WO2025090587A1

WO2025090587A1 - Cannabinoids compounds and their use in the treatment of neuronal disorders

Info

Publication number: WO2025090587A1
Application number: PCT/US2024/052535
Authority: WO
Inventors: Eric C. Hsu; James T. Kealey; Rishi K. SOMVANSHI; Ujendra Kumar
Original assignee: Inmed Pharmaceuticals Inc.
Priority date: 2023-10-23
Filing date: 2024-10-23
Publication date: 2025-05-01

Abstract

Provided herein are 3-(3,7-dimethylocta-2,6-dien-1-yl)-2,4-dihydroxy-6-(alkenyl)benzoic acid compounds of Formula (I), pharmaceutical compositions thereof, and methods for neuroprotection, stimulating neuritogenesis, improving basal and locomotor activity, anxiety-related behavior, cognitive function and memory, sound awareness, downregulation of inflammation markers and/or upregulation of neuronal function markers. The compound(s) of Formula (I) and pharmaceutical compositions comprising the same can be used in the treatment of neurodegenerative diseases, and to promote neurite elongation and/or restore neurite formation in patients in need thereof.

Description

CANNABINOIDS COMPOUNDS AND METHODS OF TREATMENT RELATED APPLICATIONS [0001] This application claims the benefit of priority to U.S. Provisional Patent Application Serial No.63/545,361, filed October 23, 2023, and U.S. Provisional Patent Application Serial No.63/573,398, filed April 2, 2024, both of which are herein incorporated by reference in their entirety. BACKGROUND [0002] Some 100 million Americans suffer from neurological and brain disorders at some point in their lives. Such diseases are often devastating, coming with a high physical, emotional, and economic cost. Indeed, according to the United States Center for Disease Control and Prevention (CDC), in 2010, the costs of treating Alzheimer’s disease alone were estimated to fall between $159 billion and $215 billion. By 2040, these costs are projected to jump to between $379 billion and $500 billion annually. Unfortunately, currently available treatments for neurodegenerative diseases may relieve some of the associated symptoms, but there are no known cures. [0003] Neurodegenerative diseases typically involve neuronal atrophy, axonal degeneration (e.g., Wallerian and/or Wallerian-like degeneration), demyelination of axons, and necrotic or programmed cell death. Different types of programmed cell death, such as apoptosis, autophagy, pyroptosis, and oncosis have been demonstrated in neurons. Accordingly, methods and compositions that block or reverse these processes and thus promote neuroprotection, would effectively prevent, reverse, or delay neurodegenerative symptoms. [0004] Cannabis plants produce many compounds, including cannabinoids, some of which may be of medical importance. Indeed, some cannabis plant extracts have shown some beneficial effects in treating brain injury (see, e.g., U.S. Patent No.9,205,063). In addition, there are many anecdotal reports of potential therapeutic effects. However, many cannabinoids and their derivatives exhibit no detectable neuroprotective effect at physiological concentrations, and others have been shown to contribute to excitotoxicity at physiological concentrations. In cases where cannabinoids may have documented effects, the therapeutic potential of cannabinoids in Alzheimer’s disease and other ailments is largely attributed to the effects of THC and CBD and other cannabinoid compounds (see, e.g., U.S. Patent Publications 2017/0273914 and 2018/0169035). Indeed, THC and CBD have been proposed to act as free-radical scavenging antioxidants and neuroprotectants (see, e.g., U.S. Patent No.6,630,507). -1- 1102826385\4\AMERICAS [0005] Given the many symptoms and presentations of neurodegenerative disease, there remains a need in the art for improved compounds, compositions, and methods for treating neurodegenerative diseases with cannabinoid compounds, such as Alzheimer’s disease. As will be clear from the detailed description that follows, the present disclosure provides for these and other needs. SUMMARY [0006] Described herein are cannabinoid compounds, compounds of Formula I, pharmaceutical compositions comprising the same, and methods of use in treating neuronal disorders, including those characterized by neurodegeneration, and/or those requiring or benefiting from neuritogenesis. Without being bound by theory, the compound of Formula I disclosed herein may inhibit or slow the progression of a neurodegenerative disease by reducing cytotoxicity in a population of affected neurons. Additionally, and remarkably, the compound of Formula I can also be used to promote neurite elongation, and/or restore neurite formation in damaged neurons, and in patients in need thereof. The compound of Formula I can be used in methods for neuroprotection, stimulating neuritogenesis, improving basal and locomotor activity, improving anxiety-related behavior, improving cognitive function and memory, improving sound awareness, downregulating inflammation markers, and/or upregulating neuronal function markers in patients in need thereof compared to other cannabinoid compounds. [0007] In a first aspect, provided is a method of treating a patient with a neuronal disorder or a method of inducing neuritogenesis, comprising administering a therapeutically effective amount of a compound of Formula I, or a pharmaceutically acceptable salt thereof; or administering a therapeutically effective amount of a pharmaceutical composition comprising a compound of Formula I, or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier, wherein the compound of Formula I is according to: wherein

;

1102826385\4\AMERICAS R² is wherein bond b is cis (Z) or trans (E); cted from 1 to 6; and R³ is H, CH3, or CH2CH3, provided that when m is 1, R³ is CH3 or CH2CH3; and wherein R³ is H, there is no cis or trans at bond b. [0008] In a second aspect, provided is a pharmaceutical composition comprising a therapeutically effective amount of a compound of Formula I: or a pharmaceutically acceptable acceptable carrier; wherein

;

