McDermid syndrome, Angelman syndrome, Pitt-Hopkins syndrome, Prader-Willi syndrome, metabolic disorders, and glycosylation disorders.

[0064] Preferably, the PANS are selected from the group consisting of PANDAS and PITAND.

[0065] In preferred embodiments, the metabolic disorder is selected from the group consisting of Hurler syndrome, Niemann-Pick disease, Tay-Sachs disease, Gaucher disease, Fabry disease and Krabbe disease, galactosemia, maple syrup urine disease, phenylketonuria, glycogen storage diseases, mitochondrial disorders, Friedreich's ataxia, peroxisomal disorders, metal metabolism disorders, organic acidemias, and urea cycle disorders.

[0066] In preferred embodiments, the glycosylation disorder is selected from the group consisting of N-glycosylation disorders, O-glycosylation disorders, glycosylphosphatidylinositol (GPI) anchor and glycolipid anchor disorders, and glycosylation pathway disorders.

[0067] In a preferred embodiment, the childhood neurological disorder is associated with neuroinflammation.

[0068] In a preferred embodiment, the composition further comprises an oil selected from the group consisting of synthetic oils, vegetable-based oils, mineral oils, canola oil, and olive oil.

[0069] In a preferred embodiment, the composition comprises less than 5% w / w terpenes.

[0070] In a preferred embodiment, the composition comprises less than 2% w / w organic plant material.

[0071] In a preferred embodiment, the composition comprises less than 2% w / w plant phenolics.

[0072] In preferred embodiments, the cannabinoid component of the composition is selected from the group consisting of those in a concentration of between 1 and 500 mg / ml, between 10 and 100 mg / ml, and 50 mg / ml.

[0073] In preferred embodiments, the CBDA component of the composition is selected from the group consisting of those in a concentration of between 1 and 500 mg / ml, between 10 and 100 mg / ml, and 50 mg / ml.

[0074] In a preferred embodiment, the composition has a UPLC mass chromatogram corresponding to FIG. 3 utilizing the conditions described in Example 1.

[0075] In a preferred embodiment, the composition further comprises an additional active ingredient.

[0076] In a preferred embodiment, the additional active ingredient is selected from the group consisting of diclofenac, prednisone, celecoxib, and psilocybin.

[0077] In a sixth aspect, the present invention provides a process for extracting a composition of the invention from cannabis plant material comprising: 1) grinding cannabis plant material to a sufficient grind size; 2) contacting the grounds produced by step a) with oil; 3) mixing the grinds and oil for a sufficient period of time to form a mixture; 4) pressing the mixture to recover the oil; 5) centrifuging the oil to further refine the oil; 6) collecting the oil extract in a suitable container / steel vessel; It is a process that includes:

[0078] In a seventh aspect, the present invention provides a process for extracting a composition of the invention from cannabis plant material comprising: 1) grinding cannabis plant material to a sufficient grind size; 2) contacting the ground material produced by step a) with alcohol; 3) mixing the grind and alcohol for a sufficient period of time to form a mixture; 4) sonicating the mixture; 5) centrifuging the mixture; 6) collecting the alcoholic extract in a suitable container; It is a process that includes:

[0079] In an eighth aspect, the present invention comprises compositions, methods or processes as described by the following examples.

[0080] Further features of the present invention are more fully described in the following description of several non-limiting embodiments thereof. This description is included solely for the purpose of illustrating the invention and is not to be understood as a limitation on the broad summary, disclosure, or description of the invention as set forth above.

[0081] Below is a brief description of each of the figures and drawings. [Brief explanation of the drawings]

[0082] [Figure 1] Figure 1 shows UPLC mass chromatograms of a cannabinoid standard mixture (10 ppm each) in a) positive and b) negative ionization mode. This is an LC-MS chromatogram of a cannabinoid standard mixture (10 ppm each) in a) positive and b) negative ionization mode.

[0083] [Figure 2] Figure 2 shows the in-source fragmentation of CBD and CBG from the reference solution.

[0084] [Figure 3] FIG. 3 presents the mass spectrometry chromatogram of NTI164.

[0085] [Figure 4] Figure 4 presents mass spectrometry chromatograms of CBD variants.

[0086] [Figure 5] FIG. 5 presents the manifestations of inflammation, including the induction of iNOS in neuronal cells.

[0087] [Figure 6] FIG. 6 presents neuronal viability quantified using MTT [3-(4,5-dimethylthiazol-2-yl-)-2,5-diphenyl-2H-tetrazolium bromide].

[0088] [Figure 7] FIG. 7 demonstrates that NTI164 stimulates the maturation of immature neurons into healthy cells, even in the absence of any glutamate-induced damage.

[0089] [Figure 8] FIG. 8 demonstrates that CBD is toxic in this paradigm, whereas NTI164 is non-toxic and has a positive effect on cell number and cell viability.

[0090] [Figure 9] FIG. 9 shows the response of microglia under inflammatory conditions assessing arginase 1 expression.

[0091] [Figure 10] Figure 10 is a schematic outlining arginine metabolism and the effect it has on the overall balance of anti-inflammatory and pro-inflammatory signals (Reference: Review. Goncalo S. Clemente, Aren van Waarde, Ines F. Antunes, Alexander Domling and Philip H. Elsinga. Arginase as a Potential Biomarker of Disease Progression: A Molecular Imaging Perspective. (2020)).

[0092] [Figure 11] FIG. 11 shows the distribution of patients actively using NTI164 for Example 10.

[0093] [Figure 12] FIG. 12 shows the distribution of disease severity among active patients at baseline according to CGI-S severity of disease for Example 10.

[0094] [Figure 13]FIG. 13 shows the maximum tolerated dose for active patients for Example 10.

[0095] [Figure 14] FIG. 14 shows CGI-S global improvement during 28 days of NTI164 treatment.

[0096] [Figure 15] FIG. 15 shows the CGI-S severity of disease after 28 days of treatment.

[0097] [Figure 16] FIG. 16 shows the CGI-S severity of disease after 28 days of treatment.

[0098] [Figure 17] FIG. 17 shows the effect of CGI-S treatment after 28 days of treatment.

[0099] [Figure 18] Figure 18 shows a heatmap depicting the top 1,000 differentially expressed genes in the whole blood transcriptomes of children with atypical OCD compared to controls. There are baseline differences in gene expression profiles between controls (pink bars) and atypical OCD patients pre-IVIG (purple bars). A comparison of pre-IVIG (purple bars) and post-IVIG (blue, green bars) shows that IVIG can modify gene expression profiles, but this effect diminishes by day 28 (Reference: Antistreptolysin-O titers: implications for adult PANDAS. Pediatric autoimmune neuropsychiatric disorders associated with streptococcal infections. Church AJ, Dale RC. Am J Psychiatry. 2002 Feb;159(2):320).

[0100] [Figure 19]Figure 19 shows a gene ontology pathway analysis showing the top 10 enriched pathways in the whole blood transcriptomes of children with pediatric acute-onset neuropsychiatric syndrome (PANS) compared to controls. Immune pathways (e.g., neutrophil degranulation, neutrophil activation) are downregulated (blue), while gene translation pathways (e.g., protein targeting to the ER, translation initiation) are upregulated (red). Abbreviations: ER, endoplasmic reticulum (Reference: Shekeeb S Mohammad and Russell C Dale. . Principles and approaches to the treatment of immune-mediated movement disorders. Eur J Paediatr Neurol. 2018 Mar;22(2):292-300).

[0101] [Figure 20] FIG. 20 shows the age distribution of patients actively using NTI164 for Example 12.

[0102] [Figure 21] Figure 21 shows the distribution of illness severity among active patients at baseline according to CGI-S severity of illness for Example 12. CGI-S refers to Clinical Global Impression Scale-Severity of Illness.

[0103] [Figure 22] FIG. 22 shows CGI-S global improvement during 20 weeks of NTI164 treatment.

[0104] [Figure 23] FIG. 23 shows CGI-S global improvement over time for up to and including 20 weeks of NTI164 treatment.

[0105] [Figure 24] Figure 24 shows the CGI-S severity of disease at 20 weeks of treatment.

[0106] [Figure 25]FIG. 25 shows CGI-S severity of disease over time for up to and including 20 weeks of treatment.

[0107] [Figure 26] Figure 26 shows the CGI-S severity of disease at 20 weeks of treatment.

[0108] [Figure 27] FIG. 27 shows the CGI-S therapeutic effect over time for up to and including 20 weeks of treatment.

[0109] [Figure 28] FIG. 28 shows the effect of CGI-S treatment over 20 weeks of treatment.

[0110] [Figure 29] Figure 29 shows CGI-S severity of disease over time up to and including 52 weeks of treatment. P=0.03.

[0111] [Figure 30] Figure 30 shows the mean severity of disease over time for up to and including 52 weeks of treatment. NTI164 treatment is associated with a significant reduction in disease severity (a 1.3 scale change, a 30% improvement). Approximately 40% of subjects were significantly or severely ill at baseline - 0% from week 4 onwards.

[0112] [Figure 31] Figure 31 shows CGI-S global improvement over time for up to and including 52 weeks of NTI164 treatment. 100% of active patients showed improvement after 20 weeks of daily treatment with NTI164. After 52 weeks of daily treatment with NTI164, 90% (n=10) of active patients had a global improvement of significantly improved, and 10% (n=1) had a score of very significantly improved.

[0113] [Figure 32]Figure 32 shows the CGI-S treatment effect over time for up to and including 52 weeks of treatment. After 52 weeks of daily NTI164 treatment, 10% of active patients demonstrated the highest possible efficacy index of 1: marked treatment effect - vast improvement; complete or near-complete remission of all symptoms. 90% of patients had an efficacy index of either 5 or 6: moderate treatment effect - clear improvement; partial remission of symptoms.

[0114] [Figure 33] FIG. 33 shows the mean change in the Revised Children's Anxiety and Depression Scale, Parent-Rated (RCADS-P) scale total score over 12 weeks.

[0115] [Figure 34] Figure 34 shows the mean change in illness severity on the Clinical Global Impression-Severity (CGI-S) scale over 12 weeks.

[0116] [Figure 35] Figure 35 shows the severity of illness ratings on the Clinical Global Impression-Severity (CGI-S) scale over a 12-week period.

[0117] [Figure 36] FIG. 36 shows the effect of treatment on the Clinical Global Impression-Severity (CGI-S) scale over 12 weeks.

[0118] [Figure 37] FIG. 37 shows the impression of improvement on the Clinical Global Impression-Improvement (CGI-I) scale over time.

[0119] [Figure 38] FIG. 38 shows the mean change in the Yale Global Tic Severity Scale (YGTSS) scale total score over time.

[0120] [Figure 39]Figure 39 shows the mean change in the Children's Yale-Brown Obsessive-Compulsive Scale (CY-BOCS) total score over time.

[0121] [Figure 40] FIG. 40 shows the mean change in the Conners Scale (assessment of Attention Deficit Hyperactivity Disorder (ADHD) behavior) scale total score over time.

[0122] [Figure 41] Figure 41 shows the mean change in the total score of the EQ-5D-Y (a standardized measure of health-related quality of life domains) scale over time. DETAILED DESCRIPTION OF THE INVENTION

[0123] Detailed Description of the Invention For convenience, the following section outlines various meanings of terms generally used herein. Following this discussion, general aspects relating to the compositions, pharmaceutical uses and methods of the present invention will be discussed, followed by specific examples demonstrating the properties of various embodiments of the invention and how they may be used.

[0124] Those skilled in the art will recognize that the invention described herein is susceptible to variations and modifications other than those specifically described. The invention includes all such variations and modifications. The invention includes all steps, features, formulations, and compounds individually or collectively referred to or indicated in the specification, as well as any and all combinations of steps or features, or any two or more of them.

[0125] Each document, reference, patent application, or patent cited in this text is expressly incorporated herein by reference in its entirety, meaning that it should be read and considered as part of this text by the reader. It is for the sake of brevity only that the documents, references, patent applications, or patents cited in this text are not repeated in this text. However, neither the cited materials nor the information contained therein should be understood to be general knowledge.

[0126] Manufacturer's directions, descriptions, product specifications, and product sheets for any products mentioned herein or in any document incorporated by reference herein are incorporated by reference herein and may be used in the practice of this invention.

[0127] The present invention is not limited in scope by any of the specific embodiments described herein. These embodiments are intended for illustrative purposes only. Functionally equivalent products, formulations, and methods are clearly within the scope of the invention as described herein.

[0128] 1.Definition The meanings of certain terms and phrases used in the specification, examples, and appended claims are provided below. If there is an apparent discrepancy between the usage of a term in the art and its definition provided herein, the definition provided in the specification shall control.

[0129] Except in the working examples or where otherwise indicated, all numbers expressing quantities of ingredients or reaction conditions used herein are to be understood in all instances as being modified by the term "about." When used in connection with percentages, the term "about" can mean ±1%.

[0130] The inventions described herein may include one or more ranges of values ​​(e.g., size, concentration, etc.). A range of values ​​will be understood to include all values ​​within the range, including the value defining the range and any adjacent values ​​within the range that lead to the same or substantially the same result as the values ​​immediately adjacent to the values ​​defining the range boundary. For example, one of ordinary skill in the art will understand that a 10% variation within the upper or lower limit of a range may be entirely appropriate and is encompassed by the present invention. More particularly, a variation within the upper or lower limit of a range will be 5%, or whichever is greater, as generally recognized in the art.

[0131] In this application, the use of the singular includes the plural unless specifically stated otherwise. In this application, the use of "or" means "and / or" unless specifically stated otherwise. Furthermore, the use of the term "including" and other forms such as "includes" and "comprises" is not limiting. Also, terms such as "element" or "component" encompass both elements and components that contain one unit and elements and components that contain more than one subunit, unless specifically stated otherwise. Also, the use of the term "portion" can include part of a portion or the entire portion.

[0132] Throughout this specification, unless the context requires otherwise, the word "comprise" or variations such as "comprises" or "comprising" will be understood to imply the inclusion of a stated integer or group of integers but not the exclusion of any other integer or group of integers.

[0133] "Pediatric age," as used herein, is consistent with its use by the Federal Food, Drug, and Cosmetic Act (FD&C Act), which defines a pediatric patient as one who is 21 years of age or younger at the time of their diagnosis or treatment. Pediatric subpopulations are further categorized as follows: Neonates—birth through 28 days of age; Infants—29 days to under 2 years of age (https: / / www.fda.gov / medical-devices / products-and-medical-procedures / pediatric-medical-devices).

[0134] "Therapeutically effective amount," as used herein with respect to methods of treatment and particularly drug dosage, refers to a dosage that provides a specific pharmacological response in a significant number of subjects in need of such treatment, at which the drug is administered. It is emphasized that a "therapeutically effective amount" administered to a particular subject in a particular case may not always be effective in treating the diseases described herein, even if such a dosage is considered "therapeutically effective" by those skilled in the art. It should be further understood that drug dosages are measured in particular cases as oral dosages or with reference to drug levels as measured in blood. The amount effective for such use will depend on the desired therapeutic effect, the potency of the biologically active material, the desired duration of treatment, the stage and severity of the disease being treated, the patient's weight and general health, and the judgment of the prescribing physician. Treatment dosages should be titrated to optimize safety and effectiveness. Thus, one of skill in the art will know that appropriate dosage levels for treatment will vary, in part, depending on the indication for which the active agent is being used, the route of administration, and the patient's size (weight, body surface, or organ size) and condition (age and general health). Accordingly, a clinician may titrate the dosage and modify the route of administration to obtain the optimal therapeutic effect. Typical dosages may range from about 0.1 μg / kg up to about 100 mg / kg or more, depending on the factors discussed above. In other embodiments, dosages may range from 0.1 μg / kg up to about 100 mg / kg, or from 1 μg / kg up to 100 mg / kg, or from 5 μg / kg up to about 100 mg / kg.

[0135] The frequency of administration will depend on the pharmacokinetic parameters of the active agent and formulation used.Typically, clinicians will administer the composition until the dosage that achieves the desired effect is reached.Therefore, the composition can be administered as a single dose, or as two or more doses (which may or may not contain the same amount of the desired molecule) over time, or as continuous infusion via implanted device or catheter.Further refinement of the appropriate dosage is routinely made by those skilled in the art and is within the scope of the tasks that are routinely performed by those skilled in the art.Appropriate dosage can be ascertained by using appropriate dose-response data.

[0136] As used herein, "pharmaceutically acceptable carrier" includes any and all solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents, and the like that are physiologically compatible.

[0137] As used herein, the term "subject" generally includes mammals, such as humans; livestock such as sheep, goats, pigs, cows, horses, and llamas; companion animals such as dogs and cats; primates; birds such as chickens, geese, and ducks; fish; and reptiles. The subject is preferably human. In one embodiment, the human subject is an infant, a child, or an adolescent. In one embodiment, the human subject is a pediatric patient, and is 21 years old or younger at the time of diagnosis or treatment.

[0138] Other definitions for selected terms used herein may be found within the detailed description of the invention and may be applied throughout. Unless otherwise defined, all other scientific and technical terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs.

[0139] Features of the present invention will now be discussed with reference to the following non-limiting descriptions and examples.

[0140] 2. Embodiment composition The present invention relates to the use of the following cannabinoids: Approximately 50 w / w% CBDA Including, All other cannabinoids amount to approximately 15% w / w. A composition is provided.

[0141] In a preferred embodiment, the present invention provides the following cannabinoids: w / w% Approximately 50% CBDA, Approximately 2% CBD, plus additional active ingredients The present invention provides a composition comprising:

[0142] In a further preferred embodiment, the present invention provides the following cannabinoids: w / w% Approximately 50% CBDA, Approximately 5% CBG, plus additional active ingredients The present invention provides a composition comprising:

[0143] In a further preferred embodiment, the present invention provides the following cannabinoids: w / w% Approximately 50% CBDA, Approximately 2% CBDP, plus additional active ingredients The present invention provides a composition comprising:

[0144] In a further preferred embodiment, the present invention provides the following cannabinoids: w / w% Approximately 50% CBDA, Approximately 2% CBDB, plus additional active ingredients The present invention provides a composition comprising:

[0145] In a further preferred embodiment, the present invention provides the following cannabinoids: w / w% Approximately 50% CBDA, Approximately 5% CBGA, plus additional active ingredients The present invention provides a composition comprising:

[0146] In a further preferred embodiment, the present invention provides a composition comprising cannabinoids, wherein the ratio of CBDA to all other cannabinoids is between 4:1 and 2:1.