R³ is H, CH3, or CH2CH3, provided that when m is 1, R³ is CH3 or CH2CH3; and wherein R³ is H, there is no cis or trans at bond b. [0009] In one or more embodiments of the first and second aspects, the compound of Formula I is a compound of any one of Formulas II, B3, C2, C3, C4, D5, E6, and F7. In one or more embodiments, the cannabinoid compound is a compound of Formula II. In one or more embodiments, the cannabinoid compound is Formula C4 (4-pentenyl-cannabigerolic acid, or 4- pentenyl-CBGA), a pharmaceutically acceptable salt thereof, a derivative thereof, prodrugs thereof, or combinations thereof. [0010] In a third aspect, methods of treating a patient with a neuronal disorder benefitting from neuritogenesis are provided, comprising administering a therapeutically effective amount of a Compound of Formula I, II, or any embodiments thereof or administering a therapeutically effective amount of a pharmaceutical composition comprising a Compound of Formula I, II, or any embodiments thereof to a patient in need thereof, wherein the compound stimulates neuritogenesis. In one or more embodiments, the compound of Formula I is a compound of any one of Formulas II, B3, C2, C3, C4, D5, E6, and F7. In one or more embodiments, the cannabinoid compound is a compound of Formula II. In one or more embodiments, the cannabinoid compound -3- 1102826385\4\AMERICAS is Formula C4 (4-pentenyl-CBGA) or a pharmaceutically acceptable salt thereof, a derivative thereof, prodrugs thereof, or combinations thereof. [0011] In one or more embodiments of, for example, the first aspect, the neuronal disorder is a Central Nervous System (CNS) or a Peripheral Nervous System (PNS) disorder. In one or more embodiments, the CNS disorder is selected from the group comprising or consisting of Alzheimer’s Disease (AD), Parkinson’s Disease (PD), Amyotrophic Lateral Sclerosis (ALS), Huntington’s Disease (HD) and Multiple Sclerosis (MS). In one or more embodiments, the CNS disorder is AD. In one or more embodiments, the PNS disorder is selected from the group comprising or consisting of entrapment neuropathy (e.g., carpal tunnel syndrome); thoracic outlet syndrome, brachial plexus injury (e.g., as seen in a motorcycle upper extremity traction injury); direct open traumatic injury, diabetic nerve problems, Guillain-Barre syndrome, hereditary sensory and autonomic neuropathies (HSANs) (e.g., familial dysautonomia). The compounds of Formula I, II, or any embodiments thereof and pharmaceutical compositions disclosed herein can be locally or systemically administered to a subject to inhibit or slow neurodegenerative disease progression and/or to stimulate neuritogenesis in the subject. In one or more embodiments, a disorder benefitting from neuritogenesis is selected from the group comprising or consisting of Alzheimer’s Disease (AD), axonal injury, ischemic stroke, schizophrenia, Down syndrome, autism spectrum disorder (ASD), amyotrophic lateral sclerosis (ALS), primary lateral sclerosis, spinal muscular atrophy, motor neuron diseases, chronic hearing loss, tinnitus, hyperacusis, presbycusis, and balance disorders associated with cochlear synaptopathy, and vestibular synaptopathy. In one or more embodiments, the methods further comprise the simultaneous or sequential administration of one or more additional active agent(s). [0012] In a fourth aspect, methods of promoting neurite elongation and/or restoring neurite formation are provided for patients in need thereof, comprising administering to the patient a therapeutically effective amount of a cannabinoid compound as described herein. In one or more embodiments, the cannabinoid compound is a compound of any one of Formulas I, II, B3, C2, C3, C4, D5, E6, and F7. In one or more embodiments, the cannabinoid compound is a compound of Formula I, , a pharmaceutically acceptable salt thereof, a derivative thereof, prodrugs thereof, or combinations thereof. In one or more embodiments, the cannabinoid compound is a compound of Formula C4 (4-pentenyl-CBGA) or a pharmaceutically acceptable salt thereof, a derivative thereof, prodrugs thereof, or combinations thereof. Patients in need of neurite elongation and/or restoration of neurite formation may include, e.g., those patients suffering from Alzheimer’s disease (AD), axonal injury, ischemic stroke, schizophrenia, Down syndrome, autism spectrum disorder (ASD), amyotrophic lateral sclerosis (ALS), primary lateral sclerosis, spinal muscular atrophy, motor -4- 1102826385\4\AMERICAS neuron diseases, chronic hearing loss, tinnitus, hyperacusis, presbycusis, and balance disorders associated with cochlear synaptopathy and vestibular synaptopathy. [0013] One or more embodiments include the use of a cannabinoid compound of any one of Formulas I, II, B3, C2, C3, C4, D5, E6, and F7 for treating neurodegeneration in a patient in need thereof. One or more embodiments include the use of a compound of Formula I, a pharmaceutically acceptable salt thereof, a derivative thereof, prodrugs thereof, or combinations thereof for treating neurodegeneration in a patient in need thereof. One or more embodiments include the use of a cannabinoid compound of any one of Formulas I, II, B3, C2, C3, C4, D5, E6, and F7 for promoting neurite elongation and/or restoring neurite formation in a patient in need thereof. One or more embodiments also include the use of a compound of Formula I, a pharmaceutically acceptable salt thereof, a derivative thereof, prodrugs thereof, or combinations thereof, for promoting neurite elongation and/or restoring neurite formation in a patient in need thereof. [0014] In one or more embodiments, the cannabinoid compound and pharmaceutical compositions comprising same can be administered by intracerebroventricular (i.c.v.) injection, which may be biweekly, weekly, two times per week, three times per week, daily, or twice daily. In one or more embodiments, the cannabinoid compound and pharmaceutical compositions comprising same can be administered systemically, e.g., intravenously. In one or more embodiments, systemic administration comprises transdermal administration. In one or more embodiments, the compound of Formula I or II, or any embodiments thereof, or the pharmaceutical composition comprising the compound of Formula I or II, or any embodiments thereof, is administered orally, e.g., as a pill, an extended-release capsule or a sublingual spray or film. In one or more embodiments, the compound of Formula I or II, or any embodiments thereof, or the pharmaceutical composition comprising the compound of Formula I or II, or any embodiments thereof, is administered locally. In another embodiment, the compound of Formula I or II, or any embodiments thereof, or the pharmaceutical composition comprising the compound of Formula I or II, or any embodiments thereof, is administered directly to the brain. [0015] In one or more embodiments, pharmaceutical compositions are provided comprising the compound of Formula I, a pharmaceutically acceptable salt thereof, a derivative thereof, prodrugs thereof, or combinations thereof. In one or more embodiments, the cannabinoid compound is a compound of any one of Formulas I, II, B3, C2, C3, C4, D5, E6, and F7. In one or more embodiments, the cannabinoid compound is Formula C4 (4-pentenyl-CBGA) or a pharmaceutically acceptable salt thereof, a derivative thereof, prodrugs thereof, or combinations thereof. The pharmaceutical composition may be an injectable formulation, an injectable microemulsion or nanoparticle formulation, an intravenous formulation, an intranasal spray, a sublingual spray or film, or an oral formulation. -5- 1102826385\4\AMERICAS [0016] In one or more embodiments, the compound of any one of Formulas I, II, B3, C2, C3, C4, D5, E6, and F7 is provided in an extended-release formulation where it can be applied locally for peripheral nerve disorders. In one or more embodiments, Formula C4 (4-pentenyl-CBGA) or a pharmaceutically acceptable salt thereof, a derivative thereof, prodrugs thereof, or combinations thereof is provided in an extended-release formulation where it can be applied locally for peripheral nerve disorders. In one or more embodiments, the compound of any one of Formulas I, II, B3, C2, C3, C4, D5, E6, and F7 is provided in an injectable microemulsion or nanoparticle formulation. In one or more embodiments, Formula C4 (4-pentenyl-CBGA) or a pharmaceutically acceptable salt thereof, a derivative thereof, prodrugs thereof, or combinations thereof is provided in an injectable microemulsion or nanoparticle formulation. [0017] In one or more embodiments, provided herein are compounds of Formula I, II, or any embodiments thereof, pharmaceutical compositions thereof, and methods for neuroprotection, stimulating neuritogenesis, improving basal and locomotor activity, anxiety-related behavior, cognitive function and memory, sound awareness, downregulation of pro-inflammation markers and/or upregulation of neuronal function markers. INCORPORATION BY REFERENCE [0018] All publications, patents, and patent applications mentioned in this specification are herein incorporated by reference to the same extent as if each individual publication, patent, or patent application was specifically and individually indicated to be incorporated by reference. BRIEF DESCRIPTION OF THE FIGURES [0019] FIG. 1 illustrates the comparative neuroprotective effect of a compound of Formula I (4-pentenyl-CBGA) in an amyloid-ß-induced cytotoxicity model in vitro on differentiated SH- SY5Y human neuronal cells compared to CBGA and CBGVA. 4-pentenyl-CBGA, CBGA, and CBGVA are shown in the presence of 5 µM Aß1-42 (“Abeta”). The assay was normalized to Abeta as 0%, where Abeta (5 µM) was in NH4OH (0.5%) and Ethanol (0.25%). Data are presented as reduction of Cell Death (%) versus Abeta 5 µM + Vehicle Control (taken as 0%). FIG. 1 shows that 4-pentenyl-CBGA displays neuroprotection in differentiated SH-SY5Y human neuronal cells and is biologically active.4-Pentenyl-CBGA provided greater reduction in cell death at 15 µM and 20 µM doses when compared to CBGA. FIG. 1 shows that CBGVA did not provide neuroprotection. [0020] FIG.2 illustrates the comparative neuroprotective effect of a compound of Formula I in an in vitro amyloid-ß-induced cytotoxicity model using differentiated SH-SY5Y human neuronal cells. 1-Pentenyl-CBGA and 4-pentenyl-CBGA are shown in the presence of 5 µM Aß1-42 -6- 1102826385\4\AMERICAS (“Abeta”). The assay was normalized to Abeta as 0%, where Abeta (5 µM) was in NH4OH (0.5%) and Ethanol (0.25%). Data are presented as a reduction in Cell Death (%) normalized to Abeta (5 µM) taken as 0% in FIG.2a and as 100% in FIG.2b. FIGS.2a and 2b, respectively, show that 1-pentenyl-CBGA and 4-pentenyl-CBGA display neuroprotection in differentiated SH-SY5Y human neuronal cells and are biologically active. Tests with 4-pentenyl-CBGA provided greater reduction in cell death at 10 µM, 15 µM, 20 µM, and 25 µM doses when compared to tests with 1-pentenyl-CBGA. ** p<0.01; *** p<0.001. [0021] FIG. 3 illustrates the impact of a compound of Formula I on neuritogenesis compared to CBGA. Differentiated SH-SY5Y cells (control) were treated with CBGA and 4-pentenyl-CBGA (5 µM to 15 µM) for 24 hours. Post-treatment, phase-contrast photomicrographs of SH-SY5Y cells were obtained with a Leica Microscope using a 10× objective and analyzed for total neurite length using NeuronJ plugin of ImageJ software to detect the neurite length. CBGA and 4-pentenyl- CBGA (5 µM to 15 µM) treated cells displayed an increase in overall neurite length in comparison to control cells. When compared to CBGA, 4-pentenyl-CBGA (5 µM to 15 µM) treated cells displayed further improvement in overall neurite extension. For statistical analysis, approximately 100 to 150 cells were analyzed from multiple images, and the average of the total neurite length per image was denoted as neurite length. The results are illustrated in FIG.3. [0022] FIG. 4 illustrates a ratio of 4-pentenyl-CBGA concentration in the brain compared to the 4-pentenyl-CBGA concentration in the plasma (brain/plasma). FIG. 4 shows that 4-pentenyl-CBGA is in a ratio of about 0.55 (brain/plasma) 30 minutes after administration, from about 0.30 to about 0.35 (brain/plasma) 75 minutes after administration, and about 0.25 (brain/plasma) 240 minutes after administration. These results demonstrate that 4-pentenyl-CBGA initially enters the brain and then concentrations in the brain decrease compared to concentrations in the plasma over at least 4 hours post-administration. [0023] FIG. 5 illustrates the difference in control (healthy, wild-type) and 4-pentenyl-CBGA treated TG mice behavior in open field-single enclosure. FIG.5a shows a 3-dimensional view of the open field-single enclosure (left), a top-down perspective view of the enclosure (right), and results of basal and locomotor activity (bottom). The mice were placed in the open field apparatus and were allowed to move freely to and from the center 503 or the inner walls 501 of the enclosure based on their preference. Transgenic (TG) mice (also called “5XFAD” or “5XFAD transgenic” mice herein) were bred with five genetic mutations that lead to Alzheimer’s disease and were treated with Vehicle Control (VC: 10% DMSO, 10% Tween, and 80% Phosphate Buffer Saline). Control mice were wild type (normal, no disease) and were treated with VC. “4-Pent-CBGA (low)” mice were TG mice treated with 10 mg/kg 4-pentenyl-CBGA in 10% DMSO, 10% Tween, and 80% Phosphate Buffer Saline. “4-Pent-CBGA (high)” mice were TG mice treated with 40 mg/kg -7- 1102826385\4\AMERICAS 4-pentenyl-CBGA in 10% DMSO, 10% Tween, and 80% Phosphate Buffer Saline. FIG.5b shows that control mice spent more relative time near the inner walls 501 of the enclosure, which is their normal behavior. Untreated TG mice spent more relative time in the center 503 compared to the control mice.4-pent-CBGA (low) treated TG mice showed behavior trending toward the untreated TG mice compared to the control mice, and 4-pent-CBGA (high) treated TG mice showed behavior similar to the control mice and trending away from untreated TG mice as dose increased (n = 4 to 6 per group). [0024] FIG. 6 illustrates the behavior of control mice and 4-pentenyl-CBGA treated TG mice in an elevated plus (+) maze behavior test and results thereof. FIG.6a shows a 3-dimensional view of an elevated plus maze, and FIG.6b shows results of the behavior test, including anxiety-related behavior. The elevated maze includes open arms 601 as an open flatform (e.g., without protective sides, or devoid of walls) and closed arms 603 as an enclosed space (e.g., with protective sides, or surrounded by side barriers). The two open arms extend across the structure as a single long arm, and the two closed arms extend outward from either side of the center point of the open arms, thereby forming a pattern in the shape of a plus (+) sign. The mice were placed on the top surface of the elevated maze test and were allowed to move freely to and from the open and closed arms based on their preference. Transgenic (TG) mice (also called “5XFAD” or “5XFAD transgenic” mice herein) were bred with five genetic mutations that lead to Alzheimer’s disease and were treated with VC. Control mice were wild type (normal, no disease) and were treated with VC. “4-Pent-CBGA (low)” mice were TG mice treated with 10 mg/kg 4-pentenyl-CBGA in 10% DMSO, 10% Tween, and 80% Phosphate Buffer Saline. “4-Pent-CBGA (high)” mice were TG mice treated with 40 mg/kg 4-pentenyl-CBGA in 10% DMSO, 10% Tween, and 80% Phosphate Buffer Saline. FIG. 6b shows that control mice spent more relative time in the closed arms 603, which is their normal behavior. Untreated TG mice spent more relative time in the open arms 601 compared to the control mice. 4-pent-CBGA (low) treated TG mice showed behavior about the same as the control mice, and 4-pent-CBGA (high) treated TG mice showed behavior similar to the control and trending away from untreated TG mice as dose increased (n = 4 to 6 per group). [0025] FIG.7 illustrates a 2-hour object recognition test. FIG.7a shows that mice were trained to recognize a normal object 701 in their environment (left). FIG. 7a shows that a new object 703 was introduced into the mice’s environment (right). FIG. 7b shows the results of this object recognition behavior over a 2-hour study, including testing cognitive function and memory (bottom). Transgenic (TG) mice (also called “5XFAD” or “5XFAD transgenic” mice herein) were bred with five genetic mutations that lead to Alzheimer’s disease and were treated with VC. Control mice were wild type (normal, no disease) and were treated with VC. “4-Pent-CBGA (low)” mice -8- 1102826385\4\AMERICAS were TG mice treated with 10 mg/kg 4-pentenyl-CBGA in 10% DMSO, 10% Tween, and 80% Phosphate Buffer Saline. “4-Pent-CBGA (high)” mice were TG mice treated with 40 mg/kg 4-pentenyl-CBGA in 10% DMSO, 10% Tween, and 80% Phosphate Buffer Saline. In general, control (WT) mice spent more time with new objects compared to old objects, and untreated TG mice demonstrated a lower preference for new objects compared to control mice. 4-pentenyl-CBGA (low) treated TG mice demonstrated lower preference for new objects compared to the control mice or untreated TG mice. As the dose increased, 4-pent-CBGA (high) treated TG mice showed behavior similar to control (WT) mice (n = 4 to 6 per group). [0026] FIG. 8 illustrates a 24-hour object recognition test. FIG. 8a shows icons that represent training mice (left), icons that represent testing mice (right), and FIG.8b shows the results of the tests, including 24-hour cognitive function and memory (bottom). FIG.8a shows that mice were trained to recognize a normal object 801 in their environment (left). FIG. 8a shows that a new object 803 was introduced into the mice’s environment (right). FIG. 8b shows the results of this object recognition behavior over a 24-hour study, including testing cognitive function and memory (bottom). Transgenic (TG) mice (also called “5XFAD” or “5XFAD transgenic” mice herein) were bred with five genetic mutations that lead to Alzheimer’s disease and were treated with VC. Control mice were wild type (normal, no disease) and were treated with VC. “4-Pent-CBGA (low)” mice were TG mice treated with 10 mg/kg 4-pentenyl-CBGA in 10% DMSO, 10% Tween, and 80% Phosphate Buffer Saline. “4-Pent-CBGA (high)” mice were TG mice treated with 40 mg/kg 4-pentenyl-CBGA in 10% DMSO, 10% Tween, and 80% Phosphate Buffer Saline. In general, control (WT) mice spent more time with new objects compared to old objects, and untreated TG mice demonstrated a lower preference for new objects compared to control mice. Both 4-pent-CBGA (low) and 4-pent-CBGA (high) treated TG mice demonstrated similar preference for new objects, which was about the same as the control (n = 4 to 6 per group). [0027] FIG. 9 illustrates observations from a pre-pulse inhibition (PPI) and acoustic startle test response. Results are shown in % PPI 78 decibel sound pressure level (dB SPL). Transgenic (TG) mice (also called “5XFAD” or “5XFAD transgenic” mice herein) were bred with five genetic