[0147] In a further preferred embodiment, the present invention provides a composition comprising cannabinoids, wherein the ratio of CBDA to all other cannabinoids is about 3:1.

[0148] In a further preferred embodiment, the present invention provides a composition comprising cannabinoids, wherein the ratio of CBDA to all other cannabinoids is about 3.21:1.

[0149] In a further preferred embodiment, the present invention provides the following cannabinoids: w / w% CBDA 40-60%, CBD 1-5%, CBG 1-10%, CBDP 1-5%, CBDB 1~5%, CBGA 1-10%, CBN 1-3%, THC<1% and additional active ingredients The present invention provides a composition comprising:

[0150] In a further preferred embodiment, the present invention provides the following cannabinoids: w / w% CBDA 45-55%, CBD 1-3%, CBG 3-7%, CBDP 1-3%, CBDB 1-3%, CBGA 3-7%, CBN 1-3%, THC<0.5% and additional active ingredients The present invention provides a composition comprising:

[0151] In a further preferred embodiment, the present invention provides the following cannabinoids: w / w% CBDA 50%, CBD 2%, CBG 5%, CBDP 2%, CBDB 2%, CBGA 5%, CBN 3%, THC<0.3% and additional active ingredients The present invention provides a composition comprising:

[0152] In a further preferred embodiment, the present invention provides the following cannabinoids: w / w% CBDA 49%, CBD 2%, CBG 5%, CBDP 2%, CBDB 2%, CBGA 5%, CBN 2%, THC<0.3% and additional active ingredients The present invention provides a composition comprising:

[0153] In a further preferred embodiment, the present invention provides the following cannabinoids: w / w% CBDA 48.78%, CBD 1.89%, CBG 4.88%, CBDP 1.68%, CBDB 1.76%, CBGA 4.76%, CBN 1%, THC<0.18% and additional active ingredients The present invention provides a composition comprising:

[0154] In a further preferred embodiment, the present invention provides the following cannabinoids: w / w% CBDA 45%, CBD 1%, CBG 4%, CBDP 1%, CBDB 2%, CBGA 4%, CBN 2%, THC<0.2%, and additional active ingredients The present invention provides a composition comprising:

[0155] In a further preferred embodiment, the present invention provides the following cannabinoids: w / w% CBDA 45.28%, CBD 1.39%, CBG 3.88%, CBDP 1.18%, CBDB 1.56%, CBGA 3.76%, CBN 1%, THC<0.18% and additional active ingredients The present invention provides a composition comprising:

[0156] In a further preferred embodiment, the present invention provides the following cannabinoids: w / w% CBDA 62.78%, CBD 5.80%, CBG 0.44%, CBGA 1.26%, CBN 1.98%, THC<0.70% and additional active ingredients The present invention provides a composition comprising:

[0157] In a further preferred embodiment, the present invention provides the following cannabinoids: w / w% CBDA 60.29%, CBD 5.34%, CBG 0.39%, CBGA 1.14%, CBN 0.85%, THC<0.65% and additional active ingredients The present invention provides a composition comprising:

[0158] In a further preferred embodiment, the present invention relates to a compound comprising: w / w% CBDA 50%, CBD 2%, CBG 5%, CBDP 2%, CBDB 2%, CBGA 5%, CBN 3%, THC<0.3%, and Additional Active Ingredients Composition 1 comprising and w / w% CBDA 45%, CBD 1%, CBG 4%, CBDP 1%, CBDB 2%, CBGA 4%, CBN 2%, THC<0.2%, and Additional Active Ingredients Composition 2 comprising is present in an amount selected from the group consisting of:

[0159] In a further preferred embodiment, the present invention provides a method for determining whether the amount of cannabinoids is determined by high performance chromatography (HPLC), proton nuclear magnetic resonance spectroscopy (H 1 The composition is determined by a method selected from the group consisting of NMR, and mass spectrometry.

[0160] In a further preferred embodiment, the present invention provides compositions derived from cannabis plant material.

[0161] In a further preferred embodiment, the present invention provides a composition wherein the listed cannabinoids are synthetic.

[0162] In a further preferred embodiment, the present invention provides a composition wherein the listed cannabinoids are a mixture of plant-derived and synthetic cannabinoids.

[0163] In a further preferred embodiment, the present invention provides a composition further comprising an oil selected from the group consisting of synthetic oil, vegetable-based oil, mineral oil, canola oil, and olive oil.

[0164] In a further preferred embodiment, the composition comprises less than 5% w / w terpenes.

[0165] In a further preferred embodiment, the composition comprises less than 2% w / w organic plant material.

[0166] In a further preferred embodiment, the composition comprises less than 2% w / w plant phenolics.

[0167] In a further preferred embodiment, the composition comprises a component selected from the group consisting of flavonoids, proteins, sterols and esters.

[0168] In a further preferred embodiment, the composition is substantially pure. Preferably, purity is measured by high performance chromatography (HPLC), proton nuclear magnetic resonance spectroscopy (H 1 Preferably, the purity is determined by a method selected from the group consisting of greater than 75% purity, greater than 80% purity, greater than 85% purity, greater than 90% purity, greater than 95% purity, greater than 96% purity, greater than 97% purity, greater than 98% purity, greater than 99% purity, greater than 99.5% purity, greater than 99.6% purity, greater than 99.7% purity, greater than 99.8% purity, greater than 99.9% purity, greater than 99.95% purity, greater than 99.96% purity, greater than 99.97% purity, greater than 99.98% purity, and greater than 99.99% purity.

[0169] In a further preferred embodiment, the composition is characterized by high performance chromatography (HPLC), proton nuclear magnetic resonance spectroscopy (H 1 Contains less than 0.1 wt% organic impurities as determined by a method selected from the group consisting of NMR, and mass spectrometry.

[0170] In a further preferred embodiment, the composition is substantially free of atmospheric oxygen.

[0171] In a further preferred embodiment, the composition is sterile. In an alternative preferred embodiment, the composition is not sterile.

[0172] In a further preferred embodiment, the present invention provides a composition wherein the cannabinoid component of the composition is at a concentration selected from the group consisting of between 1 and 500 mg / ml, between 10 and 100 mg / ml, and 50 mg / ml.

[0173] In further preferred embodiments, the present invention provides a composition wherein the CBDA component of the composition is at a concentration selected from the group consisting of between 1 and 500 mg / ml, between 10 and 100 mg / ml, and 50 mg / ml.

[0174] In a further preferred embodiment, the composition is a liquid.

[0175] In a further preferred embodiment, the composition is an oil.

[0176] In a further preferred embodiment, the composition demonstrates no cannabinoid degradation or decarboxylation when measured at a time point selected from the group consisting of 1 day, 2 days, 7 days, 14 days, 28 days, 5 weeks, 6 weeks and 32 weeks.

[0177] In a further preferred embodiment, the composition demonstrates cannabinoid stability when measured at a time point selected from the group consisting of 1 day, 2 days, 7 days, 14 days, 28 days, 5 weeks, 6 weeks and 32 weeks.

[0178] In a further preferred embodiment, the composition demonstrates no mutagenicity, no carcinogenicity, and no genotoxicity when delivered at a concentration that delivers 120 mg / ml of CBDA.

[0179] In a further preferred embodiment, the composition is adapted to inhibit the activity of any one of the following biomarkers: COX-2, iNOS, TNF-alpha, IL-2, IL-12 and GS-MCF.

[0180] Preferably, the composition is adapted to inhibit neuroinflammation. More preferably, the composition is adapted to treat a neurological disorder. More preferably, the composition is adapted to treat a pediatric neurological disorder.

[0181] In a further preferred embodiment, the present invention provides a composition having a UPLC mass chromatogram corresponding to FIG. 3 utilizing the conditions described in Example 1.

[0182] In a further preferred embodiment, the composition comprises an additional active ingredient.

[0183] Preferably, the additional active ingredient is selected from the group consisting of polypeptides; antibodies; NSAIDs; neuromodulators; and neurotransmitters, steroids - all related classes (corticosteroids), analgesics, antipsychotics, antidepressants, immunotherapy.

[0184] In one preferred embodiment, the NSAID is selected from the group consisting of aspirin, ibuprofen, naproxen, diclofenac, celecoxib, ketorolac, meloxicam, esomeprazole, naproxen, diclofenac, misoprostol, nabumetone, indomethacin, mefenamic acid, etodolac, piroxicam, ketoprofen, diflunisal, oxaprozin, flurbiprofen, sulindac, tolmetin, prednisolone, and fenoprofen.

[0185] In one embodiment, the additional active ingredient is selected from the group consisting of diclofenac, prednisone, celecoxib, and psilocybin.

[0186] In further preferred embodiments, the ratio of the cannabinoid component to the additional active ingredient is selected from the group consisting of 1 unit w / w cannabinoid:1 unit w / w of the additional active ingredient, 2:1, 3:1, 4:1, 5:1, between 10,000:1 and 1:1, between 1,000:1 and 1:1, between 500:1 and 1:1, between 100:1 and 1:1, between 50:1 and 1:1, and between 10:1 and 1:1.

[0187] In further preferred embodiments, the ratio of the additional active ingredient to the cannabinoid is selected from the group consisting of 1 unit w / w of the additional active ingredient to 1 unit w / w of the cannabinoid, 2:1, 3:1, 4:1, 5:1, between 10,000:1 and 1:1, between 1,000:1 and 1:1, between 500:1 and 1:1, between 100:1 and 1:1, between 50:1 and 1:1, and between 10:1 and 1:1.

[0188] In further preferred embodiments, the ratio of CBDA to the additional active ingredient is selected from the group consisting of 1 unit w / w CBDA:1 unit w / w of the additional active ingredient, 2:1, 3:1, 4:1, 5:1, between 10,000:1 and 1:1, between 1,000:1 and 1:1, between 500:1 and 1:1, between 100:1 and 1:1, between 50:1 and 1:1, and between 10:1 and 1:1.

[0189] In further preferred embodiments, the ratio of the additional active ingredient to CBDA is selected from the group consisting of 1 unit w / w of the additional active ingredient to 1 unit w / w of CBDA, 2:1, 3:1, 4:1, 5:1, between 10,000:1 and 1:1, between 1,000:1 and 1:1, between 500:1 and 1:1, between 100:1 and 1:1, between 50:1 and 1:1, and between 10:1 and 1:1.

[0190] In one preferred embodiment, the neuromodulator is a hallucinogenic substance.

[0191] Preferably, the neuromodulator is selected from the group consisting of 3,4-methylenedioxymethamphetamine, lysergic acid diethylamide, and psilocybin. Preferably, the neuromodulator is selected from the group consisting of steroids (all related classes (corticosteroids)), analgesics, antipsychotics, antidepressants, and immunotherapeutics.

[0192] In a further preferred embodiment, the composition demonstrates synergistic biological activity.

[0193] In a further preferred embodiment, the composition demonstrates a level of biological activity that is greater than the sum of (1) the biological activity of the cannabinoid component when delivered in the absence of the additional active ingredient and (2) the biological activity of the additional active ingredient when delivered in the absence of the cannabinoid component.

[0194] In a further preferred embodiment, the biological activity is selected from the group consisting of inhibiting inflammation, inhibiting neuroinflammation, treating neurological disorders, inhibiting the activity of COX-2, inhibiting the activity of iNOS, inhibiting the activity of TNF-alpha, inhibiting the activity of IL-2, inhibiting the activity of IL-12, and inhibiting the activity of GS-MCF.

[0195] In a further preferred embodiment, the composition is selected from the group consisting of a therapeutic composition, a pharmaceutical composition, a cosmetic composition, and a veterinary composition.

[0196] Pharmaceutical Composition The present invention also provides a pharmaceutical composition comprising a composition of the present invention together with a pharmaceutically acceptable carrier.

[0197] Therapeutic compositions are within the scope of the present invention. Preferably, the composition is combined with a pharmaceutically acceptable carrier or diluent to produce a pharmaceutical composition (which may be for human or animal use). Suitable carriers and diluents include isotonic saline solution, such as phosphate-buffered saline. As used herein, "pharmaceutically acceptable carrier" includes any and all solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents, and the like. The use of such media and agents for pharmaceutically active substances is well known in the art. Except insofar as any conventional media or agent is incompatible with the active ingredient, its use in therapeutic compositions is contemplated. Additional supplementary active ingredients can also be incorporated into the composition. See, for example, Remington's Pharmaceutical Sciences, 2nd Ed. (1995, Mack Publishing Co., Easton, Pa.), incorporated herein by reference.

[0198] Pharmaceutical compositions can contain compounding materials to modify, maintain, or preserve, for example, pH, osmolality, viscosity, clarity, color, isotonicity, odor, sterility, stability, rate of dissolution or release, adsorption, or penetration of the composition. Suitable formulation ingredients include amino acids (such as glycine, glutamine, asparagine, arginine, or lysine); antimicrobial agents; antioxidants (such as ascorbic acid, sodium sulfite or sodium bisulfite, vitamin E, vitamin E phosphate-fat-soluble vitamins, nanoemulsions, etc.); buffers (such as boric acid, bicarbonate, Tris-HCl, citric acid, phosphoric acid, or other organic acids); bulking agents (such as mannitol or glycine); chelating agents (such as ethylenediaminetetraacetic acid (EDTA)); complexing agents (such as caffeine, polyvinylpyrrolidone, beta-cyclodextrin, or hydroxypropyl-beta-cyclodextrin), bulking agents; monosaccharides, disaccharides, and other carbohydrates (such as glucose, mannose, or dextrin); proteins (such as serum albumin, gelatin, or immunoglobulins); colorants, flavorings (natural and naturally derived products), and diluents; emulsifiers; hydrophilic polymers (such as polyvinylpyrrolidone); low molecular weight preservatives (such as benzalkonium chloride, benzoic acid, salicylic acid, thimerosal, phenethyl alcohol, methylparaben, propylparaben, chlorhexidine, sorbic acid, or hydrogen peroxide); solvents (such as glycerin, propylene glycol, or polyethylene glycol); sugar alcohols (and artificial sweeteners such as mannitol or sorbitol); suspending agents; surfactants or wetting agents (such as Pluronic®; PEG; sorbitan esters; polysorbates such as polysorbate 20, polysorbate 80; Triton; tromethamine, lecithin; cholesterol; tyloxapol); stability enhancers (sucrose or sorbitol); tonicity enhancers (such as alkali metal halides, preferably sodium chloride or potassium chloride), delivery vehicles, diluents, excipients, and / or pharmaceutical adjuvants.

[0199] The optimal pharmaceutical composition will be determined by those skilled in the art depending on, for example, the intended administration route, delivery format and desired dosage.Such composition can affect the physical state, stability, in vivo release rate and in vivo clearance rate of the composition of the present invention.The preferred form of pharmaceutical composition depends on the intended administration mode and therapeutic application.

[0200] The primary vehicle or carrier in a pharmaceutical composition may be aqueous or non-aqueous in nature. For example, suitable vehicles or carriers may be water for injection or saline solution, possibly supplemented with other materials. Neutral buffered saline or saline mixed with serum albumin are further exemplary vehicles. Other exemplary pharmaceutical compositions include Tris buffer of about pH 7.0-8.5 or acetate buffer of about pH 4.0-5.5, which may further contain sorbitol or a suitable substitute. In one embodiment of the present invention, a pharmaceutical composition may be prepared for storage by mixing a selected composition having the desired purity with the necessary compounding agents in aqueous and non-aqueous form.

[0201] Formulation components are present in concentrations that are acceptable to the site of administration, for example, buffers are used to maintain the composition at physiological pH or slightly lower, typically within the pH range of about 5 (4.5) to about 8.

[0202] Additional pharmaceutical compositions, including formulations of the present invention in sustained- or controlled-delivery formulations, will be apparent to those skilled in the art. Techniques for formulating various other sustained- or controlled-delivery means, such as liposome carriers, biodegradable microparticles or porous beads, and depot injections, are also known to those skilled in the art. Additional examples of sustained-release preparations include semipermeable polymer matrices in the form of shaped articles, such as films or microcapsules. Sustained-release matrices may include polyesters, hydrogels, polylactides, copolymers of L-glutamic acid and gamma-ethyl L-glutamate, ethylene vinyl acetate, or poly-D(-)-3-hydroxybutyric acid. Sustained-release compositions may also include liposomes, which can be prepared by any of several methods known in the art.

[0203] Pharmaceutical compositions used for in vivo administration must typically be sterile. This can be achieved by filtration through a sterile filtration membrane. In addition, the composition is generally placed in a container with a sterile access port. Once the pharmaceutical composition is formulated, it can be stored as a solution in a sterile vial.

[0204] In yet a further preferred embodiment, the composition retains its effective biological activity for a period selected from the group consisting of more than 24 hours, more than 36 hours, and more than 48 hours. Preferably, the composition is stable for a period selected from the group consisting of 6 months, 1 year, and 2 years. In one example, the composition is stable at a temperature selected from the group consisting of -4°C, 4°C, 18°C, and 25°C. Dosage form

[0205] Dosage forms are within the scope of the present invention. In a preferred embodiment, the present invention provides a dosage form comprising a composition as described in the first aspect of the invention.

[0206] Preferably, the cannabinoid component of the composition in dosage form is selected from the group consisting of between 1 mg and 1000 mg, between 1 mg and 500 mg, between 1 and 100 mg, less than 400 mg, less than 300 mg, less than 200 mg, and less than 100 mg. More preferably, the cannabinoid component of the composition is selected from the group consisting of 600 mg, 400 mg, 300 mg, 200 mg, 100 mg, 50 mg, 10 mg, 5 mg, 2 mg, and 1 mg. Preferably, the CBDA component of the composition in dosage form is selected from the group consisting of between 1 mg and 1000 mg, between 1 mg and 500 mg, between 1 and 100 mg, less than 400 mg, less than 300 mg, less than 200 mg, and less than 100 mg. More preferably, the CBDA component of the composition is selected from the group consisting of 600 mg, 400 mg, 300 mg, 200 mg, 100 mg, 50 mg, 10 mg, 5 mg, 2 mg, and 1 mg.

[0207] In a further embodiment, the dosage form is in a form selected from the group consisting of a liquid, a tablet, a capsule, a cachet, a dry powder sachet, and a vial / freeze dried.

[0208] Preferably, the dosage form is stored in a sealed and sterile container.

[0209] Methods for treating The present invention also provides a method of treating a disorder, comprising administering to a patient in need thereof a therapeutically effective amount of a dosage form of the present invention.

[0210] In a further preferred embodiment, the dosage form is administered in an amount to at least partially treat the disorder.

[0211] In further preferred embodiments, the therapeutically effective amount is an amount of cannabinoid selected from the group consisting of between 1-100 mg / kg / day, between 2-50 mg / kg / day, between 5-40 mg / kg / day, between 10-30 mg / kg / day, between 20-25 mg / kg / day, and 20 mg / kg / day. Preferably, the therapeutically effective amount is an amount of cannabinoid selected from the group consisting of 10 mg / day, 15 mg / day, 40 mg / day, 400 mg / day, 600 mg / day, 800 mg / day, 1280 mg / day, and 1500 mg / day.

[0212] In further preferred embodiments, the therapeutically effective amount is an amount of CBDA selected from the group consisting of between 1-100 mg / kg / day, between 2-50 mg / kg / day, between 5-40 mg / kg / day, between 10-30 mg / kg / day, between 20-25 mg / kg / day, and 20 mg / kg / day. Preferably, the therapeutically effective amount is an amount of CBDA selected from the group consisting of 10 mg / day, 15 mg / day, 40 mg / day, 400 mg / day, 600 mg / day, 800 mg / day, 1280 mg / day, and 1500 mg / day.

[0213] In a further preferred embodiment, Tmax occurs between 1 and 4 hours.

[0214] In a further preferred embodiment, T1 / 2 occurs between 1.1 and 2.4 hours.

[0215] In a further preferred embodiment, a therapeutically effective amount is administered to a subject to treat a disorder.

[0216] Preferably, the therapeutically effective amount is administered to the subject utilizing a dosing regimen selected from the group consisting of twice hourly, hourly, once 6 hours, once 8 hours, once 12 hours, once daily, twice weekly, once weekly, once every two weeks, once every six weeks, once monthly, every two months, every three months, once every six months, and once yearly.

[0217] Preferably, the therapeutically effective amount is administered to the subject using a method selected from the group consisting of orally, intravenously, intramuscularly, intrathecally, subcutaneously, sublingually, bucally, rectally, vaginally, topically, parenterally, mucosally, by the ocular route, by the aural route, nasally, by inhalation, to the skin, transdermally, and systemically.

[0218] In a further preferred embodiment, the disorder is caused by inflammation.

[0219] In a further preferred embodiment, the disorder is caused by neuroinflammation.

[0220] Preferably, the disorder is a neurological disorder, more preferably selected from the group consisting of Alzheimer's disease, Parkinson's disease, multiple sclerosis, amyotrophic lateral sclerosis, cerebral ischemia, traumatic brain injury, rheumatoid arthritis, chronic migraine, epilepsy, autism spectrum disorder, attention deficit hyperactivity disorder, cerebral palsy and related subtypes, neuropathic pain, and depression.

[0221] In a further preferred embodiment, the ASD is ASD Level II / III, either "mildly affecting," "moderately affecting," "markedly affecting," or "severely affecting" on the CGI severity scale.

[0222] In a further preferred embodiment, the neurological disorder is a pediatric neurological disorder. For example, the pediatric neurological disorder is PANS. In one embodiment, the pediatric neurological disorder is selected from the group consisting of PANS / PANDAS, Tourette's syndrome, cerebral palsy, ataxia, attention-deficit hyperactivity disorder (ADHD), Lennox-Gastaut syndrome, Dravet syndrome, leukodystrophies and subtypes, Reye's syndrome, Rett syndrome, Fragile X syndrome, Phelan-McDermid syndrome, Angelman syndrome, Pitt-Hopkins syndrome, Prader-Willi syndrome, metabolic disorders, and glycosylation disorders.

[0223] In a preferred embodiment, the PANS are selected from the group consisting of PANDAS and PITANDS.

[0224] In preferred embodiments, the metabolic disorder is selected from the group consisting of Hurler syndrome, Niemann-Pick disease, Tay-Sachs disease, Gaucher disease, Fabry disease and Krabbe disease, galactosemia, maple syrup urine disease, phenylketonuria, glycogen storage diseases, mitochondrial disorders, Friedreich's ataxia, peroxisomal disorders, metal metabolism disorders, organic acidemias, and urea cycle disorders.

[0225] In preferred embodiments, the glycosylation disorder is selected from the group consisting of N-glycosylation disorders, O-glycosylation disorders, glycosylphosphatidylinositol (GPI) anchor and glycolipid anchor disorders, and glycosylation pathway disorders.

[0226] In a preferred embodiment, the childhood neurological disorder is associated with neuroinflammation.

[0227] In a further preferred embodiment, the treatment reduces neuroinflammation. Preferably, the treatment suppresses the activity of any one of the following biomarkers: COX-2, iNOS, TNF-alpha, IL-2, IL-12, and GS-MCF.

[0228] Subjects that may be treated with the present invention will include humans and other mammals and animals.

[0229] In a further preferred embodiment, the method comprises administering to a patient in need thereof a therapeutically effective amount of a dosage form of the present invention together with an additional active ingredient. In a preferred form, the additional active ingredient is administered using a dosing regimen selected from the group consisting of: simultaneously with administering a dosage form of the present invention; before administering a dosage form of the present invention; after administering a dosage form of the present invention; concurrently with administering a dosage form of the present invention; sequentially before administering a dosage form of the present invention; and sequentially after administering a dosage form of the present invention.

[0230] Preferably, the additional active ingredient is selected from the group consisting of polypeptides; antibodies; NSAIDs; neuromodulators; and neurotransmitters, steroids - all related classes (corticosteroids), analgesics, antipsychotics, antidepressants, immunotherapy.

[0231] In one preferred embodiment, the NSAID is selected from the group consisting of aspirin, ibuprofen, naproxen, diclofenac, celecoxib, ketorolac, meloxicam, esomeprazole, naproxen, diclofenac, misoprostol, nabumetone, indomethacin, mefenamic acid, etodolac, piroxicam, ketoprofen, diflunisal, oxaprozin, flurbiprofen, sulindac, tolmetin, prednisolone, and fenoprofen.

[0232] In one embodiment, the additional active ingredient is selected from the group consisting of diclofenac, prednisone, celecoxib, and psilocybin.

[0233] In further preferred embodiments, the ratio of the cannabinoid component to the additional active ingredient is selected from the group consisting of 1 unit w / w cannabinoid:1 unit w / w of the additional active ingredient, 2:1, 3:1, 4:1, 5:1, between 10,000:1 and 1:1, between 1,000:1 and 1:1, between 500:1 and 1:1, between 100:1 and 1:1, between 50:1 and 1:1, and between 10:1 and 1:1.

[0234] In further preferred embodiments, the ratio of the additional active ingredient to the cannabinoid is selected from the group consisting of 1 unit w / w of the additional active ingredient to 1 unit w / w of the cannabinoid, 2:1, 3:1, 4:1, 5:1, between 10,000:1 and 1:1, between 1,000:1 and 1:1, between 500:1 and 1:1, between 100:1 and 1:1, between 50:1 and 1:1, and between 10:1 and 1:1.

[0235] In further preferred embodiments, the ratio of CBDA to the additional active ingredient is selected from the group consisting of 1 unit w / w CBDA:1 unit w / w of the additional active ingredient, 2:1, 3:1, 4:1, 5:1, between 10,000:1 and 1:1, between 1,000:1 and 1:1, between 500:1 and 1:1, between 100:1 and 1:1, between 50:1 and 1:1, and between 10:1 and 1:1.

[0236] In further preferred embodiments, the ratio of the additional active ingredient to CBDA is selected from the group consisting of 1 unit w / w of the additional active ingredient to 1 unit w / w of CBDA, 2:1, 3:1, 4:1, 5:1, between 10,000:1 and 1:1, between 1,000:1 and 1:1, between 500:1 and 1:1, between 100:1 and 1:1, between 50:1 and 1:1, and between 10:1 and 1:1.

[0237] In one preferred embodiment, the neuromodulator is a hallucinogenic substance.

[0238] Preferably, the neuromodulator is selected from the group consisting of 3,4-methylenedioxymethamphetamine, lysergic acid diethylamide, and psilocybin.

[0239] The effectiveness of the administered therapeutic compositions can be monitored by standard diagnostic procedures.

[0240] Use of the composition in the manufacture of a medicament The use is within the scope of the present invention.The present invention also provides the use of a composition of the first aspect of the invention in the manufacture of a medicament for the treatment of a disorder.

[0241] In one preferred embodiment, the present invention provides the use of the following cannabinoids in the manufacture of a medicament for the treatment of a disorder: w / w% CBDA 40-60%; CBD 1-5%; CBG 1-10%; CBDP 1-5%; CBDB 1~5%; CBGA 1-10%; CBN 1-3% and THC<1% The use of a composition comprising:

[0242] In a further embodiment, the cannabinoid of the composition is used in the manufacture of a medicament for the treatment of a pediatric neurological disorder:

[0243] w / w% CBDA 50%; CBD 2%; CBG 5%; CBDP 2%; CBDB 2%; CBGA 5%; CBN 3% and THC<0.3%; Composition 1 comprising and w / w% CBDA 45%; CBD 1%; CBG 4%; CBDP 1%;CBDB 2%; CBGA 4%; CBN 2%, and THC<0.2% Composition 2 comprising is present in an amount selected from the group consisting of:

[0244] In a further embodiment, the childhood neurological disorder is PANS.

[0245] In a further embodiment, the PANS is selected from the group consisting of PANDAS and PITAND.

[0246] In a further embodiment, the composition further comprises an oil selected from the group consisting of synthetic oils, vegetable-based oils, mineral oils, canola oil, and olive oil.

[0247] In a further embodiment, the composition comprises less than 5% w / w terpenes.

[0248] In a further embodiment, the composition comprises less than 2% w / w organic plant material.

[0249] In a further embodiment, the composition comprises less than 2% w / w plant phenolics.

[0250] In further embodiments, the cannabinoid component of the composition is selected from the group consisting of those in a concentration of between 1 and 500 mg / ml, between 10 and 100 mg / ml, 50 mg / ml.

[0251] In further embodiments, the CBDA component of the composition is selected from the group consisting of: a concentration of between 1 and 500 mg / ml, between 10 and 100 mg / ml, or 50 mg / ml.

[0252] In a further embodiment, the composition has a UPLC mass chromatogram corresponding to FIG. 3 utilizing the conditions described in Example 1.

[0253] process The present invention provides a process for extracting the composition of the first aspect of the invention from cannabis plant material comprising: 1) grinding cannabis plant material to a sufficient grind size; 2) contacting the grounds produced by step a) with oil; 3) mixing the grinds and oil for a sufficient period of time to form a mixture; 4) pressing the mixture to recover the oil; 5) centrifuging the oil to further refine the oil; 6) collecting the oil extract in a suitable container / steel vessel; Also provided is a process including:

[0254] In a further preferred embodiment, the cannabis plant material is derived from Cannabis sativa L.

[0255] In further preferred embodiments, the sufficient grind size is selected from the group consisting of between 0.1 mm and 3 mm, between 1 mm and 2 mm, and between 0.5 mm and 2.5 mm.

[0256] In further preferred embodiments, the sufficient period of time is selected from the group consisting of between 30 minutes and 2 hours, between 45 minutes and 1.5 hours, and 1 hour.

[0257] In a further preferred embodiment, the ratio of ground material to oil in step (2) is selected from the group consisting of 400 mg ground material:1 ml oil, 300 mg ground material:1 ml oil, 200 mg ground material:1 ml oil, 100 mg ground material:1 ml oil, and 333 mg ground material:1 ml oil.

[0258] Preferably, the oil is olive oil.

[0259] The present invention provides an alternative process for extracting the composition of the first aspect of the invention from cannabis plant material, comprising: 1) grinding cannabis plant material to a sufficient grind size; 2) contacting the ground material produced by step a) with alcohol; 3) mixing the grind and alcohol for a sufficient period of time to form a mixture; 4) sonicating the mixture; 5) centrifuging the mixture; 6) collecting the alcoholic extract in a suitable container / steel vessel; Also provided is a process including:

[0260] In a further preferred embodiment, the alcohol is ethanol.

[0261] In a further preferred embodiment, the alcohol is selected from the group consisting of ethanol, isopropyl alcohol, methyl alcohol, benzyl alcohol, 1,4-butanediol, 1,2,4-butanetriol, butanol, 1-butanol, 2-butanol, tert-butyl alcohol.

[0262] In further preferred embodiments, the sufficient grind size is selected from the group consisting of between 0.1 mm and 3 mm, between 1 mm and 2 mm, and between 0.5 mm and 2.5 mm. In further preferred embodiments, the sufficient period of time is selected from the group consisting of between 30 minutes and 2 hours, between 45 minutes and 1.5 hours, and 1 hour.

[0263] In a further preferred embodiment, the ratio of ground material to alcohol in step (2) is selected from the group consisting of 400 mg ground material:1 ml alcohol, 300 mg ground material:1 ml alcohol, 200 mg ground material:1 ml alcohol, 100 mg ground material:1 ml alcohol, 100 mg ground material:4 ml alcohol, 100 mg ground material:3 ml alcohol, 100 mg ground material:2 ml alcohol, and 333 mg ground material:1 ml alcohol.

[0264] Process product The present invention also provides products produced by the above-described processes.

[0265] kit The present invention also provides a kit comprising a dosage form of one aspect of the invention together with instructions for its use.

[0266] device Devices are within the scope of the present invention. In a preferred embodiment, the present invention provides a device, comprising: (1) a composition as described in the first aspect of the present invention; and (2) an applicator.

[0267] Stabilization methods Methods for stabilizing the compositions are within the scope of the present invention.

[0268] In a further preferred embodiment, the method protects the composition from degradation.

[0269] In still further preferred embodiments, the composition retains its effective biological activity for a period selected from the group consisting of greater than 24 hours, greater than 36 hours, and greater than 48 hours.

[0270] The addition of approved pharmaceutical excipients to stabilize compositions is preferable from a safety perspective, as simpler methodologies are more likely to produce less variable results and may limit excipient choices to those with Generally Regarded as Safe (GRAS) status. Excipients for stabilizing protein solutions can be classified into four broad categories based on their chemical properties and mechanism of action: salts, sugars, polymers, or proteins / amino acids. Salts (e.g., chlorides, nitrates) stabilize protein tertiary structure by shielding charges through ionic interactions. Sugars (e.g., glycerol, sorbitol, fructose, trehalose) increase the surface tension and viscosity of the solution, preventing protein aggregation. Similarly, polymers (e.g., polyethylene glycol, cellulose derivatives) stabilize protein tertiary structure by increasing solution viscosity, preventing protein aggregation and intra- and intermolecular electrostatic interactions between amino acids in proteins. Proteins (e.g., human serum albumin) can stabilize the structure of other proteins through ionic, electrostatic, and hydrophobic interactions. Similarly, small amino acids with no net charge, such as alanine and glycine, stabilize proteins by forming weak electrostatic interactions.

[0271] As discussed above, the medicament of the present invention can comprise one or more pharmaceutically acceptable carriers.The use of such media and agents for the preparation of medicaments is well known in the art.Except where any conventional media or agent is incompatible with pharmaceutically acceptable materials, its use in the preparation of pharmaceutical compositions according to the present invention is contemplated.The pharmaceutically acceptable carrier according to the present invention can comprise one or more of the following examples: a. surfactants and polymers, including but not limited to polyethylene glycol (PEG), polyvinylpyrrolidone, polyvinyl alcohol, crospovidone, polyvinylpyrrolidone-polyvinyl acrylate copolymer, cellulose derivatives, HPMC, hydroxypropyl cellulose, carboxymethyl ethyl cellulose, hydroxypropyl methylcellulose phthalate, polyacrylates and polymethacrylates, urea, sugars, polyols, and their polymers, emulsifiers, sugar gums, starches, organic acids and their salts, vinylpyrrolidone, and vinyl acetate; and / or b. binders such as various celluloses and cross-linked polyvinylpyrrolidone, microcrystalline cellulose, and / or (3) fillers such as lactose monohydrate, anhydrous lactose, microcrystalline cellulose, and various starches, and / or c. bulking agents such as lactose monohydrate, anhydrous lactose, mannitol, microcrystalline cellulose, and various starches, and / or d. lubricants, such as agents that act to increase the ability of the dosage form to be extruded from the packaging cavity, and / or e. sweeteners, such as any natural or artificial sweetener, including sucrose, xylitol, sodium saccharin, cyclamate, aspartame, and acesulfame K; and / or f. flavoring agents; and / or g. preservatives, such as potassium sorbate, methylparaben, propylparaben, benzoic acid and its salts, other esters of parahydroxybenzoic acid such as butylparaben, alcohols such as ethyl or benzyl alcohol, phenolic chemicals such as phenol, or quaternary compounds such as benzalkonium chloride; and / or h. buffers, and / or i. a diluent, such as a pharmaceutically acceptable inert filler, e.g., microcrystalline cellulose, lactose, dicalcium phosphate, sugars, and / or mixtures of any of the foregoing, and / or j. absorption enhancers, such as glyceryl trinitrate, and / or k. Other pharmaceutically acceptable excipients.

[0272] Medicaments of the invention suitable for use in animals, and particularly in humans, typically must be sterile and stable under the conditions of manufacture and storage.

[0273] The present invention also provides compositions, methods and processes as described by the foregoing examples.

[0274] The present invention will now be described with reference to the following non-limiting examples. The description of the examples does not in any way limit the preceding paragraphs of this specification, but is provided to illustrate the methods and compositions of the present invention. [Example]

[0275] It will be apparent to those skilled in the milling and pharmaceutical arts that numerous improvements and modifications can be made to the above-described process without departing from the basic inventive concept. For example, in some applications, the biologically active material may be pretreated and fed to the process in a pretreated form. All such modifications and improvements are considered to be within the scope of the present invention, the nature of which is to be determined from the foregoing description and the appended claims. Furthermore, the following examples are provided for illustrative purposes only and are not intended to limit the scope of the process or compositions of the present invention.

[0276] Example 1 A. Example 1 - Extraction and Purification of NTI164 A.1 Research Aims To extract and identify the most desirable constituents from the NTI164 plant strain using an inert oil-based extraction process. A.2 Materials and Methods A.2.1 NTI164 Plant Material

[0277] The NTI164 plant is a full-spectrum medicinal cannabis plant (genus species Cannabis sativa) that the inventors subsequently identified as containing cannabidiolic acid (CBDA), cannabidiol (CBD), cannabigerolic acid (CBGA) and cannabidivarin (CBDV), cannabinol (CBN), but with greater than 0.03% tetrahydrocannabinol (THC). The NTI164 plant was grown, dried, and packaged under license and permit from the Drug Enforcement Administration (ODC) in accordance with Good Manufacturing Practice (GMP) and TGO 93 and 100 guidelines.