mutations that lead to Alzheimer’s disease and were treated with VC. Control mice were wild type (normal, no disease) and were treated with VC. “4-Pent-CBGA (low)” mice were TG mice treated with 10 mg/kg 4-pentenyl-CBGA in 10% DMSO, 10% Tween, and 80% Phosphate Buffer Saline. “4-Pent-CBGA (high)” mice were TG mice treated with 40 mg/kg 4-pentenyl-CBGA in 10% DMSO, 10% Tween, and 80% Phosphate Buffer Saline. Untreated TG mice had reduced PPI to acoustic sound compared to control mice. Both 4-pent-CBGA (low) and 4-pent-CBGA (high) treated TG mice showed improvement in PPI compared to the untreated TG mice (n = 4 to 6 per group). -9- 1102826385\4\AMERICAS [0028] FIG. 10 illustrates glial fibrillary acidic protein (GFAP) levels of treated mice. FIG.10 shows densitometry data of GFAP protein and compares results of control mice, TG mice, 4-pent-CBGA (low) treated TG mice, and 4-pent-CBGA (high) treated TG mice. Transgenic (TG) mice (also called “5XFAD” or “5XFAD transgenic” mice herein) were bred with five genetic mutations that lead to Alzheimer’s disease and were treated with VC. Control mice were wild type (normal, no disease) and were treated with VC. “4-Pent-CBGA (low)” mice were TG mice treated with 10 mg/kg 4-pentenyl-CBGA in 10% DMSO, 10% Tween, and 80% Phosphate Buffer Saline. “4-Pent-CBGA (high)” mice were TG mice treated with 40 mg/kg 4-pentenyl-CBGA in 10% DMSO, 10% Tween, and 80% Phosphate Buffer Saline. After euthanasia, the brain was collected and cortex was isolated. Increased GFAP expression in the cortex is shown in untreated TG mice compared to control mice. Both 4-pent-CBGA (low) treated TG mice and 4-pent-CBGA (high) treated TG mice had improved GFAP levels in the brain. As the dose increased from 4-pent-CBGA (low) treated TG mice to 4-pent-CBGA (high) treated TG mice, GFAP protein expression approached that of the control mice. [0029] FIG. 11 illustrates ß-amyloid concentration in the cortex of control mice, untreated TG mice (5XFAD transgenic mice), 4-pent-CBGA (low) treated TG mice, and 4-pent-CBGA (high) treated TG mice. Results shown are normalized to the control. Transgenic (TG) mice (also called “5XFAD” or “5XFAD transgenic” mice herein) were bred with five genetic mutations that lead to Alzheimer’s disease and were treated with VC. Control mice were wild type (normal, no disease) and were treated with VC. “4-Pent-CBGA (low)” mice were TG mice treated with 10 mg/kg 4-pentenyl-CBGA in 10% DMSO, 10% Tween, and 80% Phosphate Buffer Saline. “4-Pent-CBGA (high)” mice were TG mice treated with 40 mg/kg 4-pentenyl-CBGA in 10% DMSO, 10% Tween, and 80% Phosphate Buffer Saline. Both 4-pent-CBGA (low) mice and 4-pent-CBGA (high) mice resulted in less ß-amyloid concentration in the cortex compared to TG mice. DETAILED DESCRIPTION Definitions [0030] When referring to the compounds provided herein, the following terms have the following meanings unless indicated otherwise. Unless defined otherwise, all technical and scientific terms used herein have the same meaning as is commonly understood by one of ordinary skill in the art. In the event that there is a plurality of definitions for a term herein, those in this section prevail unless stated otherwise. Unless specified otherwise, where a term is defined as being substituted, the groups in the list of substituents are themselves unsubstituted. -10- 1102826385\4\AMERICAS [0031] Reference to “about” a value or parameter herein includes (and describes) variations that are directed to that value or parameter per se. For example, description referring to “about X” includes description of “X”. As used herein, and unless otherwise specified, the terms “about” and “approximately,” when used in connection with temperatures, doses, amounts, or weight percent of ingredients of a composition or a dosage form, mean a dose, amount, or weight percent that is recognized by those of ordinary skill in the art to provide a pharmacological effect equivalent to that obtained from the specified dose, amount, or weight percent. Specifically, the terms “about” and “approximately,” when used in this context, contemplate a dose, amount, or weight percent within 15%, within 10%, within 5%, within 4%, within 3%, within 2%, within 1%, or within 0.5% of the specified dose, amount, or weight percent. [0032] The terms “a” or “an,” as used in herein means one or more, unless context clearly dictates otherwise. [0033] As used herein, “a patient in need thereof,” and the like such as “patient,” “subject,” and “subject in need thereof,” refers to a mammal, preferably a human. [0034] As used herein and unless specified otherwise (i.e., as specified otherwise for a compound), “alkyl” means a linear or branched hydrocarbon group having one to twenty carbon atoms. In one or more embodiments, alkyl has one to twelve carbon atoms. In one or more embodiments, alkyl has one to six carbon atoms. In one or more embodiments, alkyl is methyl, ethyl, propyl, isopropyl, butyl, s-butyl, t-butyl, isobutyl, pentyl, hexyl, and the like. [0035] “Alkoxy,” as used herein, means an –OR group, where R is an alkyl group, as defined in this section of the definitions. [0036] “Alkoxycarbonyl,” as used herein, means a -C(O)OR group where R is an alkyl group, as defined herein. [0037] “Alkoxycarbonyloxy,” as used herein, means an -OR group where R is an alkoxycarbonyl group, as defined herein. [0038] “Alkoxycarbonyloxymethyl,” as used herein, means a -CH₂OR group where R is an alkoxycarbonyl group, as defined herein. [0039] “Alkoxycarbonyloxyethyl,” as used herein, means a -CH₂CH₂-OR group where R is an alkoxycarbonyl group, as defined herein. [0040] “Alkoxycarbonylamino,” as used herein, means an -NR group where R is an alkoxycarbonyl group, as defined herein. [0041] “Alkoxycarbonylaminomethyl,” as used herein, means a -CH₂NR group where R is an alkoxycarbonyl group, as defined herein. [0042] “Alkoxycarbonylaminoethyl,” as used herein, means a -CH₂CH₂-OR group where R is an alkoxycarbonyl group, as defined herein. -11- 1102826385\4\AMERICAS [0043] “Alkanoyl,” as used herein, means a -C(O)R group where R is an alkyl group, as defined herein. [0044] “Alkanoyloxy,” as used herein, means an -OR group where R is an alkanoyl group, as defined herein. [0045] “Alkanoyloxymethyl,” as used herein, means a -CH2OR group where R is an alkanoyl group, as defined herein. [0046] “Alkanoyloxyethyl,” as used herein, means a -CH2CH2OR group where R is an alkanoyl group, as defined herein. [0047] “Succinoyl,” as used herein, means a -C(O)-CH2CH2-C(O)- group. [0048] “Amino,” as used herein, means a -NH₂ group. [0049] “Arylacyl,” as used herein, means a -C(O)R group wherein R is aryl. Examples of aryl include, but are not limited to, phenyl, naphthyl, anthracenyl, tolyl, and xylyl. [0050] “Aminoacyl,” as used herein, means a -C(O)R group wherein R is amino as defined herein. [0051] “Alkylamino,” as used herein, means a -NHR group where R is alkyl, as defined in this section of the definitions. [0052] “Alkylaminoalkyl,” as used herein means an alkylamino group, as defined in this section of the definitions, substituted with an alkyl group. [0053] The term “geranyl” herein refers to a functional group derived from geraniol (i.e., geraniol without the terminal -OH group). The geranyl group can also be called a 2-(3,7-dimethylocta-2,6- dien-1-yl) group, and may be cis (Z) or trans (E). [0054] As used herein, “CBGA” or “Cannabigerolic Acid” refers to 3-[(2E)-3,7-dimethylocta-2,6-dienyl]-2,4-dihydroxy-6-pentylbenzoic acid. [0055] As used herein, “3-but” and “3-butenyl” (e.g., on 3-but-CBGA and 3-butenyl-CBGA) refers to but-3-en-1-yl [0056] As used herein, “4-pent” and “4-pentenyl” (e.g., on 4-pent-CBGA and 4-pentenyl-CBGA) refers to pent-4-en-1-yl. [0057] As used herein, “3-pent” and “3-pentenyl” (e.g., on 3-pent-CBGA and 3-pentenyl-CBGA) refers to pent-3-en-1-yl. [0058] As used herein, “2-pent” and “2-pentenyl” (e.g., on 2-pent-CBGA and 2-pentenyl-CBGA) refers to pent-2-en-1-yl. [0059] As used herein, “1-pent” and “1-pentenyl” (e.g., on 1-pent-CBGA and 1-pentenyl-CBGA) refers to pent-1-en-1-yl. [0060] As used herein, “5-hex” and “5-hexenyl” (e.g., on 5-hex-CBGA and 5-hexenyl-CBGA) refers to hex-5-en-1-yl. -12- 1102826385\4\AMERICAS [0061] As used herein, “6-hept” and “6-heptenyl” (e.g., on 6-hept-CBGA and 6-heptenyl-CBGA) refers to hept-6-en-1-yl. [0062] As used herein, “7-oct” and “7-octenyl” (e.g., on 6-oct-CBGA and 7-octenyl-CBGA) refers to oct-7-en-1-yl. [0063] “Salt” refers to acid or base salts of the compounds used in one or more methods of the present disclosure. Illustrative examples of pharmaceutically acceptable salts are mineral acid (hydrochloric acid, hydrobromic acid, phosphoric acid, and the like) salts, organic acid (acetic acid, propionic acid, glutamic acid, citric acid and the like) salts, quaternary ammonium (methyl iodide, ethyl iodide, and the like) salts. It is understood that the pharmaceutically acceptable salts are non-toxic. Additional information on suitable pharmaceutically acceptable salts can be found in Remington's Pharmaceutical Sciences, 17th ed., Mack Publishing Company, Easton, Pa., 1985, which is incorporated herein by reference. [0064] Thus, when a therapeutically active agent alone or as included in a pharmaceutical composition according to the present disclosure, such as, but not limited to, the compound of any one of Formulas I, II, B3, C2, C3, C4, D5, E6, and F7 or a derivative thereof, possesses a sufficiently acidic, a sufficiently basic, or both a sufficiently acidic and a sufficiently basic functional group, this