[0278] A.2.2 Extraction Methods - Oil-Based Equipment: The following equipment was used: 10 mL glass scintillation bottles with lids; Cobram Estate Olive Oil; vegetable grinder (similar to a coffee or food grade grinder) pore size maximum 50 μM; Whatman paper, grade 1; pipettes; weighing scale (transfer boat and spoon); Eppendorf tubes; 50 mL Falcon tubes; benchtop centrifuge (Eppendorf Centrifuge 5702); Oz Design brand 6 liter fruit, wine and cider press.

[0279] Extraction: Pressing and Centrifugation: All operations were carried out at standard laboratory temperature (18-22°C). NTI164 buds were stripped of their tough stems and discarded. The grinder was cleaned with 70% EtOH, and the grinding compartment was filled with dried plant material. The material was ground for 10 seconds at the finest setting (1-2 mm particle size). The grind was then mixed with 100 ml of olive oil at a vegetable / oil ratio of 333 mg / mL in an autoclaved Schott bottle. It was then placed in a mixer at room temperature for 1 hour and stirred with a magnetic stirrer (50 rpm). The oil-plus-vegetable mixture was then placed in an Oz Design brand 6-liter fruit, wine, and cider press to recover the oil components from the plant matter (mash). The recovered oil was then placed in a 50 ml Falcon tube and spun at 300 g for 15 minutes at room temperature (Isolation 1). The oil was then removed into a clean shot bottle, and the recovered volume was tracked. The oil recovery rate for isolation 1 was approximately 40%. The mash was discarded after each isolation. To the recovered oil, we added another 333 mg / mL of ground plant / oil material (another 100 ml), repeated mixing for 1 hour, and recovered and reused the oil until a total of 999 μg / mL (3 × 100 ml) of plant / oil mixture had passed (isolation 2). The oil recovery rate for isolation 2 was approximately 50%. Finally, we placed it in a Falcon tube and spun it as discussed above (isolation 3). The oil recovery rate for isolation 3 was approximately 50%. We then collected only the oil and placed it in an Eppendorf tube for processing. This triple extraction method resulted in a final product with a total volume of 50 ml, with a concentration of 48 mg CBDA per ml of olive oil, as determined using UPLC potency testing using the method described below.

[0280] A.2.3 Extraction Method - Ethanol-Based Extraction: Squeezing and Centrifugation: An alternative method involves extraction based on the use of ethanol. In this method, 500 milligrams of crushed plant material of NTI164 is mixed with 20 ml of ethanol in a 50 ml centrifuge tube. The tube is shaken vigorously for 60 seconds and then placed in a sonication bath at 30°C for 10 minutes. The sample is then placed on a shaker (200 rpm) for 30 minutes. Once complete, it is placed in a centrifuge and centrifuged at 4400 rcf for 5 minutes. The supernatant can then be evaluated in various preclinical models.

[0281] A.2.4 Analytical analysis Ultra-performance liquid chromatography (UPLC) reversed-phase and liquid chromatography mass spectrometry (LCMS) were used to identify the components in the NTI164 concentrate derived from the method discussed above. The analysis was performed using an integrated (U)HPLC system and a single quadrupole mass spectrometer detector with an electrospray ionization (ESI) interface.

[0282] The UPLC settings and conditions used were as follows: Cortex UPLC shield RP18 (0A 1.6 μM, 2.1 × 100 mm); analytical flow rate: 0.7 ml / min; mobile phase A: water 0.1% TFA; mobile phase B: acetonitrile; isocratic: 41:59 mobile phase A / mobile phase B; temperature: 35°C; detector: Acquity UPLC PDA; injection volume: 0.7 μL for a 1.0 mg / ml reference standard preparation, appropriately scaled sample solution; software: Empower 3CDS. Reference standard solutions were obtained from Novachem, Cerilliant Corporation (TX, USA). These were all predissolved solutions previously shown to be suitable for generating calibration curves.

[0283] Cannabidivarin (CBDV), cannabidiol (CBD), cannabigerol (CBG), tetrahydrocannabivarin (THCV), cannabinol (CBN), Δ 9 -Tetrahydrocannabinol (Δ 9 -THC), Δ 8-Tetrahydrocannabinol (Δ 8 A mixture of 16 cannabinoids in methanol containing 10 ppm each of (-THC), cannabichromene (CBC), their respective acidic forms, and cannabicyclol (CBL) was prepared. All solvents used were LCMS grade, and standards were prepared by dilution with 90% mobile phase B and 10% deionized water. Detailed analytical conditions for UPLC-LCMS analysis are listed in Table 1.

[0284] Table 1: Parameters and conditions for UPLC and LCMS analysis [Table 1]

[0285] A.3 Results A.3.1 UPLC and LCMS Analysis Results Figure 1 shows the separation of cannabinoids in a mixed standard solution (i.e., reference solution). Under experimental conditions, Δ 9 Neutral cannabinoids such as -THC, CBD, and CBL ionize in positive mode, whereas their respective acidic forms ionize in negative mode. CBD and CBG co-elute from the column, but their molecular weights are different and can be identified by mass spectrometry. In addition, Figure 2 shows the differences between the SID fragmentation patterns obtained for CBD and CBG (i.e., as an additional reference solution). These highly specific results demonstrate the advantages of LCMS over LC-UV for the analysis and identification of cannabinoids.

[0286] Figure 3 presents a UPLC mass chromatogram for NTI164 extracted using an oil-based method. These results show that the NTI164 extract (oil suspension) contains the following components, as presented in Table 2. Additional components include flavonoids, proteins, phenols, sterols, and esters. These are known components that make up 30-40% of whole plant cannabis material. Table 4 presents the associated elution times and areas under the peaks for the identified CBD peaks for the UPLC mass chromatogram in Figure 3.

[0287] Table 2: Components of extracted NTI164 oil (to two decimal places, rounded up if over 0.5, rounded down if under 0.5) [Table 2-1] [Table 2-2]

[0288] Table 3 presents the NTI164 composition extracted using ethanol extraction and the components quantified using the methods described herein.

[0289] Table 3: Components in extracted NTI164 ethanol (to two decimal places, rounded up if over 0.5, rounded down if under 0.5) [Table 3]

[0290] Table 4 presents the accompanying elution times and areas under the peaks for the identified CBD peaks for the UPLC mass chromatogram of Figure 3 (NTI164, extracted oil).

[0291] Table 4: Elution times and areas under the peaks [Table 4]

[0292] Note that rarer cannabinoids such as CBDB and CBDP were only detected using quadrupole MS (unlike routine HPLC used for other cannabinoids). These results are presented in Figure 4.

[0293] Example 2 B Example 2 - Characterization of the stability properties of NTI164 B.1 Research Aims To evaluate the stability of NTI164 samples suspended in oil formulations at room temperature.

[0294] B.2 Materials and Methods B.2.1 Sample preparation Triplicate samples of NTI164 were prepared using the method described above.

[0295] For control samples, three representative pre-prepared concentrated samples NTI164 (oil and dried flowers) were obtained as follows: Oil S = Samples were prepared as outlined above: For flowers, a portion of the homogenized plant material was added to acetonitrile or ethanol and sonicated for 20 minutes. The subsequent extract was filtered through a 0.22 μm syringe-tip filter directly into a 2 mL sample vial for analysis. Concentrates were similarly prepared using isopropanol as the extraction solvent.

[0296] B.2.2 Sampling NTI164 samples were assayed weekly, with CBDA used as the primary marker / stability indicator. An ACQUITY UPLC H-Class System coupled with Cortex UPLC Shield RP18 particle chemistry was used to provide a UPLC isocratic separation of the primary cannabinoids with a cycle time of 10.5 minutes. The analytical method using UPLC was used as described above.

[0297] Reference standard solutions were obtained from Cerilliant Corporation (Round Rock, TX). These pre-dissolved solutions have previously been shown to be suitable for generating calibration curves.

[0298] The standard curve was prepared as follows: Primary cannabinoid (-) Δ 9 - Linearity of THC and CBD was assessed at 10 concentrations between 0.004 mg / mL and 1.000 mg / mL prepared via serial dilution in methanol using appropriate standards as a representative demonstration of linearity. Table 5 outlines the cannabinoids used in the isolation.

[0299] Table 5: Cannabinoids used in isolation [Table 5]

[0300] B.3 Results B.3.1 UPLC analysis results An ACQUITY UPLC H-Class system coupled with Cortex UPLC Shield RP18 particle chemistry was used to provide a UPLC isocratic separation of the major cannabinoids with a cycle time of 10.5 minutes. Samples of NTI164 were assayed weekly, with CBDA as the primary marker and stability indicator. The results, presented in Table 6, demonstrate that NTI164 is stable in an inert oil medium at room temperature for 6 weeks. No decarboxylation or product degradation is observed over this time frame.

[0301] Table 6: Stability of NTI164 at room temperature [Table 6-1] [Table 6-2]

[0302] Example 3 C. Example 3 - Characterization of the biological properties of NTI164 C.1 Research Aims To evaluate the anti-inflammatory and neuroprotective effects of NTI164 in neuronal and microglial cell lines.

[0303] Neuroinflammation is one of the main triggers of neurodegeneration. Investigation of the factors and pathways that can induce the first step of the inflammatory response may lead to the identification of potential therapeutic targets to halt the progression of many disorders.

[0304] C.2 Materials and Methods C.2.1 Sample preparation and dilution 500 mg of dried plant material from NTI164 was suspended in 20 ml of absolute ethanol (using a 50 ml blue-top Falcon tube suitable for centrifugation) and vigorously stirred / shaken for 60 seconds. The tube was then placed in a sonication bath at 35-40°C for 10 minutes. Once sonication was complete, the sample was then placed on a tray shaker (200 rpm) at room temperature for 30 minutes. Once complete, the sample was then centrifuged at 4400 rpm for 5 minutes. The supernatant was collected for testing and development.

[0305] Units used to describe the treatment and concentration of NTI164 for the test product: a. 1 / 1000 dilution of extract - 10 UL (stock material is NTI164 - 10 UL, which is equivalent to 2 μg / ml of CBDA) b. 1 / 3000 dilution of extract - 3UL (stock material is NTI164-3UL, which is equivalent to 6µg / ml CBDA) c. 1 / 10000 dilution of extract - 1UL (stock material is NTI164-1UL, which is equivalent to 0.1 μg / ml of CBDA).

[0306] For the CBD samples, pure standards (in powder form) were used. CBD 98% isolate was purchased as a reference standard from LGC Standards (London, UK) (CAS number 13956-29-1). The CBD standard reference was prepared at a concentration of 1 mg / ml (in acetonitrile). The CBD dilutions were performed in acetonitrile as follows: 2 μg / ml, 6 μg / ml, and 0.1 μg / ml.

[0307] The final concentrations of NTI164 (CBDA equivalent) and CBD used in these studies were 2 μg / ml.

[0308] C.2.2 Microglial BV2 culture The immortalized microglial cell line BV2 was purchased from the American Tissue Culture Collection. BV2 was cultured in RPMI medium containing gentamicin and supplemented with 10% FBS for expansion and 5% fetal bovine serum (FBS) when plated for experiments. All cells were derived from passages between 39 and 45. Cells were cultured at 45,000 cells / mm. 2 The cells were plated in PBS and treated 24 hours after plating with phosphate-buffered saline (PBS, as a control) or interleukin-1B plus interferon-y (IL-1B + IFNy, to induce inflammation). To test the effect of NTI164 in altering the inflammatory response, NTI164 was applied 1 hour before (pretreatment) or 1 hour after (posttreatment) inflammation. NTI164 was applied at 10 μL, 3 μL, or 1 μL from isolates obtained using the original extraction protocol: range = 1.0–0.1 μg CBDA as determined from mass spectrometry data.

[0309] C.2.3 Multiplex Cytokine / Chemokine Assays Microglial culture media harvested after treatment initiation were briefly centrifuged (300 g for 10 min) to remove particulate matter. Cytokine and chemokine levels in the microglial culture media were measured in a 96-well magnetic plate assay using a Bio-Plex 200 according to the manufacturer's instructions (Bio-Rad). Measured cytokines and chemokines included IL-1α, IL-1β, IL-2, IL-6, IL-10, IL-12 (p70), IL-13, IL-17, G-CSF, GM-CSF, IFNγ, TNFα, CXCL1 (KC), CCL2 (MCP-1), and CCL5 (RANTES). All samples were run in duplicate, and data were analyzed using Bio-Plex Manager software.

[0310] C.2.4 Immunohistochemistry (protein level) assays Cells were fixed with 4% paraformaldehyde (PFA) in PBS for 10 minutes. After three 5-minute washes with PBS, cells were incubated overnight at 4°C with primary antibodies (anti-COX2, anti-ARG1) at 1:1000. After three 5-minute washes in PBS, cells were then incubated in the appropriate fluorescent secondary antibodies at 1:250 (Invitrogen) for 2 hours at room temperature. After the final wash, cell nuclei were stained with DAPI in mounting medium as before. Photomicrographs of cells from duplicate wells in three fields per well were analyzed for area coverage of each marker using Fiji.

[0311] C.2.5 Cell viability (mitochondrial activity) assay Microglial viability was quantified using MTT [3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl-2H-tetrazolium bromide; Sigma]. In this assay, the tetrazolium dye MTT is bioreduced by mitochondria to a formazan product that is insoluble in tissue culture medium. Briefly, after treatment with PBS, LPS, or IL-4 with or without the test product, MTT was added to cells at various time points to a final concentration of 250 μg / ml. After 30 min, the formazan was dissolved in DMSO, and the absorbance was measured at 490 nm using a spectrophotometer (Glomax Multi+; Promega, UK).

[0312] C.2.6 Statistics Data for replicates within an experiment were averaged, and data from at least three independent experiments were then analyzed using Graph Pad Prism or Student's t-test.

[0313] C.3 Results C.3.1 iNOS expression NTI164 normalized inflammation-induced iNOS expression. iNOS expression is increased by inflammation and in inflammation-activated microglial cells, and NTI164 normalized expression toward control levels, thus reducing the inflammatory process triggered by iNOS. Inducible nitric oxide synthase (iNOS) is one of the three major enzymes that generate nitric oxide (NO) from the amino acid L-arginine. iNOS plays a critical role in regulating multiple sclerosis (MS) and experimental autoimmune encephalomyelitis (EAE). Previous studies have shown that iNOS plays pathogenic and regulatory roles in MS and EAE, as well as many other neuroinflammatory disorders. Figure 5 demonstrates that NTI164 normalized inflammation-induced iNOS expression.

[0314] C.3.2 Neuronal viability NTI164 increased the number of surviving neurons under basal conditions (short-term exposure). Neuronal viability was quantified using MTT [3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl-2H-tetrazolium bromide; Sigma]. NTI164-treated cells were able to increase the number of "healthy" cells under basal conditions after short-term glutamate exposure. Cell excitotoxicity was achieved via glutamate activation (3 mM). NTI164 was able to stimulate cell growth after short-term glutamate-induced "damage."

[0315] The cell viability (mitochondrial activity) assay (or MTT assay) was used to determine the viability or metabolic activity of cells in intracellular microcapsules. It is based on the ability of metabolically active cells to convert a water-soluble dye [3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide] to insoluble formazan. Cell viability is a measure of the proportion of live, healthy cells within a population, and cell viability assays are used to determine the overall health of cells. Figure 6 presents neuronal viability quantified using MTT [3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl-2H-tetrazolium bromide].

[0316] C.3.3 Maturation of immature neurons NTI164 stimulated the maturation of immature neurons into healthy cells, even in the absence of any glutamate-induced damage. This study demonstrates that NTI164 can stimulate the "healthy maturation" of immature neurons, a process that may be essential after trauma or damage. NTI164 can provide healthy neuronal cytogenesis, an essential process in recovery from neuroinflammation, neuronal damage. Figure 7 demonstrates that NTI164 stimulates the maturation of immature neurons into healthy cells, even in the absence of any glutamate-induced damage.

[0317] C.3.4 Cell death NTI164 does not increase cell death in an excitotoxic cytotoxicity paradigm.

[0318] Figure 7 demonstrates that CBD is toxic in this paradigm, whereas NTI164 is non-toxic and has a positive effect on cell number and cell viability.

[0319] C.3.5 ARG1 expression NTI164 (NTI) normalizes pro-inflammatory (injured cell) Arg1 expression. Macrophage-specific upregulation of arginase-1 is generally thought to promote inflammation. Arginase-1 expression remains elevated by inflammation in inflammatory-activated cells, and NTI164 normalizes expression toward control levels. Figure 9 shows the response of microglia under inflammatory conditions assessing arginase-1 expression.

[0320] FIG. 10 provides an overview of arginine metabolism and the effect it has on the overall balance of anti-inflammatory and pro-inflammatory signals.

[0321] Example 4 D Example 4 - Preclinical studies related to biomarkers involved in neuroinflammation D.1 Research Aims To determine the effects of NTI164 on the levels of COX-2, IL2, and TNF-alpha in human-derived microglial cells.

[0322] Many neurological disorders arise from inflammation induced by dysregulated immune responses.

[0323] For example, multiple sclerosis (MS) is a progressive inflammatory disease characterized by the loss of myelin sheaths within the central nervous system. Typical symptoms include fatigue, difficulty walking, and speech and vision abnormalities. Cyclooxygenase-2 (COX-2) is considered the main enzyme responsible for causing inflammation, a common mechanism of disease involved in MS. COX-2 is a powerful clinical biomarker for assessing disease progression and overall treatment management.

[0324] IL-2 plays a key role in immune regulation and in the progression of MS. IL-12 is a cytokine that plays a major role in the pathogenesis of multiple sclerosis. Blocking this cytokine via a neutralizing antibody causes dramatic improvements in animal models of the disease and in multiple human trials.

[0325] TNF-alpha plays a key role in the dysregulation of acute inflammation involved in MS pathogenesis.

[0326] D.2 Materials and Methods D.2.1 COX-2 Immunohistochemistry (protein level) assay: Cells were fixed with 4% paraformaldehyde (PFA) in PBS for 10 minutes. After 3 x 5-minute washes with PBS, cells were incubated with primary antibody (anti-COX2) 1:1000 overnight at 4°C. After 3 x 5-minute washes in PBS, cells were then incubated in the appropriate fluorescent secondary antibody 1:250 (Invitrogen) for 2 hours at room temperature. After the final wash, cell nuclei were stained with DAPI in mounting medium as before. Photomicrographs of cells from duplicate wells in three fields per well were analyzed for area coverage of each marker using Fiji.

[0327] D.2.2 IL-2 and TNF-alpha Multiplex cytokine / chemokine assay: Microglial culture media harvested after treatment initiation were briefly centrifuged (300 g for 10 min) to remove particulate matter. Cytokine and chemokine levels in the microglial culture media were measured in a 96-well magnetic plate assay using a Bio-Plex 200 according to the manufacturer's instructions (Bio-Rad). Measured cytokines and chemokines included IL-1α, IL-1β, IL-2, IL-6, IL-10, IL-12 (p70), IL-13, G-CSF, GM-CSF, IFNγ, TNFα, CXCL1 (KC), CCL2 (MCP-1), and CCL5 (RANTES). All samples were run in duplicate, and data were analyzed using Bio-Plex Manager software.

[0328] D.2.3 Sample preparation and dilution 500 mg of dried plant material from NTI164 was suspended in 20 ml of absolute ethanol (using a 50 ml blue-top Falcon tube suitable for centrifugation) and vigorously stirred / shaken for 60 seconds. The tube was then placed in a sonication bath at 35-40°C for 10 minutes. Once sonication was complete, the sample was then placed on a tray shaker (200 rpm) at room temperature for 30 minutes. Once complete, the sample was then centrifuged at 4400 rpm for 5 minutes. The supernatant was collected for testing and development.

[0329] Units used to describe the treatment and concentration of NTI164 for the test product: a. 1 / 1000 dilution of extract - 10 UL (stock material is NTI164 - 10 UL, which is equivalent to 2 μg / ml of CBDA) b. 1 / 3000 dilution of extract - 3UL (stock material is NTI164-3UL, which is equivalent to 6µg / ml CBDA) c. 1 / 10000 dilution of extract - 1UL (stock material is NTI164-1UL, which is equivalent to 0.1 μg / ml of CBDA).

[0330] For the CBD samples, pure standards (in powder form) were used. CBD 98% isolate was purchased as a reference standard from LGC Standards (London, UK) (CAS number 13956-29-1). The CBD standard reference was prepared at a concentration of 1 mg / ml (in acetonitrile). The CBD dilutions were performed in acetonitrile as follows: 2 μg / ml, 6 μg / ml, and 0.1 μg / ml.

[0331] The final concentrations of NTI164 (CBDA equivalent) and CBD used in these studies were 2 μg / ml.

[0332] D.3 Results D.3.1 COX-2 Preclinical studies conducted on cells using immunohistochemistry demonstrated that NTI164 can suppress and inhibit COX-2 expression in human-derived microglial cells. Compared to CBD alone, NTI164 was up to three times more potent at suppressing COX-2 both before and after inflammatory injury. See Table 7 below.

[0333] Table 7: Summary of COX-2 inhibition in cells when treated with NTI164 versus CBD alone. [Table 7]

[0334] D.3.2 IL-2 and TNF-alpha NTI164 is statistically more potent in suppressing key biomarkers: IL-12 and TNF-alpha when compared to CBD alone and a CBD / THC (1:1) mixture.

[0335] These results demonstrate that NTI164 IL-12 P=0.0011 vs. CBD alone was highly significant; NTI164 TNF-alpha P=0.0575 vs. CBD alone trended positive; NTI164 IL-12 P=0.0069 vs. CBD / THC combination was highly significant; and NTI164 TNF-alpha P=0.0446 vs. CBD / THC combination was significant.

[0336] Table 8 summarizes the significance between NTI164 versus CBD alone and the CBD / THC combination (1:1 concentration ratio) in suppressing TNF-alpha and IL-12. [Table 8]

[0337] D.4 Discussion D.4.1 COX-2, IL2, and TNF-alpha These results demonstrating the suppression of COX-2, IL2 and TNF-alpha reaffirm the potent properties of NTI164 in modulating inflammatory processes in neuropathies where immune response-induced inflammation is dysregulated.

[0338] Example 5 E. Example 5 - Further characterization of NTI164 E.1 Research Aims Compositional analysis of NTI164 extracted via oil using UPLC / MS methods (as outlined in the examples above).

[0339] E.2 Materials and Methods An ACQUITY UPLC H-Class system coupled with Cortex UPLC Shield RP18 particle chemistry was used to provide a UPLC isocratic separation of the major cannabinoids with a cycle time of 10.5 minutes. Samples of NTI164 were assayed weekly, with CBDA as the primary marker and stability indicator. The results, presented in Table 6, demonstrate that NTI164 is stable in an inert oil medium at room temperature for 6 weeks. No decarboxylation or product degradation is observed over this time frame.

[0340] Equipment: The following equipment was used: 10 mL glass scintillation bottles with lids; Cobram Estate Olive Oil; vegetable grinder (similar to a coffee or food-grade grinder) with a pore size of 50 μM to 80 μM maximum; Whatman paper, Grade 1; pipettes; weighing scale (transfer boat and spoon); Eppendorf tubes; 50 mL Falcon tubes; benchtop centrifuge (Eppendorf Centrifuge 5702); and an Oz Design brand 6-liter fruit, wine, and cider press.

[0341] Extraction: Pressing and Centrifugation: All operations were carried out at standard laboratory temperature (18-22°C). NTI164 buds were stripped of their tough stems and discarded. The grinder was cleaned with 70% EtOH, and the grinding compartment was filled with dried plant material. The material was ground for 10 seconds at the finest setting (1-2 mm particle size). The grind was then mixed with 100 ml of olive oil at a vegetable / oil ratio of 333 mg / mL in an autoclaved Schott bottle. It was then placed in a mixer at room temperature for 1 hour and stirred with a magnetic stirrer (50 rpm). The oil-plus-vegetable mixture was then placed in an Oz Design brand 6-liter fruit, wine, and cider press to recover the oil components from the plant matter (mash). The recovered oil was then placed in a 50 ml Falcon tube and spun at 300 g for 15 minutes at room temperature (Isolation 1). The oil was then removed into a clean shot bottle, and the recovered volume was tracked. The oil recovery rate for isolation 1 was approximately 40%. The mash was discarded after each isolation. To the recovered oil, we added another 333 mg / mL of ground plant / oil material (another 100 ml), repeated mixing for 1 hour, and recovered and reused the oil until a total of 999 μg / mL (3 × 100 ml) of plant / oil mixture had passed (isolation 2). The oil recovery rate for isolation 2 was approximately 50%. Finally, we placed it in a Falcon tube and spun it as discussed above (isolation 3). The oil recovery rate for isolation 3 was approximately 50%. We then collected only the oil and placed it in an Eppendorf tube for processing. This triple extraction method resulted in a final product with a total volume of 50 ml, with a concentration of 48 mg CBDA per ml of olive oil, as determined using UPLC potency testing using the method described below.

[0342] E.3 Results The results of the UPLC analysis are presented below in Table 9.

[0343] Table 9 presents the NTI164 composition extracted using ethanol extraction and the components quantified using the UPLC method described herein. [Table 9]

[0344] By increasing the pore size in the mill system from 50 μM to 80 μM, we were able to extract 1-3% cannabinol (CBN) in the final oil extract product.

[0345] Example 6 F. Example 6 - Evaluating the anti-inflammatory properties of NTI164 in combination with diclofenac F.1 Research Aims To evaluate the anti-inflammatory properties of NTI164 in combination with diclofenac compared to CBD in combination with diclofenac.

[0346] Diclofenac is a nonsteroidal anti-inflammatory drug (NSAID) used to treat mild to moderate pain or the signs and symptoms of osteoarthritis, rheumatoid arthritis, and neuropathic pain. F.2 Materials and Methods F.2.1 Immunohistochemistry (protein level) assays

[0347] Human-derived microglial cells were fixed with 4% paraformaldehyde (PFA) in PBS for 10 minutes. After three 5-minute washes in PBS, cells were incubated overnight at 4°C with primary antibody (anti-COX2) at 1:1000. After three 5-minute washes in PBS, cells were then incubated with the appropriate fluorescent secondary antibody at 1:250 (Invitrogen) at room temperature for 2 hours. After the final wash, cell nuclei were stained with DAPI in mounting medium as before. Photomicrographs of cells were taken from duplicate wells in three fields per well and analyzed for area coverage of each marker using Fiji.

[0348] COX-2 is measured using immunohistochemical assay as described above.As a part of positive control, cells are treated with interleukin and interferon, which makes cells enter "active inflammatory state".In treatment group, these cells are also treated with various treatments, and then COX-2 expression is evaluated after these treatments (1 hour after treatment). F.2.2 Sample preparation and dilution

[0349] The following samples were prepared: CBD alone, NTI164 alone, diclofenac alone, diclofenac + NTI164.

[0350] In this example, ethanol extraction was used. 500 mg of dried plant material from NTI164 was suspended in 20 ml of absolute ethanol (using a 50 ml blue-top Falcon tube suitable for centrifugation) and vigorously stirred / shaken for 60 seconds. The tube was then placed in a sonication bath at 35-40°C for 10 minutes. Once sonication was complete, the sample was then placed on a tray shaker (200 rpm) at room temperature for 30 minutes. Once complete, the sample was then centrifuged at 4400 rpm for 5 minutes. The supernatant was collected for testing and development.

[0351] Units used to describe treatments for test products and concentrations for NTI164. a. 1 / 1000 dilution of extract - 10 UL (stock material is NTI164-10 UL, which is equivalent to 2 μg / ml CBDA) b. 1 / 3000 dilution of extract - 3UL (stock material is NTI164-3UL, which is equivalent to 6µg / ml CBDA) c. 1 / 10000 dilution of extract - 1UL (stock material is NTI164-1UL, which is equivalent to 0.1 μg / ml of CBDA).

[0352] For the CBD samples, a pure standard (in powder form) was used. CBD 98% isolate was purchased as the standard from LGC Standards (London, UK) (CAS number 13956-29-1). The CBD standard reference was prepared at a concentration of 1 mg / ml (in acetonitrile). The CBD dilutions were made in acetonitrile as follows: 2 μg / ml, 6 μg / ml, and 0.1 μg / ml.

[0353] Diclofenac (CAS number 15307-86-5) was purchased from Merck Chemicals (purity, 98% HPLC). A reference stock standard of 1 mg / ml was made using acetonitrile, and the following dilutions were made: 2 μg / ml, 6 μg / ml, and 0.1 μg / ml.

[0354] The final concentrations of NTI164 (CBDA equivalent), CBD and diclofenac used in this study were 2 μg / ml. F.3 Results F.3.1 Synergy

[0355] A synergistic effect was observed with the NTI164 + diclofenac combination: COX-2 inflammation was reduced by 8% with the NTI164 + diclofenac combination compared to 24% with diclofenac alone and 55% with NTI164 alone.

[0356] Treatment with NTI164 alone is highly effective in reducing cellular inflammatory processes, but when combined with diclofenac, these anti-inflammatory effects are even stronger.

[0357] Table 10 presents the inflammation results for the combination study (N=9), NTI164 plus diclofenac. [Table 10]

[0358] Example 7 G. Example 7 - Evaluating the anti-inflammatory properties of NTI164 in combination with celecoxib G.1 Research Aims To evaluate the anti-inflammatory properties of NTI164 in combination with diclofenac compared to CBD in combination with celecoxib.

[0359] Celecoxib is a nonsteroidal anti-inflammatory drug (NSAID). Diclofenac is used to treat mild to moderate pain or the signs and symptoms of conditions such as osteoarthritis or rheumatoid arthritis. G.2 Materials and Methods G.2.1 Microglial BV2 culture

[0360] The immortalized microglial cell line, BV2, was purchased from the American Tissue Culture Collection. BV2 was cultured in RPMI medium containing gentamicin and supplemented with 10% fetal bovine serum (FBS) for expansion and 5% FBS when plating for experiments. All cells were derived from passages between 39 and 45. Cells were cultured at 45,000 cells / mm. 2 The cells were plated with PBS and treated 24 hours after plating with phosphate-buffered saline (PBS, as a control) or interleukin-1B plus interferon-γ (IL-1B + IFNγ, to induce inflammation). To test the effect of NTI164 on modifying the inflammatory response, NTI164 and synergistic treatments (see below) were applied 1 hour after inflammation. Extracted NTI164 was applied at 10 μL, 3 μL, or 1 μL from isolates obtained using the original extraction protocol: range = 1.0–0.1 μg CBDA, as determined from mass spectrometry data. Treatments included celecoxib at 5, 25, and 125 μM. G.2.2 Multiplex Cytokine / Chemokine Assays

[0361] Microglial culture media harvested after treatment initiation were briefly centrifuged (300 g for 10 min) to remove particulate matter. Cytokine and chemokine levels in the microglial culture media were measured in a 96-well magnetic plate assay using a Bio-Plex 200 according to the manufacturer's instructions (Bio-Rad). Measured cytokines and chemokines included IL-1α, IL-1β, IL-2, IL-6, IL-10, IL-12 (p70), IL-13, G-CSF, GM-CSF, IFNγ, TNFα, CXCL1 (KC), CCL2 (MCP-1), and CCL5 (RANTES). All samples were run in duplicate and averaged for analysis; at least three samples were run per group. G.2.3 Immunohistochemistry (protein level) assays

[0362] Cells were fixed with 4% paraformaldehyde (PFA) in PBS for 10 minutes. After three 5-minute washes with PBS, cells were incubated with primary antibody (anti-COX2) at 1:1000 overnight at 4°C. After three 5-minute washes in PBS, cells were then incubated with the appropriate fluorescent secondary antibody at 1:250 (Invitrogen) for 2 hours at room temperature. After the final wash, cell nuclei were stained with DAPI in mounting medium as before. Photomicrographs of cells were taken from duplicate wells in three fields per well and analyzed for area coverage of each marker using Fiji. G.2.4 Cell viability (mitochondrial activity) assay

[0363] Microglial viability was quantified using MTT [3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl-2H-tetrazolium bromide; Sigma]. In this assay, the tetrazolium dye MTT is bioreduced by mitochondria to a formazan product that is insoluble in tissue culture medium. Briefly, after treatment with PBS, LPS, or IL-4 with or without the test product, MTT was added to cells at various time points to a final concentration of 250 μg / ml. After 30 min, the formazan was dissolved in DMSO, and the absorbance was measured at 490 nm using a spectrophotometer (Glomax Multi+; Promega, UK). G.3 Results G.3.1 Synergy

[0364] A synergistic effect was observed with the NTI164 + celecoxib combination. Inflammation, as measured by MTT assay, cytokine release (TNF-alpha, G-CSF, IL-1a, IL-6), and COX-2 protein, was reduced with the NTI164 + celecoxib combination compared with celecoxib alone and NTI164 alone.

[0365] Treatment with NTI164 alone is very effective in reducing cellular inflammatory processes, but when combined with celecoxib, these anti-inflammatory effects are even stronger.

[0366] Table 11 presents the inflammation results for the combination study to demonstrate the synergistic effect of NTI164 and Celebrex. [Table 11-1] [Table 11-2]

[0367] Example 8 H Example 8 - Evaluating the anti-inflammatory properties of NTI164 in combination with prednisone H.1 Research Aims To evaluate synergistic suppression of inflammatory responses using combined prednisone and NTI164 treatment in a preclinical in-vitro study. H.2 Materials and Methods

[0368] Cells were fixed with 4% paraformaldehyde (PFA) in PBS for 10 minutes. After three 5-minute washes with PBS, cells were incubated overnight at 4°C with primary antibody (anti-COX2) at 1:1000. After three 5-minute washes in PBS, cells were then incubated with the appropriate fluorescent secondary antibody at 1:250 (Invitrogen) for 2 hours at room temperature. After the final wash, cell nuclei were stained with DAPI in mounting medium as before. Photomicrographs of cells from duplicate wells in three fields per well were analyzed for area coverage of each marker using Fiji.

[0369] The treatment groups were:

[0370] (1) Control: PBS buffer

[0371] (2) Positive control: Inflammatory stimulation by interferon gamma and interleukin-1B activation, prednisone (PDN) concentration 5 μM

[0372] (3) Combination therapy: Prednisone (PDN) 5uM + NTI164 concentration 7.5ug / ml Includes. H.3 Results

[0373] Results analysis: PDN vs. combination therapy (Prednisone 5 uM + NTI164 concentration 7.5 ug / ml), calculated as % reduction in inflammation. Student's t-test was used for statistical analysis.

[0374] Treatment with NTI164 alone is very effective in reducing cellular inflammatory processes, but when combined with prednisone, these anti-inflammatory effects are even stronger. Table 12 presents inflammation results for combination studies to demonstrate synergistic effects of NTI164 and prednisone. [Table 12]

[0375] Example 9 I Example 9 - Evaluating the anti-inflammatory properties of NTI164 in combination with psilocybin I.1 Research Aims To evaluate the synergistic suppression of inflammatory responses using combined psilocybin and NTI164 treatment in a preclinical in-vitro study. I.2 Materials and Methods

[0376] Microglial culture media harvested after treatment initiation were briefly centrifuged (300 g for 10 min) to remove particulate matter. TNFα levels in microglial culture media were measured in a 96-well magnetic plate assay using a Bio-Plex 200 according to the manufacturer's instructions (Bio-Rad). Samples were run in duplicate and averaged for analysis. At least three samples were run per group. I.3 Results

[0377] Result analysis: Table 13: TNF-alpha assessment Table 13 presents TNF-alpha ratings for psilocybin-psilocybin combination studies [Table 13]

[0378] Treatment with NTI164 alone is highly effective in reducing cellular inflammatory processes, but when combined with psilocybin, these anti-inflammatory effects are even stronger.

[0379] Example 10 J Example 10 - NTI164 for treatment of ASD Level II / III - 4 weeks J.1 ASD Research Design and Methods Of the 18 patients enrolled in the study, those who received NTI164 comprised 94% (n=17). Active patients comprised 78% (n=14), patients who discontinued after receiving the first dose of NTI164 comprised 16% (n=3), and patients who discontinued before receiving NTI164 but after enrollment comprised 6% (n=1). The mean age of active patients was 13.4 years, with the youngest patient being 10 years old and the oldest being 17 years old (Figure 11).

[0380] All active patients were diagnosed with ASD level II / III and rated as either "mildly ill," "moderately ill," "markedly ill," or "severely ill" at baseline on the CGI severity scale (Figure 12).