group or groups can accordingly react with any of a number of inorganic or organic bases, and inorganic and organic acids, to form a pharmaceutically acceptable salt. Examples of pharmaceutically acceptable salts include those salts prepared by reaction of the pharmacologically active compound with a mineral or organic acid or an inorganic base, such as salts including sulfates, pyrosulfates, bisulfates, sulfites, bisulfites, phosphates, monohydrogenphosphates, dihydrogenphosphates, metaphosphates, pyrophosphates, chlorides, bromides, iodides, acetates, propionates, decanoates, caprylates, acrylates, isobutyrates, caproates, heptanoates, propiolates, oxalates, malonates, succinates, suberates, sebacates, fumarates, maleates, butyne-1,4-dioates, hexyne-1,6-dioates, benzoates, chlorobenzoates, methylbenzoates, dinitrobenzoates, hydroxybenzoates, methoxybenzoates, phthalates, sulfonates, xylenesulfonates, phenylacetates, phenylpropionates, phenylbutyrates, citrates, lactates, ^-hydroxybutyrates, glycolates, tartrates, methane-sulfonates, propanesulfonates, naphthalene-1-sulfonates, naphthalene-2-sulfonates, and mandelates. [0065] If the pharmacologically active compound has one or more basic functional groups, the desired pharmaceutically acceptable salt may be prepared by any suitable method available in the art, for example, treatment of the free base with an inorganic acid, such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid and the like, or with an organic acid, such as acetic acid, maleic acid, succinic acid, mandelic acid, fumaric acid, malonic acid, pyruvic -13- 1102826385\4\AMERICAS acid, oxalic acid, glycolic acid, salicylic acid, or with a pyranosidyl acid, such as glucuronic acid or galacturonic acid, or with an alpha-hydroxy acid, such as citric acid, tartaric acid, or with an amino acid, such as aspartic acid, glutamic acid, or with an aromatic acid, such as benzoic acid, cinnamic acid, or with a sulfonic acid, such as p-toluenesulfonic acid or ethanesulfonic acid, or the like. [0066] If the pharmacologically active compound has one or more acidic functional groups, the desired pharmaceutically acceptable salt may be prepared by any suitable method available in the art, for example, treatment of the free acid with an inorganic or organic base, such as an amine (primary, secondary, or tertiary), an alkali metal hydroxide or alkaline earth metal hydroxide, or the like. Illustrative examples of suitable salts include organic salts derived from amino acids, such as glycine and arginine, ammonia, primary, secondary, and tertiary amines, and cyclic amines, such as piperidine, morpholine and piperazine, and inorganic salts derived from sodium, calcium, potassium, magnesium, manganese, iron, copper, zinc, aluminum, and lithium. [0067] By “pharmaceutically acceptable” it is meant the salt, carrier, diluent, or excipient are compatible with the other ingredients of the composition and not deleterious to the recipient thereof. [0068] “Pharmaceutically acceptable excipient” refers to a substance that aids the administration of an active agent to the subject and/or absorption by a subject. Pharmaceutical excipients useful in the present disclosure include, but are not limited to buffers, binders, fillers, disintegrants, lubricants, coatings, sweeteners, flavors, and colors. One of skill in the art will recognize that other pharmaceutical excipients are useful in the present disclosure. [0069] As used herein, the terms “therapeutically effective quantity,” “therapeutically effective dose,” or “therapeutically effective amount” refer to a dose of one or more compounds or to a dose of pharmaceutical compositions described herein that produces therapeutic effects for which it is administered. The exact dose will depend on the purpose of the treatment, and will be ascertainable by one skilled in the art using known techniques (see, e.g., Lieberman, Pharmaceutical Dosage Forms (vols.1-3, 1992); Lloyd, The Art, Science and Technology of Pharmaceutical Compounding (1999); Pickar, Dosage Calculations (1999); and Remington: The Science and Practice of Pharmacy, 20th Edition, 2003, Gennaro, Ed., Lippincott, Williams & Wilkins). Cannabinoid Compounds [0070] Cannabinoids are a group of chemicals known to activate cannabinoid receptors in cells throughout the human body, including the skin. Phytocannabinoids are the cannabinoids derived from cannabis plants. They can be isolated from plants or produced synthetically. -14- 1102826385\4\AMERICAS Endocannabinoids are endogenous cannabinoids produced naturally by cells in the human body. Canonical phytocannabinoids are tricyclic terpenoid compounds bearing a benzopyran moiety. [0071] Cannabinoids include, but are not limited to, phytocannabinoids. In some cases the cannabinoids include, but are not limited to, cannabinol (CBN), cannabidiols (CBD), ^⁹-tetrahydrocannabinol ( ^⁹-THC), the non-natural cannabinoid HU-210 (6aR,10aR)-9-(hydroxymethyl)-6,6-dimethyl-3-(2-methyloctan-2-yl)-6H,6aH,7H,10H,10aH- benzo[c]isochromen-1-ol), HU-308 ([(1R,2R,5R)-2-[2,6-dimethoxy-4-(2-methyloctan-2- yl)phenyl]-7,7-dimethyl-4-bicyclo[3.1.1]hept-3-enyl]methanol), HU-433 an enantiomer of HU-308, cannabidivarin (CBDV), cannabichromene (CBC), cannabichromevarin (CBCV), cannabigerol (CBG), cannabigerolic acid (CBGA), cannabigerovarin (CBGV), cannabielsoin (CBE), cannabicyclol (CBL), cannabivarin (CBV), and cannabitriol (CBT). Still other cannabinoids include, including tetrahydrocannibivarin (THCV) and cannabigerol monomethyl ether (CBGM). Additional cannabinoids include cannabichromenic acid (CBCA), ^⁹- tetrahydrocannabinolic acid (THCA); and cannabidiolic acid (CBDA); these additional cannabinoids are characterized by the presence of a carboxylic acid group in their structure. [0072] Still other cannabinoids include nabilone, rimonabant, JWH-018 (naphthalen-1-yl-(1- pentylindol-3-yl)methanone), JWH-073 naphthalen-1-yl-(1-butylindol-3-yl)methanone, CP-55940 (2-[(1R,2R,5R)-5-hydroxy-2-(3-hydroxypropyl) cyclohexyl]-5-(2-methyloctan-2- yl)phenol), dimethylheptylpyran, HU-331 (3-hydroxy-2-[(1R)-6-isopropenyl-3-methyl-cyclohex- 2-en-1-yl]-5-pentyl-1,4-benzoquinone), SR144528 (5-(4-chloro-3-methylphenyl)-1-[(4- methylphenyl)methyl]-N-[(1S,2S,4R)-1,3,3-trimethylbicyclo[2.2.1]heptan-2-yl]-1H-pyrazole-3- carboxamide), WIN 55,212-2 ((11R)-2-methyl-11-[(morpholin-4-yl)methyl]-3-(naphthalene-1- carbonyl)-9-oxa-1-azatricyclo[6.3.1.0⁴,¹²]dodeca-2,4(12),5,7-tetraene), JWH-133 ((6aR,10aR)-3- (1,1-dimethylbutyl)-6a,7,10,10a-tetrahydro-6,6,9-trimethyl-6H-dibenzo[b,d]pyran), levonatradol, and AM-2201 (1-[(5-fluoropentyl)-1H-indol-3-yl]-(naphthalen-1-yl)methanone). Other cannabinoids include ^⁸-tetrahydrocannabinol ( ^⁸-THC), 11-hydroxy- ^⁹-tetrahydrocannabinol, ^¹¹-tetrahydrocannabinol, and 11-hydroxy-tetracannabinol. [0073] Cannabinoids exert their effects by interacting with cannabinoid receptors present on the surface of the cells. To date, two types of cannabinoid receptors have been identified, the CB1 receptor and the CB2 receptor. These two receptors share about 48% amino acid sequence identity and are distributed in different tissues and have distinct cell signaling mechanisms. They also differ in their sensitivity to agonists and antagonists, and the myriad cannabinoids exert myriad impacts on one or sometimes both receptors, making functional generalizations difficult. Notably, it was recently shown that a cannabinoid-based agonist of the CB2 receptor may induce neuronal damage, -15- 1102826385\4\AMERICAS Wojcieszak et al., J. Mol. Neurosci. (2016) 58:441-445, and as such determining the appropriate type and/or level of cannabinoid receptor interaction in neuronal tissues has thus far proven elusive. [0074] Without being bound by theory, and contrary to the findings of Wojcieszak et al. as previously described herein, in one or more embodiments, compounds of Formula I, II, or any embodiments thereof according to the present disclosure may selectively bind the CB2 cannabinoid receptor and act as a partial or full agonist. In one or more embodiments, the compounds of Formula I, II, or any embodiments thereof of the present disclosure may bind to both the CB1 and CB2 receptors but exhibit a higher affinity to the CB2 receptor. In one or more embodiments, the compounds of Formula I, II, or any embodiments thereof of the present disclosure may down- regulate the expression of the CB1 receptor, and/or modulate the translocation of CB1R to the membrane of the neuron. In one or more embodiments, the compounds of Formula I, II, or any embodiments thereof of the present disclosure may up-regulate the expression of the CB2 receptor, and/or increase the translocation of CB2R to the membrane. In one or more embodiments, the compound of Formula I is according to Formula II. [0075] Without being bound by theory, the compounds of Formula I, II, or any embodiments thereof according to the present disclosure may increase neurite outgrowth, and/or enhance expression of neuronal microtubule-associated protein (MAP2) in the cells and neurites, and thereby provide stability to neuronal cells. In one or more embodiments, the compounds of Formula I, II, or any embodiments thereof of the present disclosure may enhance the expression of the building blocks of microtubules, e.g., the Tuj1 protein, and thereby stabilize axonal structures and dendrites to improve neuronal communication. [0076] In one or more embodiments, structures in this disclosure include a double bond, including as depicted . In such structures, the double bond (bond a or