[0381] Patients began treatment with NTI164 at 5 mg / kg / day, increasing by 5 mg / kg / day weekly for a period of 4 weeks until 20 mg / kg / day or the maximum tolerated dose was achieved. The daily dose was calculated by multiplying the dosage by the patient's weight and then dividing by the concentration of CBDA in the oil (53 mg / mL). This resulted in a total daily volume in mL (Table 14), which was divided into twice-daily (BD) AM and PM doses.

[0382] Table 14 - Calculation of daily dose for each patient. [Table 14]

[0383] The mean maximum daily dose for active patients was 16.7 mg / kg / day, with 64% of patients tolerating a maximum dose of 20 mg / kg / day and 36% of patients tolerating maximum daily doses ranging between 6 mg / kg / day and 19 mg / kg / day (Figure 13). J.2 Research results

[0384] The Clinical Global Impression-Severity (CGI-S) scale was used to assess:

[0385] Global improvement: assesses overall improvement as to whether it is entirely due to drug treatment, in the clinician's judgment;

[0386] Disease severity: comparison of baseline and post-baseline (28 days of NTI164 treatment); and

[0387] Efficacy index: Scored based on drug efficacy alone. This is a score calculated based on the degree of therapeutic effect and side effects.

[0388] General improvements

[0389] 93% of active patients showed improvement after 28 days of daily treatment with NTI164. 64% of these patients had a global improvement of "much improved," 29% had a global improvement of "minimally improved," and only 1 patient (7%) had "no change" (Figure 14). Statistical significance was assessed using Wilcoxon signed-rank tests and paired t-tests:

[0390] Paired t-test: The mean difference in CGI-S between 28 days of treatment and baseline was -0.714, 95% confidence interval = -1.332, -0.097, p-value = 0.027. The Wilcoxon signed rank test statistic was -15 and the corresponding p-value was 0.047.

[0391] Severity of the disease

[0392] The mean disease severity rating at baseline was 4.4 (Figure 12), which reduced to a mean rating of 3.6 after 28 days of NTI164 treatment (Figures 15 and 16).

[0393] Treatment effect

[0394] After 28 days of daily treatment with NTI164, 14% of active patients demonstrated the second highest possible efficacy index of 2: a significant therapeutic effect with side effects that did not significantly interfere with patient function.

[0395] 72% of active patients had an efficacy index of either 5 or 6: half of these patients had no side effects and the other half had a moderate therapeutic effect, with side effects that did not significantly interfere with the patient's function, 7% had an efficacy index of 9: a minimal therapeutic effect with no side effects, and only one patient (7%) had an efficacy index of 13: unchanged or worsening, based on no change in condition and no side effects (Figure 17).

[0396] Example 11 K Example 11 - NTI164 for treatment of ASD Level II / III - 20 weeks K.1 ASD Research Design and Methods Example 10 above presents treatment results (n=14 effective) at 4 weeks (28 days). This Example 11 presents treatment results (n=12 effective) at 20 weeks. As discussed in Example 10 above, patients began treatment with NTI164 at 5 mg / kg / day, which was increased by 5 mg / kg / day weekly for a period of 4 weeks until 20 mg / kg / day or the maximum tolerated dose was achieved, and (in this study) the maximum tolerated dose was continued for 16 weeks (providing a total daily dosing period of 20 weeks).

[0397] The overall objective of this study was to evaluate the ongoing safety and efficacy of NTI164 administered daily over a 20-week period. A secondary objective was to evaluate the efficacy of NTI164 in treating symptoms associated with autism spectrum disorder. Efficacy was measured using a variety of standard physician- and patient-initiated questionnaires used in the art.

[0398] Patients (n=12) The mean age of active patients at week 20 was 13.3 years, with the youngest patient being 10 years old and the oldest being 17 years old (Error! Reference source not found). All active patients were diagnosed with ASD level II / III and rated as either "mildly affected," "moderately affected," "markedly affected," or "severely affected" at baseline on the CGI severity scale (Error! Reference source not found 1).

[0399] dose Based on pediatric trials undertaken worldwide, the maximum dose selected for this study was 20 mg / kg / day.

[0400] To reduce the risk of side effects, the study drug was initiated at 5 mg / kg / day and titrated over a 4-week course, increasing by 5 mg per week until the maximum tolerated dose or 20 mg / kg / day was achieved. The maximum tolerated dose was then administered over a 20-week course. The daily dose was administered in two doses, AM and PM.

[0401] The formula used to calculate each patient's dose was body weight × dose / NTI164 concentration = daily dose / 2 = twice-daily dose. During the first week of treatment, each patient received 5 mg / kg / day of NTI164. During the second week of treatment, each patient received 10 mg / kg / day of NTI164. During the third week of treatment, each patient received 15 mg / kg / day of NTI164. During the fourth week of treatment, each patient received 20 mg / kg / day of NTI164. Between weeks 5 and 20 of treatment, each patient received their maximum tolerated dose or 20 mg / kg / day of NTI164.

[0402] NTI164 was formulated in oil for oral administration. The total oil concentration was 53 mg / ml.

[0403] At the end of week 20, participants had the option to either terminate participation and taper at 5 mg / kg / week until study medication was discontinued, or continue at their maximum tolerated dose until week 52.

[0404] Primary endpoint Safety was monitored and measured using procedures standard in the art. Safety was monitored and measured using parent / caregiver and physician questionnaires completed at baseline and every 4 weeks through week 20, as well as complete blood tests, liver and kidney function tests, and vital signs.

[0405] Secondary endpoints Efficacy was monitored and measured using standard procedures in the art.

[0406] Clinical Global Impression Scale-Illness Severity (CGI-S), reflecting the clinician's impression of illness severity on a 7-point scale ranging from 1 = not at all to 7 = most extremely ill [Timeframes: Baseline, Week 4, Week 8, Week 12, Week 20].

[0407] Vineland Adaptive Behavior Scales, Third Edition (Vineland-3). Used to measure adaptive functioning across three core domains (communication, daily living skills, and socialization) and two need-based domains (motor skills and maladaptive behaviors), items are rated on a 3-point scale (0 = never; 1 = occasionally; 2 = usually or often). Core domains are summed to form a total Adaptive Behavior Composite [Timeframe: Baseline, Week 20].

[0408] Social Responsiveness Scale, 2nd Edition - School-Age Version (SRS-2). Assessing five domains including social awareness, social cognition, social communication, social motivation, and restricted interests and repetitive behaviors. Items are scored on a 4-point scale (ranging from 1 = not true to 4 = almost always true). [Timeframe: Baseline, Week 20]

[0409] Clinical Global Impression-Improvement-Caregiver (CGI-I-Ca), a 7-point scale measuring symptom change from baseline, administered as baseline and post-baseline caregiver and clinician questionnaires [timeframes: baseline, week 4, week 8, week 12, week 20].

[0410] Clinical Global Impression Scale-Improvement-Clinician (CGI-I-Cl), a 7-point scale measuring symptom change from baseline, administered as baseline and post-baseline caregiver and clinician questionnaires [Timeframe: baseline, week 4, week 8, week 12, week 20].

[0411] Clinical Global Impression Scale-Change in Target Behavior (CGI-C). Reflects the clinician's impression of behavior change on a 7-point scale ranging from 1 = not at all to 7 = very severe problem. Provided as a baseline and post-baseline questionnaire [Timeframe: baseline, week 4, week 8, week 12, week 20].

[0412] Clinical Global Impression Scale-Attentional Change (CGI-CA). Reflects the clinician's impression of attentional changes on a 7-point scale ranging from 1 = not at all to 7 = very severe problems. Provided as a baseline and post-baseline questionnaire [Timeframe: baseline, week 4, week 8, week 12, week 20].

[0413] Anxiety Scale for Children-Autism Spectrum Disorder-Parent Version (ASC-ASD-P). A parent / caregiver version developed to detect symptoms of anxiety in youth with ASD. It consists of four subscales (Performance Anxiety, Uncertainty, Anxious Arousal, and Separation Anxiety), and items are rated on a 4-point scale (0 = never and 3 = always). The sum of the subscales equals the total score [Timeframes: Baseline, Week 4, Week 8, Week 12, Week 20].

[0414] Anxiety Scale for Children - Autism Spectrum Disorder - Child Version (ASC-ASD-C). A child version developed to detect symptoms of anxiety in young people with ASD. It consists of four subscales (performance anxiety, uncertainty, anxious arousal, and separation anxiety), and items are rated on a 4-point scale (0 = never and 3 = always). The sum of the subscales equals the total score [Timeframes: Baseline, Week 4, Week 8, Week 12, Week 20].

[0415] Sleep Disorders Scale for Children (SDSC), which has six subscales including sleep onset and sleep maintenance disorders, sleep-disordered breathing, wake disorders, sleep-wake transition disorders, excessive somnolence, and hyperhydrosis. Items are rated on a 5-point scale, where 1 = never and 5 = always (every day). The sum of the subscale scores equals the total score [timeframes: baseline, week 4, week 8, week 12, week 20].

[0416] K.2 Research results safety results Safety data conclude that NTI164 at doses of 5, 10, 15, and 20 mg / kg administered twice daily was safe and well tolerated in this study population. This conclusion is further supported by laboratory values. No changes were observed in patients' complete blood tests or liver or kidney function tests. No changes were observed in patients' vital signs.

[0417] Efficacy Results Wilcoxon signed-rank test and paired t-test were used to assess the statistical significance of the analyzed data sets.

[0418] Paired t-test: The mean difference in CGI-S between 20 weeks of treatment and baseline was -1.08, 95% confidence interval = -1.772, -0.3948, p-value = 0.005303.

[0419] The Wilcoxon signed rank test statistic was -15 and the corresponding p-value was 0.009654.

[0420] One hundred percent of patients (n=12) showed a "much improved" improvement in symptoms related to disease severity after 20 weeks of daily treatment with NTI164.

[0421] Table 15 below summarizes the results from the Wilcoxon signed rank test and paired t-test for the analyzed data set at week 20. Table 15 - Wilcoxon Signed Rank Test and the Mean Average for the Analyzed Data Set at 20 Weeks Overview of Paired and Paired T-Tests [Table 15]

[0422] Global Improvement. 100% (n=12) of active patients showed improvement after 20 weeks of daily treatment with NTI164. All patients had a global improvement of "2. Much improved." Three of these patients had previously been scored as "3. Minimally improved" after 4 weeks of treatment. See Figures 22 and 23.

[0423] Disease Severity. The mean disease severity rating at baseline was 4.3. This reduced to a mean rating of 3.3 after 20 weeks of daily NTI164 treatment. See Figures 24-26.

[0424] Treatment Efficacy. After 20 weeks of daily NTI164 treatment, 67% of active patients demonstrated the highest possible efficacy index of 1 and 2: Marked Treatment Efficacy - Great Improvement; Complete or Near-Complete Remission of All Symptoms. 33% of patients had an efficacy index of either 5, 6, or 7: Moderate Treatment Efficacy - Definitive Improvement; Partial Remission of Symptoms. See Figures 27-28.

[0425] Conclusion. NTI164 was shown to be safe and well-tolerated at doses up to 20 mg / kg / day. NTI164 demonstrated statistically significant efficacy in improving symptoms associated with autism spectrum disorder after 20 weeks of daily therapy.

[0426] Example 12 Example 12 - NTI164 for the treatment of ASD Level II / III - 52 weeks K.3 ASD Research Design and Methods Example 10 above presents treatment results (n=14 active) at 4 weeks (28 days). Example 11 above presents treatment results (n=12 active) at 20 weeks. This example presents treatment results (n=11 active) at 52 weeks.

[0427] As discussed above in Examples 10 and 11, patients began treatment with NTI164 at 5 mg / kg / day, which was increased by 5 mg / kg / day weekly for a period of 4 weeks until 20 mg / kg / day or the maximum tolerated dose was reached, and (in this study) the maximum tolerated dose was continued for 48 weeks (providing a total daily dosing period of 52 weeks).

[0428] The overall objective of this study was to evaluate the ongoing safety and efficacy of NTI164 administered daily over a 52-week period. A secondary objective was to evaluate the efficacy of NTI164 in treating symptoms associated with autism spectrum disorder. Efficacy was measured using a variety of standard physician- and patient-initiated questionnaires used in the art. Patients (n=11)

[0429] The mean age of active patients at week 52 was 12.5 years, with the youngest patient being 10 years old and the oldest being 17 years old. All active patients were diagnosed with ASD level II / III and rated as either "mildly affected," "moderately affected," "markedly affected," or "severely affected" on the CGI severity scale at baseline. dose

[0430] Based on pediatric trials undertaken worldwide, the maximum dose selected for this study was 20 mg / kg / day.

[0431] To reduce the risk of side effects, the study drug was initiated at 5 mg / kg / day and titrated over a 4-week course, increasing by 5 mg each week until the maximum tolerated dose or 20 mg / kg / day was achieved. The maximum tolerated dose was then administered over a 48-week course. The daily dose was administered in two doses, AM and PM.

[0432] The formula used to calculate each patient's dose was body weight × dose / NTI164 concentration = daily dose / 2 = twice-daily dose. During the first week of treatment, each patient received 5 mg / kg / day of NTI164. During the second week of treatment, each patient received 10 mg / kg / day of NTI164. During the third week of treatment, each patient received 15 mg / kg / day of NTI164. During the fourth week of treatment, each patient received 20 mg / kg / day of NTI164. Between weeks 5 and 52 of treatment, each patient received their maximum tolerated dose or 20 mg / kg / day of NTI164.

[0433] NTI164 was formulated in olive oil (extra virgin) for oral administration. The total oil concentration was 53 mg / ml.

[0434] At the end of week 20, participants had the option to either terminate participation and taper at 5 mg / kg / week until study medication was discontinued, or continue at their maximum tolerated dose until week 52. Primary endpoint

[0435] Safety was monitored and measured using procedures standard in the art. Completed parent / caregiver and physician questionnaires at baseline and every 4 weeks through week 52, as well as complete blood tests, liver and kidney function tests, and vital signs were used to monitor and measure safety. Secondary endpoints

[0436] Efficacy was monitored and measured using standard procedures in the art.

[0437] Clinical Global Impression Scale-Illness Severity (CGI-S), reflecting the clinician's impression of illness severity on a 7-point scale ranging from 1 = not at all to 7 = most extremely ill [Timeframes: baseline, weeks 4, 8, 12, 20, and 52].

[0438] Vineland Adaptive Behavior Scales, Third Edition (Vineland-3). Used to measure adaptive functioning across three core domains (communication, daily living skills, and socialization) and two need-based domains (motor skills and maladaptive behaviors), items are rated on a 3-point scale (0 = never; 1 = occasionally; 2 = usually or often). Core domains are summed to form a total Adaptive Behavior Composite [Timeframes: Baseline, Week 20, Week 52].

[0439] Social Responsiveness Scale, 2nd Edition - School-Age Form (SRS-2). Assessing five domains including social awareness, social cognition, social communication, social motivation, and restricted interests and repetitive behaviors. Items are scored on a 4-point scale (ranging from 1 = not true to 4 = almost always true) [Timeframe: Baseline, Week 20, Week 52].

[0440] Clinical Global Impression-Improvement-Caregiver (CGI-I-Ca), a 7-point scale measuring symptom change from baseline, administered as baseline and post-baseline caregiver and clinician questionnaires [Timeframes: baseline, weeks 4, 8, 12, 20, and 52].

[0441] Clinical Global Impression-Improvement-Clinician (CGI-I-Cl), a 7-point scale measuring symptom change from baseline, administered as baseline and post-baseline caregiver and clinician questionnaires [Timeframes: baseline, weeks 4, 8, 12, 20, and 52].

[0442] Clinical Global Impression Scale-Change in Target Behavior (CGI-C). Reflects the clinician's impression of behavior change on a 7-point scale ranging from 1 = not at all to 7 = very severe problem. Provided as baseline and post-baseline questionnaires [Timeframe: baseline, week 4, week 8, week 12, week 20, week 52].

[0443] Clinical Global Impression Scale-Attentional Change (CGI-CA). Reflects the clinician's impression of attentional changes on a 7-point scale ranging from 1 = not at all to 7 = very severe problems. Provided as baseline and post-baseline questionnaires [Timeframe: Baseline, Week 4, Week 8, Week 12, Week 20, Week 52].

[0444] Anxiety Scale for Children-Autism Spectrum Disorder-Parent Version (ASC-ASD-P). A parent / caregiver form developed to detect symptoms of anxiety in youth with ASD. It consists of four subscales (Performance Anxiety, Uncertainty, Anxious Arousal, and Separation Anxiety), and items are rated on a 4-point scale (0 = never and 3 = always). The sum of the subscales equals the total score [Timeframes: Baseline, Week 4, Week 8, Week 12, Week 20, Week 52].

[0445] Anxiety Scale for Children - Autism Spectrum Disorder - Child Version (ASC-ASD-C). This pediatric form was developed to detect symptoms of anxiety in young people with ASD. It consists of four subscales (performance anxiety, uncertainty, anxious arousal, and separation anxiety), and items are rated on a 4-point scale (0 = never and 3 = always). The sum of the subscales equals the total score [Timeframes: Baseline, Week 4, Week 8, Week 12, Week 20, Week 52].

[0446] Sleep Disorders Scale for Children (SDSC). Six subscales include sleep onset and sleep maintenance disorders, sleep-disordered breathing, wake disorders, sleep-wake transition disorders, disorder of excessive somnolence, and hyperhydrosis. Items are rated on a 5-point scale, where 1 = never and 5 = always (every day). The sum of the subscale scores equals the total score [Timeframes: Baseline, Week 4, Week 8, Week 12, Week 20, Week 52]. K.4 Research results safety results

[0447] Safety data conclude that NTI164 at doses of 5, 10, 15, and 20 mg / kg administered twice daily was safe and well tolerated in this study population. This conclusion is further supported by laboratory values. No changes were observed in patients' complete blood tests or liver or kidney function tests. No changes were observed in patients' vital signs. Efficacy Results

[0448] Wilcoxon signed-rank test and paired t-test were used to assess the statistical significance of the analyzed data sets.

[0449] Paired t-test: The mean difference in CGI-S between 52 weeks of treatment and baseline was -1.1, 95% confidence interval = -2.080, -0.120, p-value = 0.0317.

[0450] Table 16 below summarizes the results from the paired T-test for the analyzed data set at 52 weeks. Table 16 - Summary of paired T-tests for the analyzed data set at 52 weeks [Table 16]

[0451] One hundred percent of patients (n=11) showed "much improved" improvement in symptoms related to disease severity after 52 weeks of daily treatment with NTI164.