unless context provides otherwise, for example, when R³ is H. In one or more embodiments, each double bond is independently in the E-configuration. [0077] Embodiment 2. In an embodiment of the first, second, third or fourth aspect, the compound of Formula I is a compound of Formula II:

1102826385\4\AMERICAS (II) or a pharmaceutically acceptable salt thereof. [0078] Embodiment 3. In an embodiment of the first, second, third or fourth aspect or embodiment 2, R² contains a total of 4, 5, 6, 7, or 8 carbon atoms. [0079] Embodiment 4. In an embodiment of the first, second, third or fourth aspect or any one of embodiments 2 to 3, R² contains a total of 5, 6, 7, or 8 carbon atoms. [0080] Embodiment 5. In an embodiment of the first, second, third or fourth aspect or any one of embodiments 2 to 4, R² contains a total of 5 carbon atoms. [0081] Embodiment 6. In an embodiment of the first, second, third or fourth aspect or any one of embodiments 2 to 5, R³ is H. [0082] Embodiment 7. In an embodiment of the first, second, third or fourth aspect or any one of embodiments 2 to 5, R³ is CH3. [0083] Embodiment 8. In an embodiment of the first, second, third or fourth aspect or any one of embodiments 2 to 5, R³ is CH2CH3. [0084] Embodiment 9. In an embodiment of the first, second, third or fourth aspect or any one of embodiments 2 to 8, the double bond in R² is trans. [0085] Embodiment 10. In an embodiment of the first, second, third or fourth aspect or any one of embodiments 2 to 8, the double bond in R² is cis. [0086] Embodiment 11. In an embodiment of the first, second, third or fourth aspect, the compound of Formula (I) is selected from the group consisting of: OH O

7); or a pharmaceutically [0087] Embodiment 12. In an embod men o e rs , second, third or fourth aspect, the compound of Formula (I) is selected from the group consisting of: OH O OH O or a

[0088] Embodiment 13. In an embodiment of the first, second, third or fourth aspect, the compound of Formula (I) is: OH O ; or a pharmaceutically

[0089] Embodiment 14. In an embodiment of the first, second, third or fourth aspect, or any one of embodiments 1-13, the compound of Formula (I) or (II) is not a pharmaceutically acceptable salt. [0090] Embodiment 15. In an embodiment of the first, second, third or fourth aspect, or any one of embodiments 1-13, the compound of Formula (I) or (II) is a pharmaceutically acceptable salt thereof. [0091] Embodiment 16. In an embodiment of the first, third or fourth aspect, or any one of embodiments 1 to 15, the method comprises inducing neuritogenesis. [0092] Embodiment 17. In an embodiment of the second aspect, or any one of embodiments 2 to 15, the concentration of the compound is from 1 to 30 µM in contact with the target neuron or target neuronal population. -18- 1102826385\4\AMERICAS [0093] Embodiment 18. In an embodiment of the second aspect, or any one of embodiments 2 to 15, the concentration of the compound is systemic concentration from about 0.5 mg/kg to about 6 mg/kg. [0094] In one or more embodiments, systemic administration concentration is what is administered to provide the appropriate concentration of the compound in contact with the target neuron or target neuronal population. [0095] Embodiment 19. In an embodiment of the first, third or fourth aspect, or any one of embodiments 2 to 15, the neuronal disorder is Alzheimer’s disease. [0096] In one or more embodiments, including of the first, second, third, and fourth aspect, the compound of Formula I or II or a derivative is a compound according to Formula B3: Formula B3 is (E)-6-(but-3-en-1-

dien-1-yl)-2,4-dihydroxybenzoic acid, or 3-butenyl-CBGA. [0097] In one or more embodiments, provided is a compound according to Formula C1: is named 3-((E)-3,7-

6-((E)-pent-1-en-1-yl)benzoic acid, or 1-pentenyl-CBGA. [0098] In one or more embodiments, including of the first, second, third, and fourth aspect, the compound of Formula I or II or a derivative is a compound according to Formula C2: OH O

Formula C2 is 3-((E)-3,7-dimethylocta-2,6-dien-1-yl)-2,4-dihydroxy-6-((E)-pent-2-en-1- yl)benzoic acid, or 2-pentenyl-CBGA. -19- 1102826385\4\AMERICAS [0099] In one or more embodiments, including of the first, second, third, and fourth aspect, the compound of Formula I or II or a derivative is a compound according to Formula C3: OH O O^H Formula C3 is 3-((E)-3,7- 6-((E)-pent-3-en-1-

yl)benzoic acid, or 3-pentenyl- [00100] In one or more embodiments, including of the first, second, third, and fourth aspect, the compound of Formula I or II or a derivative is a compound according to Formula C4: OH O Formula C4 is (E)-3-(3,7-

6-(pent-4-en-1-yl)benzoic acid, or 4-pentenyl-CBGA. [00101] In one or more embodiments, the compound of Formula I or II or a derivative is a compound according to Formula C4: OH O Formula C4 is (E)-3-(3,7-

6-(pent-4-en-1-yl)benzoic acid, or 4-pentenyl-CBGA. [00102] In one or more embodiments, including of the first, second, third, and fourth aspect, the compound of Formula I or II or a derivative is a compound according to Formula D5: OH O

1102826385\4\AMERICAS Formula D5 is (E)-3-(3,7-dimethylocta-2,6-dien-1-yl)-6-(hex-5-en-1-yl)-2,4-dihydroxybenzoic acid, or 5-hexenyl-CBGA. [00103] In one or more embodiments, including of the first, second, third, and fourth aspect, the compound of Formula I or II or a derivative is a compound according to Formula E6: OH O O^H

Formula E6 is (E)-3-(3,7- - en-1-yl)-2,4-dihydroxybenzoic acid, or 6-heptenyl-CBGA. [00104] In one or more embodiments, including of the first, second, third, and fourth aspect, the compound of Formula I or II or a derivative is a compound according to Formula F7:

Formula F7 is (E)-3-(3,7-dimethylocta-2,6-dien-1-yl)-2,4-dihydroxy-6-(oct-7-en-1-yl)benzoic acid, or 7-octenyl-CBGA. [00105] In one or more embodiments, including of the first, second, third, and fourth aspect, the compound of Formula I or II or derivative is a compound selected from the group consisting of: OH O ; ;

OH O OH O (_E) ^OH _(E) ^OH

fourth aspect, the compound of Formula I or II or derivative is a compound selected from the group consisting of: OH O OH O and/or a