[0452] Vineland-3. The mean difference in the Vineland-3 adaptive behavior composite domain between 52 weeks of treatment and baseline was 6.375, 95% CI=0.940, 11.810, p-value=0.02756. See Table 17 for further presentation of results. Table 17 - Vineland-3 - Mean Differences in Adaptive Behavior Composite Value Domains for Vineland-3 [Table 17]

[0453] The mean difference in the Vineland-3 communication subdomain between 52 weeks of treatment and baseline was 6.25, 95% confidence interval = 4.264, 8.236, p value = 0.0001442.

[0454] The mean difference in the Vineland-3 daily living skills subdomain between 52 weeks of treatment and baseline was 8.5, 95% confidence interval = 3.504, 13.496, p value = 0.005041.

[0455] The mean difference in the Vineland-3 socialization subdomain between 52 weeks of treatment and baseline was 6.5, 95% confidence interval = -2.131, 15.131, p value = 0.1181.

[0456] One patient achieved scores within the normative average range: Adaptive Behavior Composite = 102, 55th percentile rank; Communication = 96, 39th percentile rank; Daily Living Skills = 101, 53rd percentile rank; Socialization = 109, 73rd percentile rank.

[0457] Clinical Global Impression Scale-Severity of Illness (CGI-S). The mean difference in the severity of illness domain of the CGI-S scale between 52 weeks of treatment and baseline was -1.1, 95% confidence interval = -2.080, -0.120, p-value = 0.03179.

[0458] Interpersonal Responsiveness Scale, Second Edition (SRS-2). The mean difference in SRS-2 total T-score between 52 weeks of treatment and baseline was -4.1, 95% confidence interval = -8.170, -0.033, p-value = 0.04852. See Table 18 for further presentation of results. Table 18-SRS-2 results [Table 18]

[0459] See Figures 29-32 for further presentation of results. Safety results.

[0460] Safety data conclude that NTI164 at 5, 10, 15, and 20 mg / kg administered twice daily up to week 52 was safe and well tolerated in this study population. A total of six adverse events were reported by four participants between weeks 20 and 52. None of these adverse events were considered serious or to significantly interfere with patient function. Conclusion.

[0461] NTI164 was shown to be safe and well-tolerated at doses up to 20 mg / kg / day. NTI164 demonstrated statistically significant efficacy in improving symptoms associated with autism spectrum disorder after 52 weeks of daily treatment.

[0462] Example 13 Example 13 - NTI164 for the treatment of PANS L.1 Background The studies presented above using human microglial and neuronal cells demonstrated that NTI164 has the ability to "modulate" pro-inflammatory processes, reducing microglial inflammation, inhibiting COX-2, and suppressing iNOS activation, allowing the cells to return to a "normal" state.

[0463] Despite ongoing debate about the clinical definition and etiology of childhood acute-onset neuropsychiatric syndromes (PANS), experts agree that atypical idiopathic obsessive-compulsive disorder (OCD), associated with other alterations in functioning, exists as a phenomenon and may be increasing in prevalence. Although many vulnerability genes have been identified for OCD, disease manifestation is driven by complex gene-environment interactions. Common environmental risk factors include perinatal stress and maternal inflammation during pregnancy (e.g., infections, autoimmune diseases). Population studies and previous work have shown that many children with PANS or atypical OCD exhibit evidence of immune dysfunction, such as recurrent infections and infection-induced exacerbations of symptoms. When traditional psychiatric medications fail, immunomodulatory treatments such as intravenous immunoglobulin (IVIG) and antibiotics have shown some therapeutic success in patients with atypical OCD. However, a lack of biomarkers and limited understanding of disease mechanisms hinder the discovery of further treatments, including precision medicine approaches. Using whole blood RNA sequencing, a transcriptomic signature of immune dysfunction has been identified in children with atypical idiopathic OCD (PANS). PANS is an epigenetic immune-brain dysregulation syndrome likely related to microglial activation resulting from immune priming during pregnancy or early life. Differential gene expression and bioinformatics pathway-driven analysis have been used to identify common pathways of difference between patients and controls (Figure 18).

[0464] Using bioinformatics approaches, immune and gene translation pathways have been shown to be dysregulated in children with PANS compared to neurotypical controls (Figure 19). The data indicate that this disease signature is modifiable by IVIG treatment (Figure 18) and is associated with clinical improvement in these children.

[0465] IVIG is invasive because it involves injecting immunoglobulin via a cannula every four weeks. Therapeutic benefits typically last only two to three weeks, with symptoms reversing one week before a further dose of IVIG is scheduled. Therefore, an alternative anti-inflammatory approach is needed. NTI164 is a very attractive product for this purpose. NTI164 has a clear anti-inflammatory effect and a low THC content, making it suitable for pediatric use. L.2 Research Aims

[0466] To use our pre-post "omic" approach to test the potential immunomodulatory, anti-inflammatory, behavioral, and gene regulatory effects of NTI164 in children with PANS / PANDAS in an open-label setting.

[0467] Studies have shown significant improvements in behavioral outcomes for children with atypical sudden-onset OCD (PANS phenotype). L.3 Research design and methods

[0468] participants

[0469] Patient group:

[0470] A cohort of 15 children (ages 2–17 years) meeting PANS / PANDAS criteria was recruited from the clinic.

[0471] Inclusion criteria for the patient population were: (1) fulfillment of the PANDAS criteria (E. Swedo S. From research subgroup to clinical syndrome: modifying the PANDAS criteria to describe PANS (pediatric acute-onset neuropsychiatric syndrome). Pediatrics & Therapeutics. 2012;02(02); Chang K, Frankovich J, Cooperstock M, et al. Clinical evaluation of youth with pediatric acute-onset neuropsychiatric syndrome (PANS): recommendations from the 2013 PANS Consensus Conference. J Child Adolesc Psychopharmacol. 2015;25(1):3-13); and (2) a score on the Children's Yale-Brown Obsessive-Compulsive Scale (CY-BOCS) greater than 24, indicating significant impact (moderate or higher). Patients could receive other medications (e.g., SSRIs), but this treatment had to be established for at least 3 months. Patients should not receive IVIG (they can be recruited after 3 months or longer without IVIG).

[0472] Study control group:

[0473] The 15-child study control group provided baseline comparisons of transcriptome signatures and immune function between participants with PANS / PANDAS and typically developing children only. Children without neurodevelopmental disorders undergoing scheduled blood testing (e.g., endocrine testing for short stature) were recruited. Therefore, these study blood draws for this study could be coordinated with clinical collections to minimize patient anxiety. The study control group was recruited such that the gender ratio and age (mean, median, and range) were not significantly different from the patient group, allowing for data analysis of gender effects. Language interpreters were provided as needed.

[0474] Inclusion criteria for neurotypical controls were: (1) no definable immune, autoimmune, or inflammatory conditions; (2) no neurodevelopmental or neuropsychiatric disorders; and (3) no immunomodulatory therapy.

[0475] treatment

[0476] An open-label clinical study of NTI164 in 15 children with PANS / PANDAS. Patients were recruited under an ethically approved clinical trial process.

[0477] Research Protocol

[0478] The study included the following phases:

[0479] Baseline: Patients were assessed and scored as above and baseline blood samples were obtained as follows:

[0480] Baseline / Titration Phase: Patients received a baseline dose of 5 mg / kg / day of NTI164, which was increased by 5 mg / kg weekly for a period of 4 weeks until the maximum tolerated dose or 20 mg / kg was achieved.

[0481] Treatment Phase: Patients received the maximum tolerated dose daily or 20 mg / kg / day for a period of 8 weeks.

[0482] Clinical monitoring of patient population: All participants (n=15) underwent routine clinical evaluation using a screening tool developed by our team. This evaluation covered demographics, family medical history, maternal health during pregnancy, and pediatric medical history. Disease severity was assessed at baseline using the following gold-standard validated clinical assessment tools that are part of standard care in neurology: OCD was the primary problem in this cohort, and therefore the CY-BOCS was the primary outcome measure. However, these patients have a broader range of clinical problems, and therefore gold-standard measures of anxiety and depression, tics, emotion regulation, and attention were also collected: the Revised Child Anxiety and Depression Scales-Parent Version (RCADS-P) (Becker, SP, et al., Psychometric validation of the Revised Child Anxiety and Depression Scales-Parent Version (RCADS-P) in children evaluated for ADHD. Assessment, 2019. 26(5): p. 811-82), the Children's Yale-Brown Obsessive-Compulsive Scale (CY-BOCS) (Scahill L, Riddle MA, McSwiggin-Hardin M, et al. Children's Yale-Brown Obsessive Compulsive Scale: reliability and validity. J Am Acad Child Adolesc Psychiatry. 1997;36(6):844-852); the Yale Global Tic Severity Scale (YGTSS) (Leckman JF, Riddle MA, Hardin MT, et al. The Yale Global Tic Severity Scale: initial testing of a clinician-rated scale of tic severity. J Am Acad Child Adolesc Psychiatry.1989;28(4):566-573); Clinical Global Impression (CGI) (Busner J, Targum SD. The clinical global impressions scale: applying a research tool in clinical practice. Psychiatry (Edgmont). 2007;4(7):28-37); Children's Global Assessment Scale (CGAS) (Green B, Shirk S, Hanze D, Wanstrath J. The Children's Global Assessment Scale in clinical practice: an empirical evaluation. J Am Acad Child Adolesc Psychiatry. 1994;33(8):1158-1164; Shaffer D, Gould MS, Brasic J, et al. A children's global assessment scale (CGAS). Arch Gen Psychiatry. 1983;40(11):1228-1231); Strengths and Difficulties Questionnaire (SDQ) (Goodman R. Psychometric properties of the strengths and difficulties questionnaire. J Am Acad Child Adolesc Psychiatry. 2001;40(11):1337-1345); Spence Anxiety Scale for Children (Spence) - General Anxiety Disorder / Excessive Anxiety Disorder subscale (questions 1, 3, 4, 18, 20, 22) (Spence SH. A measure of anxiety symptoms among children. Behav Res Ther. 1998;36(5):545-566); Conners Brief Rating Scale (Conners) (Volpe RJ, Gadow KD.Creating abbreviated rating scales to monitor classroom inattention-overactivity, aggression, and peer conflict: reliability, validity, and treatment sensitivity. School Psych Rev. 2019;39(3):350-363);Affective Reactivity Index (ARI)(Stringaris A, Goodman R, Ferdinando S, et al. The Affective Reactivity Index: a concise irritability scale for clinical and research settings. J Child Psychol Psychiatry. 2012;53(11):1109-1117). .

[0483] Transcriptomics-RNA sequencing: methylome biomarker and immune biomarker assessment was also performed as part of a series of observational analyses. L.4 Research results

[0484] Summary of results Table 19. Summary of t-test scores for all endpoints [Table 19]

[0485] Primary endpoint

[0486] Revised Children's Anxiety and Depression Scale, Parent Rating (RCADS-P)

[0487] The RCADS-P is a 47-item parent-report questionnaire that measures symptoms of depression and anxiety in children and adolescents. The RCADS-P consists of six subscales that help screen children for high-prevalence disorders, including: Separation Anxiety Disorder (SAD) ·Social phobia (SP) Generalized Anxiety Disorder (GAD) Panic disorder (PD) Obsessive-compulsive disorder (OCD) · Major depressive disorder (MDD). Table 20 - Score ranges for each subscale of the RCADS-P [Table 20]

[0488] A paired t-test was used to assess the statistical significance of the analyzed data sets. The mean difference in total RCADS-P score between baseline and 12 weeks of treatment was -25.5, 95% confidence interval = 7.121, 43.879, p-value = 0.0161 (see Table 19). Table 21 - Means of the Revised Children's Anxiety and Depression Scale, Parent Rating (RCADS-P) Total and Subscale Scores by Group at Week 12 (where a decrease in score demonstrates improvement). [Table 21]

[0489] See Tables 19, 20 and 21, and Figure 33.

[0490] Clinical Global Impression-Severity (CGI-S)

[0491] The Clinical Global Impression-Severity (CGI-S) scale was used to assess: (a) disease severity: comparison between baseline and week 12 of NTI164 treatment; and (b) treatment effect: rated based on drug effect alone, which is a calculated score based on the extent of treatment effect and side effects.

[0492] Disease Severity. The mean disease severity rating at baseline was 5. This reduced to a mean rating of 4.1 after 12 weeks of daily NTI164 treatment. See Figure 34. The mean difference in disease severity scores between baseline and 12 weeks of treatment was -0.9, 95% confidence interval = 0.680, 1.197, p-value = 0.0005371 (see Table 19). See Figure 35.

[0493] Treatment Efficacy. After 12 weeks of daily NTI164 treatment, 53% of active patients demonstrated moderate improvement, 40% demonstrated minimal improvement, and only 1 patient (7%) was rated as unchanged. See Figure 36.

[0494] Clinical Global Impression-Improvement (CGI-I)

[0495] The Clinical Global Impression-Improvement (CGI-I) scale was used to assess patients' overall improvement, with 53% of patients experiencing a significant improvement, 40% experiencing a minimal improvement, and only one patient experiencing no change (7%). See Figure 37.

[0496] Secondary endpoints

[0497] Yale Global Tic Severity Scale (YGTSS)

[0498] The YGTSS is a tool used to quantify the severity of tic symptoms in individuals aged 6 to 17. It consists of a semi-structured interview followed by a questionnaire in which individuals rate the severity of their tic symptoms (both motor and vocal) in domains such as number, frequency, intensity, complexity, and interference.

[0499] The total tic severity score has a range of 0-50, and the overall tic severity score has a range of 0-100.

[0500] Higher scores on all scales suggest more severe tics or a greater impact of tics on a person's life.

[0501] See Table 22. Table 22. Mean Yale Global Tic Severity Scale (YGTSS) total and subscale scores by group at week 12 (where a decrease in score demonstrates improvement). [Table 22]

[0502] Please refer to Figure 38.

[0503] Children's Yale-Brown Obsessions and Compulsions Scale (CY-BOCS)

[0504] The CY-BOCS is a clinician-administered scale designed to rate the severity of obsessive-compulsive symptoms in children and adolescents aged 6-17 years. Obsessions are considered to be thoughts, ideas, or sights that keep entering your consciousness despite not wanting them. They can be unpleasant, silly, or bothersome. Compulsions are things that you feel you have to do even though you may know they don't make sense. Sometimes you may try to stop yourself from doing them, but this may not be possible. You may feel anxious, or angry, or disappointed until you finish what you have to do.

[0505] See Table 23. Table 23. Severity range of total CY-BOCS scores. [Table 23] Table 24. Mean Children's Yale-Brown Obsessive-Compulsive Scale (CY-BOCS) Total and Subscale Scores by Group at Week 12 (where a decrease in score demonstrates improvement) [Table 24]

[0506] Please refer to Figure 39.

[0507] Conners Scale (assessment of attention-deficit hyperactivity disorder (ADHD) behavior).

[0508] The Conners Scale is an assessment tool used to obtain observations about adolescent behavior. This instrument is designed to assess attention-deficit / hyperactivity disorder (ADHD) and its most common comorbid problems in children and adolescents aged 6 to 18 years. A total score of 15 or above may suggest ADHD.

[0509] See Table 25. Table 25. Mean Conners Scale Total Scores by Group at Week 12 (where a decrease in score demonstrates improvement). [Table 25]

[0510] Please refer to Figure 40.

[0511] EQ-5D-Y (standardized measure of health-related quality of life domains)

[0512] The EQ-5D-Y records patients' self-rated health on a vertical visual analog scale (VAS), where endpoints are labeled "best imaginable health" (equivalent to a score of 100) and "worst imaginable health" (equivalent to a score of 0).

[0513] See Table 26. Table 26. Mean EQ-5D-Y scale total scores by group at week 12 (where a decrease in score demonstrates improvement). [Table 26]

[0514] Please refer to Figure 41. L.5 Discussion of results

[0515] Results demonstrate that children with atypical, sudden-onset OCD (PANS / PANDAS phenotype) have clinical improvement in neuropsychiatric symptoms (using the CGI, CY-BOCS, and RCADS-P as primary endpoints; Becker, SP, et al., Psychometric validation of the Revised Child Anxiety and Depression Scales-Parent Version (RCADS-P) in children evaluated for ADHD. Assessment, 2019. 26(5): pp. 811-824.). 'Omic' and immune biomarker studies show changes consistent with clinical improvement.

[0516] Statistically significant p-values ​​were observed when assessing the primary endpoint of the study, the R-CADS-P scale, i.e., total score (p=0.0161) and within the subscales: social phobia (p=0.00174), separation anxiety (0.03712), generalized anxiety (0.02062) and obsessive-compulsiveness (p=0.04413).

[0517] For the CGI-S, the mean difference in the disease severity subscale was -0.9 after 12 weeks of treatment, with 53% of patients experiencing a moderate improvement based on treatment effect, 40% experiencing a minimal improvement, and only one patient (7%) being rated as unchanged.

[0518] For the CGI-I, all patients demonstrated improvement at 4 weeks (33% greatly improved, 67% minimally improved); after 12 weeks of treatment, 53% of patients demonstrated greatly improved, 33% demonstrated minimal improvement, and only one patient (13%) was rated as having no change.

[0519] These results demonstrate the efficacy of daily administration of NTI164 in the treatment of pediatric acute-onset neuropsychiatric syndromes.

[0520] Example 14 Example 14 - NTI164 for the treatment of Rett Syndrome M.1 Background Rett syndrome (RTT) is a widespread neurological disorder. This inherited neurological disorder primarily affects females and can be found very rarely in males. RTT is a neurodegenerative disorder characterized by an apparently normal prenatal and perinatal period and healthy development for 6 to 18 months, followed by a period of neurodevelopmental stagnation and then rapid regression. During regression, infants lose motor, cognitive, and communication skills. In most cases, Rett syndrome is caused by mutations within the methylcytosine-binding protein 2 (MECP2) gene. M.2 Research Aims

[0521] To test the potential immunomodulatory, anti-inflammatory, behavioral, and gene-modulatory effects of NTI164 in girls with Rett syndrome.

[0522] Open-label studies show: significant improvements in behavioral outcomes in girls with Rett syndrome; NTI164 aids in communication, attention, and eye contact; and functional impairments resulting from Rett syndrome are reduced with NTI164 treatment. M.3 Participants

[0523] Patient group:

[0524] A cohort of 14 girls (ages 5-20 years) with classic / typical RTT will be recruited from the clinic.

[0525] Inclusion criteria for the patient population included: girls and women aged 5 to 20 years; weight ≥ 12 kg; classic / typical RTT; documented disease causing mutations in the MECP2 gene; at least 6 months post-regression at screening (i.e., no loss or decline in walking ability, hand function, speech, nonverbal communication, or social skills within 6 months of screening); Rett Syndrome Clinical Severity Scale rating of 10 to 36; CGI score ≥ 4; and no stable pattern of epileptic seizures or epileptic seizures within 8 weeks of screening.

[0526] Exclusion criteria for the patient population included the following: current clinically significant cardiovascular, endocrine (e.g., hypo- or hyperthyroidism, type 1 diabetes, or uncontrolled type 2 diabetes), renal, hepatic, respiratory, or gastrointestinal disease (e.g., celiac disease or inflammatory bowel disease), or major surgery planned during the study; known history or symptoms of long QT syndrome; QTcF interval >450 ms, history of risk factors for torsades de pointes, or clinically significant QT prolongation thought to increase risk; insulin, IGF-1, or growth hormone therapy within 12 weeks of baseline. currently receiving treatment with Mon; currently receiving treatment with DAYBUE™ (trophinetide); currently using other unregistered medications for the treatment of Rett syndrome, such as Anavex; currently using, or has used within 12 weeks prior to screening, recreational or medical cannabis, cannabinoid-based medications (including Sativex®, or Epidiolex®) and not wanting to stop during the study; and the participant has or is suspected of having any known hypersensitivity to cannabinoids or any of the excipients.

[0527] Study control group:

[0528] The study control group of 14 girls will provide a baseline comparison of transcriptome signatures and immune function between participants with classical / neurotypical RTT and typically developing children only. Children without neurodevelopmental disorders will be recruited who undergo planned blood testing (e.g., endocrine testing for short stature). Therefore, these study blood draws for this study can be coordinated with clinical collections to minimize patient anxiety. The study control group will be recruited such that the gender ratio and age (mean, median, and range) are not significantly different from the patient group, allowing for data analysis of gender effects. Language interpreters will be provided as needed. Inclusion criteria for neurotypical controls will be: (1) no identifiable immune, autoimmune, or inflammatory conditions; (2) no neurodevelopmental or neuropsychiatric disorders; and (3) no immunomodulatory therapy. M.4 Actions

[0529] An open-label clinical study of NTI164 in 14 girls with classic / typical RTT. Patients will be recruited under an ethically approved clinical trial process. M.5 Research Protocol

[0530] The study included the following phases:

[0531] Baseline: Patients will be assessed and scored as above and baseline blood will be obtained as follows:

[0532] Baseline / Titration Phase: Patients receive a baseline dose of NTI164 of 5 mg / kg / day, which is increased by 5 mg / kg every week for a period of 4 weeks until the maximum tolerated dose or 20 mg / kg is achieved.

[0533] Treatment Phase: Patients receive the maximum tolerated dose daily or 20 mg / kg / day for a period of 8 weeks.

[0534] Clinical monitoring of the patient population: All participants (n = 14) will undergo routine clinical evaluation using a screening tool developed by our team. This evaluation will cover demographics, family medical history, maternal health during pregnancy, and pediatric medical history. Disease severity will be assessed at baseline using the following gold-standard validated clinical assessment tools that are part of standard care in neurology:

[0535] The clinical data questionnaire includes:

[0536] Clinical Global Impression-Improvement (CGI-I), a 7-point scale measuring symptom change from baseline, will be administered as baseline and post-baseline caregiver and clinician questionnaires [timeframe: baseline, weeks 5, 13, and 15].

[0537] Rett Syndrome: Symptom Index Score (RTT-SIS), a questionnaire developed by A / Prof Ellaway to monitor differences and changes in the range of symptoms associated with RTT [timeframe: baseline, week 13].

[0538] Clinical Global Impression Scale-Severity (CGI-S), reflecting the clinician's impression of the severity of the illness on a 7-point scale ranging from 1 = not at all to 7 = most extremely ill [Timeframe: Baseline, Weeks 5, 13, and 15].

[0539] Rett Syndrome Behavioral Questionnaire (RSBQ). The RSBQ is a 45-item rating scale completed by caregivers that assesses a range of neurobehavioral traits impaired in RTT. Symptoms assessed include mood disturbances, maladaptive behaviors, fear / anxiety, repetitive movements, hand behaviors, breathing abnormalities, and gross motor skills (walking / standing). Caregivers rate items as 0 = not true, 1 = somewhat or sometimes true, or 2 = very true. This instrument has been validated and FDA-approved for RTT research and has been widely used to assess RTT symptoms in several RTT studies. The lower score is 4 (lowest score / worst) and the upper score (maximum score / best) is 75 [Timeframe: Baseline, Weeks 5, 13, and 15].

[0540] RTT-Clinical Domain Specific Interest-Visual Analog Scale (RTT-DSC-VAS). Each area of ​​functional impairment is rated on an 8-point Likert scale, from 0 = normal function to 7 = most severe impairment: hand function, walking and gross motor skills, ability to communicate choices or preferences (including the use of nonverbal means such as eye contact and gestures), and ability to communicate verbally. For each rating, function during the previous visit is assessed. Raters may rely on both caregiver report and the rater's own observations and tests [timeframe: baseline, 5, 13, and 15 weeks].

[0541] The Communication and Symbolic Behavior Scale Development Profile™ Infant-Toddler Checklist (CSBS-DP-IT Social) consists of 24 items completed by caregivers. Each item is scored using three levels of frequency: "Not Yet," "Sometimes," and "Frequently." The checklist is comprised of three composite scores: Social, Vocal, and Symbolic. The first 13 items comprise the Social Composite Score, which includes affective and gaze, communication, and gesture components. Items comprising the Social Composite Score represent the modalities most commonly used by people with RTT to communicate [41, 42]. The Social Composite Score has previously been used in a placebo-controlled study of mecasermin in the treatment of RTT

[20] . The CSBS-DP-IT identification of skill delays suggests that the delays are permanent, rather than temporary [timeframes: baseline, 5, 13, and 15 weeks].

[0542] Impact of Childhood Neurological Disorders Scale (ICND). The ICND total score assesses the impact a child's condition has on the child's and family's daily life, currently and over the past three months. Parents or caregivers rate the effect of four conditions or health problems (inattention, impulsivity, or mood; ability to think and remember; neurological or physical limitations; epilepsy) on 11 aspects of the child's or family's daily life: "very," "some," "a little," "not at all," or "not applicable." [Timeframe: Baseline, Week 13]

[0543] RTT Caregiver Burden Inventory (RTT-CBI). This is a symptom-specific, caregiver-administered questionnaire based on the Caregiver Burden Inventory designed for Alzheimer's disease. The RTT-CBI assesses four different aspects of burden (physical, emotional, and social burden, as well as time dependency). Caregivers describe each statement as their feeling or experience using a 5-point Likert scale to rate frequency: 0 = never; 1 = rarely; 2 = sometimes; 3 = frequently; and 4 = almost always. Items 1–24 are negatively worded, with a total maximum score of 96. The total score is defined as the total burden score [Timeframe: Baseline, Week 13].

[0544] Infantile Neurological Disorders Impact Scale Global Quality of Life Rating (ICND-QoL). An individual's quality of life is assessed by asking caregivers to rate the subject's overall quality of life on a 6-point scale from 1 ("poor") to 6 ("excellent") [Timeframe: Baseline, Week 13].

[0545] Blood tests will be performed at each visit and will include routine monitoring / safety tests including checking complete blood count (FBC), electrolytes, creatinine, T and B cell subsets, immunoglobulin G / A / M levels, and liver and kidney function tests.

[0546] The primary problem in this cohort is OCD, and therefore the CY-BOCS is the primary outcome measure. However, because these patients have a broader range of clinical problems, gold standard measures of tics, emotion regulation, and attention are also collected:

[0547] Children's Yale-Brown Obsessive-Compulsive Scale (CY-BOCS) (Scahill L, Riddle MA, McSwiggin-Hardin M, et al. Children's Yale-Brown Obsessive Compulsive Scale: reliability and validity. J Am Acad Child Adolesc Psychiatry. 1997;36(6):844-852);

[0548] The Yale Global Tic Severity Scale (YGTSS) (Leckman JF, Riddle MA, Hardin MT, et al. The Yale Global Tic Severity Scale: initial testing of a clinician-rated scale of tic severity. J Am Acad Child Adolesc Psychiatry. 1989;28(4):566-573); Clinical Global Impressions (CGI) (Busner J, Targum SD. The clinical global impressions scale: applying a research tool in clinical practice. Psychiatry (Edgmont). 2007;4(7):28-37); Children's Global Assessment Scale (CGAS) (Green B, Shirk S, Hanze D, Wanstrath J. The Children's Global Assessment Scale in clinical practice: an empirical evaluation. J Am Acad Child Adolesc Psychiatry. 1994;33(8):1158-1164; Shaffer D, Gould MS, Brasic J, et al. A children's global assessment scale (CGAS). Arch Gen Psychiatry. 1983;40(11):1228-1231); Strengths and Difficulties Questionnaire (SDQ) (Goodman R. Psychometric properties of the strengths and difficulties questionnaire. J Am Acad Child Adolesc Psychiatry. 2001;40(11):1337-1345); Spence Anxiety Scale for Children (Spence) - General Anxiety Disorder / Excessive Anxiety Disorder subscale (questions 1, 3, 4, 18, 20, 22) (Spence SH. A measure of anxiety symptoms among children. Behav Res Ther.1998;36(5):545-566); Conners Abbreviated Rating Scale (Conners) (Volpe RJ, Gadow KD. Creating abbreviated rating scales to monitor classroom inattention-overactivity, aggression, and peer conflict: reliability, validity, and treatment sensitivity. School Psych Rev. 2019;39(3):350-363); Affective Reactivity Index (ARI) (Stringaris A, Goodman R, Ferdinando S, et al. The Affective Reactivity Index: a concise irritability scale for clinical and research settings. J Child Psychol Psychiatry. 2012;53(11):1109-1117).

[0549] Transcriptomics-RNA sequencing: Methylome biomarker and immune biomarker assessment will be performed as part of a series of observational analyses. M.6 Research results

[0550] Results demonstrate that girls with classic / typical RTT demonstrate the following:

[0551] (1) mean CGI-I score of 3 or lower at the end of study treatment;

[0552] (2) Improvement in clinically used gold-standard measures assessing symptoms, behavior, interest, development, disability, and quality of life are our secondary outcome measures, including the Rett Syndrome Symptom Index Score (RTT-SIS); Rett Syndrome Behavior Questionnaire (RSBQ); RTT-Clinical Domain Specific Interest-Visual Analog Scale (RTT-DSC-VAS); Communication and Symbolic Behavior Scale Development Profile™ Infant-Toddler Checklist (CSBS-DP-IT Social); Pediatric Neurological Disorder Impact Scale (ICND); RTT Caregiver Burden Inventory (RTT-CBI); Pediatric Neurological Disorder Impact Scale Global Quality of Life (ICND-QoL);

[0553] (3) the three domains of the Clinical Global Impression Scale-Severity (CGI-S), disease severity, overall improvement, and treatment effect improvement; and

[0554] (4) NTI164 was effective and safe in this pediatric population.

Claims

1. 1. A method of treating a pediatric neurological disorder, comprising administering to a patient in need thereof a therapeutically effective amount of a composition, wherein the composition comprises one of the following cannabinoids: w / w% CBDA 40-60%; CBD 1-5%; CBG 1-10%; CBDP 1-5%; CBDB 1-5%; CBGA 1-10%; CBN 1-3% and THC<1% A method comprising:

2. wherein the cannabinoid of the composition is w / w% CBDA 50%, CBD 2%, CBG 5%, CBDP 2%, CBDB 2%, CBGA 5%, CBN 3%, THC < 0.3%, and Additional Active Ingredients Composition 1 comprising and w / w% CBDA 45%, CBD 1%, CBG 4%, CBDP 1%, CBDB 2%, CBGA 4%, CBN 2%, THC < 0.2%, and Additional Active Ingredients Composition 2 comprising 10. The method of claim 1, wherein the compound is present in an amount selected from the group consisting of:

3. 3. The method of claim 1 or 2, wherein the pediatric neurological disorder is selected from the group consisting of PANS / PANDAS, Tourette's syndrome, cerebral palsy, ataxia, attention deficit hyperactivity disorder (ADHD), Lennox-Gastaut, Dravet syndrome, leukodystrophies and subtypes, Reye's syndrome, Rett syndrome, Fragile X syndrome, Phelan-McDermid syndrome, Angelman syndrome, Pitt-Hopkins syndrome, Prader-Willi syndrome, metabolic disorders, and glycosylation disorders.

4. 4. The method of claim 3, wherein the PANS is selected from the group consisting of PANDAS and PITANDS.

5. 10. The method of any one of the above claims, wherein the composition further comprises an oil selected from the group consisting of synthetic oils, vegetable-based oils, mineral oils, canola oil, and olive oil.

6. 10. The method of any one of the preceding claims, wherein the composition comprises less than 5% w / w of terpenes.

7. 10. The method of any one of the preceding claims, wherein the composition comprises less than 2% w / w organic plant material.

8. 10. The method according to any one of the preceding claims, wherein the composition comprises less than 2% w / w of plant phenolics.

9. 10. The method of any one of the preceding claims, wherein the cannabinoid component of the composition is at a concentration selected from the group consisting of between 1 and 500 mg / ml, between 10 and 100 mg / ml, and 50 mg / ml.

10. 10. The method of any one of the preceding claims, wherein the CBDA component of the composition is at a concentration selected from the group consisting of between 1 and 500 mg / ml, between 10 and 100 mg / ml, and 50 mg / ml.

11. 4. The composition of any one of the preceding claims, wherein the composition has a UPLC mass chromatogram corresponding to Figure 3 utilizing the conditions described in Example 1.

12. 10. The method of any one of the preceding claims, wherein the composition further comprises an additional active ingredient.

13. 13. The method of claim 12, wherein the additional active ingredient is selected from the group consisting of diclofenac, prednisone, celecoxib, and psilocybin.

14. 1. A pharmaceutical composition adapted for treating childhood neurological disorders, comprising the following cannabinoids: w / w% CBDA 40-60%; CBD 1-5%; CBG 1-10%; CBDP 1-5%; CBDB 1-5%; CBGA 1-10%; CBN 1-3% THC<1% together with a pharmaceutically acceptable carrier.

15. 1. A dosage form adapted for treating pediatric neurological disorders, comprising the following composition: w / w% CBDA 40-60%; CBD 1-5%; CBG 1-10%; CBDP 1-5%; CBDB 1-5%; CBGA 1-10%; CBN 1-3% THC<1% Including, the CBDA component of the composition is selected from the group consisting of between 1 mg and 1000 mg, between 1 mg and 500 mg, between 1 and 100 mg, less than 400 mg, less than 300 mg, less than 200 mg, and less than 100 mg; Dosage form.

16. 1. A dosage form adapted for treating pediatric neurological disorders, comprising the following composition: w / w% CBDA 40-60%; CBD 1-5%; CBG 1-10%; CBDP 1-5%; CBDB 1-5%; CBGA 1-10%; CBN 1-3% THC<1% Including, A dosage form wherein the CBDA component of the composition is selected from the group consisting of 600 mg, 400 mg, 300 mg, 200 mg, 100 mg, 50 mg, 10 mg, 5 mg, 2 mg, and 1 mg.

17. 1. A kit adapted for treating a pediatric neurological disorder, comprising the following composition: w / w% CBDA 40-60%; CBD 1-5%; CBG 1-10%; CBDP 1-5%; CBDB 1-5%; CBGA 1-10%; CBN 1-3% THC<1% , along with instructions included in the kit.

18. 1. In the manufacture of a medicament for the treatment of a pediatric neurological disorder, the following cannabinoids: w / w% CBDA 40-60%; CBD 1-5%; CBG 1-10%; CBDP 1-5%; CBDB 1-5%; CBGA 1-10%; CBN 1-3% and THC<1% Use of a composition comprising:

19. wherein the cannabinoid of the composition is w / w% CBDA 50%, CBD 2%, CBG 5%, CBDP 2%, CBDB 2%, CBGA 5%, CBN 3%, THC < 0.3%, and Additional Active Ingredients Composition 1 comprising and w / w% CBDA 45%, CBD 1%, CBG 4%, CBDP 1%, CBDB 2%, CBGA 4%, CBN 2%, THC < 0.2%, and Additional Active Ingredients Composition 2 comprising 19. The use of claim 18, wherein the composition is present in an amount selected from the group consisting of:

20. 20. The use of claim 18 or 19, wherein the childhood neurological disorder is selected from the group consisting of PANS / PANDAS, Tourette's syndrome, cerebral palsy, ataxia, attention deficit hyperactivity disorder (ADHD), Lennox-Gastaut, Dravet syndrome, leukodystrophies and subtypes, Reye's syndrome, Rett syndrome, Fragile X syndrome, Phelan-McDermid syndrome, Angelman syndrome, Pitt-Hopkins syndrome, Prader-Willi syndrome, metabolic disorders, and glycosylation disorders.

21. 21. The use of claim 20, wherein the PANS is selected from the group consisting of PANDAS and PITAND.

22. 22. The use according to any one of claims 18 to 21, wherein the composition further comprises an oil selected from the group consisting of synthetic oils, vegetable-based oils, mineral oils, canola oil, and olive oil.

23. 23. The use according to any one of claims 18 to 22, wherein the composition comprises less than 5% w / w of terpenes.

24. 23. The use according to any one of claims 18 to 22, wherein the composition comprises less than 2% w / w of organic plant material.

25. 23. The use according to any one of claims 18 to 22, wherein the composition comprises less than 2% w / w of plant phenolics.

26. 26. The use of any one of claims 18 to 25, wherein the cannabinoid component of the composition is at a concentration selected from the group consisting of between 1 and 500 mg / ml, between 10 and 100 mg / ml, and 50 mg / ml.

27. 27. The use of any one of claims 18 to 26, wherein the CBDA component of the composition is at a concentration selected from the group consisting of between 1 and 500 mg / ml, between 10 and 100 mg / ml, and 50 mg / ml.

28. 28. The use according to any one of claims 18 to 27, wherein the composition has a UPLC mass chromatogram corresponding to Figure 3 using the conditions described in Example 1.

29. The use according to any one of claims 18 to 28, wherein the composition further comprises an additional active ingredient.

30. 30. The use of any one of claims 29, wherein the additional active ingredient is selected from the group consisting of diclofenac, prednisone, celecoxib, and psilocybin.

31. The methods, compositions, dosage forms, kits and uses as described by the preceding examples.

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