[00107] In some cases, the compounds of Formula I or precursors thereof, can be purified, derivatized (e.g., to form a prodrug, or salt, or to form a target cannabinoid from the precursor), and/or formulated in a pharmaceutical composition. [00108] As used herein, the term “prodrug” refers to a derivative that is a precursor compound that, following administration, releases the biologically active compound in vivo via some chemical or physiological process (e.g., a prodrug on reaching physiological pH or through enzyme action is converted to the biologically active compound). A prodrug itself may either lack or possess the desired biological activity. Thus, the term “prodrug” refers to a precursor of a biologically active compound that is pharmaceutically acceptable. In certain cases, a prodrug has improved physical and/or delivery properties over a parent compound from which the prodrug has been derived. The prodrug often offers advantages of solubility, tissue compatibility, or delayed release in a mammalian organism (H. Bundgard, Design of Prodrugs (Elsevier, Amsterdam, 1988), pp. 7-9, 21-24). A discussion of prodrugs is provided in T. Higuchi et al., “Pro-Drugs as Novel -22- 1102826385\4\AMERICAS Delivery Systems,” ACS Symposium Series, Vol.14 and in E.B. Roche, ed., Bioreversible Carriers in Drug Design (American Pharmaceutical Association & Pergamon Press, 1987). Exemplary advantages of a prodrug can include, but are not limited to, its physical properties, such as enhanced drug stability for long-term storage. [00109] The term “prodrug” is also meant to include any covalently bonded carriers which release the active compound in vivo when the prodrug is administered to a subject. Prodrugs of a therapeutically active compound, as described herein, can be prepared by modifying one or more functional groups present in the therapeutically active compound, including cannabinoids, such as 4-pentenyl-CBGA, or a 4-pentenyl-CBGA derivative, and other therapeutically active compounds used in methods according to the present disclosure or included in compositions according to the present disclosure, in such a way that the modifications are cleaved, either in routine manipulation or in vivo, to yield the parent therapeutically active compound. Prodrugs include compounds wherein a hydroxy, amino, or mercapto group is covalently bonded to any group that, when the prodrug of the active compound is administered to a subject, cleaves to form a free hydroxy, free amino, or free mercapto group, respectively. Examples of prodrugs include, but are not limited to, formate or benzoate derivatives of an alcohol or acetamide, formamide or benzamide derivatives of a therapeutically active agent possessing an amine functional group available for reaction, and the like. In some cases, the prodrug is a protecting group modified derivative of the cannabinoid compound, such as a protecting group modified 4-pentenyl-CBGA or a protecting group modified derivative of 4-pentenyl-CBGA. [00110] For example, if a therapeutically active agent or a pharmaceutically acceptable form of a therapeutically active agent contains a carboxylic acid functional group, a prodrug can comprise an ester formed by the replacement of the hydrogen atom of the carboxylic acid group with a group such as C1-8 alkyl, C2-12 alkanoyloxymethyl, 1-(alkanoyloxy)ethyl having from 4 to 9 carbon atoms, 1-methyl-1-(alkanoyloxy)ethyl having from 5 to 10 carbon atoms, alkoxycarbonyloxymethyl having from 3 to 6 carbon atoms, 1-(alkoxycarbonyloxy)ethyl having from 4 to 7 carbon atoms, 1-methyl-1-(alkoxycarbonyloxy)ethyl having from 5 to 8 carbon atoms, N-(alkoxycarbonyl)aminomethyl having from 3 to 9 carbon atoms, 1-(N-(alkoxycarbonyl)amino)ethyl having from 4 to 10 carbon atoms, 3-phthalidyl, 4-crotonolactonyl, gamma-butyrolacton-4-yl, di-N,N(C₁-C₂)alkylamino(C₂-C₃)alkyl (such as (3-dimethylaminoethyl), carbamoyl-(C1-C2)alkyl, N,N-di-(C1-C2)alkylcarbamoyl-(C1-C2)alkyl and piperidino-, pyrrolidino-, or morpholino(C₂-C₃)alkyl. [00111] In some cases, the therapeutically active agent or a pharmaceutically acceptable form of a therapeutically active agent is a compound of Formula I, and the prodrug comprises a 3,6,9,12-tetraoxatridecanoyl ester; an N,N-dimethylglycyl ester; a -23- 1102826385\4\AMERICAS 3,6,9,12-tetraoxatridecyl carbonate; an N-formylglycyl ester; an N-formylsarcosyl ester; a 3,6,9,12-tetraoxatridecyl oxalate; a hemisuccinate; a 4-aminobutyl carbamate; a prolyl ester; a 3-dimethylamino propionate; a glycolate; a (D)-Ribonate; a phosphate ammonium salt; an (R)-2,3-dihydroxypropyl carbonate; a 3-hydroxy-2-(hydroxymethyl)-2-methylpropanoate; a glycinate; a β-alaninate; an (S)-2,3-dihydroxypropanoate; an (S)-2,3-dihydroxypropyl carbonate; or an (R)-2,3-dihydroxypropyl carbonate at the acid of Formula I. [00112] In some cases, the therapeutically active agent or a pharmaceutically acceptable form of a therapeutically active agent is 4-pentenyl-CBGA (i.e. contains a carboxylic acid functional group) and the prodrug comprises a 3,6,9,12-tetraoxatridecanoyl ester; an N,N-dimethylglycyl ester; a 3,6,9,12-tetraoxatridecyl carbonate; an N-formylglycyl ester; an N-formylsarcosyl ester; a 3,6,9,12-tetraoxatridecyl oxalate; a hemisuccinate; a 4-aminobutyl carbamate; a prolyl ester; a 3-dimethylamino propionate; a glycolate; a (D)-Ribonate; a phosphate ammonium salt; an (R)-2,3-dihydroxypropyl carbonate; a 3-hydroxy-2-(hydroxymethyl)-2- methylpropanoate; a glycinate; a β-alaninate; an (S)-2,3-dihydroxypropanoate; an (S)-2,3-dihydroxypropyl carbonate; or an (R)-2,3-dihydroxypropyl carbonate derivative at the carboxylic acid of Formula I. [00113] Similarly, a prodrug can be formed by the replacement of the hydrogen atom of an alcohol group of the Compound of Formula I with a group such as (C1-C6)alkanoyloxymethyl, 1-((C₁-C₆))alkanoyloxy)ethyl, 1-methyl-1-((C₁-C₆)alkanoyloxy)ethyl (C₁- C6)alkoxycarbonyloxymethyl, N(C1-C6)alkoxycarbonylaminomethyl, succinoyl, (C1-C6)alkanoyl, ^-amino(C₁-C₄)alkanoyl, arylacyl and ^-aminoacyl, or ^-aminoacyl- ^-aminoacyl, where each ^- aminoacyl group is independently selected from the naturally occurring L-amino acids, P(O)(OH)2, P(O)(O(C₁-C₆)alkyl)₂ or glycosyl (the radical resulting from the removal of a hydroxyl group of the hemiacetal form of a carbohydrate). [00114] The use of prodrug systems is described in T. Järvinen et al., “Design and Pharmaceutical Applications of Prodrugs” in Drug Discovery Handbook (S.C. Gad, ed., Wiley- Interscience, Hoboken, NJ, 2005), ch.17, pp.733-796. Other alternatives for prodrug construction and use are known in the art. When a method or pharmaceutical composition according to the present disclosure, uses or includes a prodrug of cannabigerolic acid or other therapeutically active agent, prodrugs and active metabolites of a compound may be identified using routine techniques known in the art. See, e.g., Bertolini et al., J. Med. Chem., 40, 2011-2016 (1997); Shan et al., J. Pharm. Sci., 86 (7), 765-767; Bagshawe, Drug Dev. Res., 34, 220-230 (1995); Bodor, Advances in Drug Res., 13, 224-331 (1984); Bundgaard, Advanced Drug Discovery Reviews (Elsevier Press 1992); Larsen, Design and Application of Prodrugs, Drug Design and Development (Krogsgaard- -24- 1102826385\4\AMERICAS Larsen et al., eds., Harwood Academic Publishers, 1991); Dear et al., J. Chromatogr. B, 748, 281- 293 (2000); Spraul et al., J. Pharmaceutical & Biomedical Analysis, 10, 601-605 (1992). [00115] Exemplary prodrugs useful in the compositions and methods of one or more embodiments of the present disclosure include, but are not limited to, the following compounds (in one or more embodiments, prodrugs of Formula II including, but not limited to, prodrugs of 4-pentenyl-CBGA), according to Formula II-A or II-B: from 1 to 6;

wherein R³ is H, there is no cis or trans at bond b; and wherein R^1a is a prodrug moiety; and wherein X and Y can be the same or different and are selected from the group consisting of: hydrogen, alkali metals (e.g., sodium and potassium), alkaline earth metals (e.g., calcium and magnesium); and cations of pharmaceutically acceptable organic amines (e.g., quaternated or protonated amines, including alkyl amines, hydroxyalkylamines, monoamines, diamines, and naturally occurring amines). Examples of such pharmaceutically acceptable organic bases include choline, betaine, caffeine, N,N′-dibenzylethylenediamine, diethylamine, 2-diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine, ethylenediamine, N-ethylmorpholine, N-ethylpiperidine, glucamine, hydrabamine, isopropylamine, methylglucamine, morpholine, piperidine, polyamine resins, procaine, purines, theobromine, triethylamine, trimethylamine, tripropylamine, tromethamine, tetramethylammonium hydroxide, benzyltrimethylammonium hydroxide, tris(hydroxymethyl)aminomethane (TRIS), N-(2-hydroxyethyl)pyrrolidine, piperazine, glucosamine, arginine, lysine and histidine. In one or more embodiments, X and Y are different substituent groups. In one or more embodiments, X and Y are the same substituent group. In one or more embodiments, the P(=O)(OX)(OY) group is selected from the group consisting of a diphosphate and triphosphate. In one or more embodiments, -25- 1102826385\4\AMERICAS the compound is the salt form of the di or tri phosphate. In one or more embodiments, the compound is according to one of the following formulas: wherein R² trans (E); m is an integer selected from 1 to 6; R³ is

1, R³ is CH3 or CH2CH3; and wherein R³ is H, there is no cis or trans at bond b; and wherein R^4a is a straight or branched substituted or unsubstituted alkyl or R^4a is alkoxyalkyl, akylamine, hydroxyalkyl, or hydroxyalkylamine, preferably wherein R^4a comprises from 1 to 12 carbons and optionally no more than 4 substituents, more preferably wherein R^4a comprises from 1 to 6 carbons and optionally no more than 2 substituents; wherein R² is trans (E); m is an integer selected from 3

1 to 6; R is or m is 1, R³ is CH3 or CH2CH3; and wherein R³ is H, there is no cis or trans at bond b; and wherein R^4a is a straight or branched substituted or unsubstituted alkyl or R^4a is alkoxyalkyl, akylamine, hydroxyalkyl, or hydroxyalkylamine, preferably wherein R^4a comprises from 1 to 12 carbons and optionally no more than 4 substituents, more preferably wherein R^4a comprises from 1 to 6 carbons and optionally no more than 2 substituents; -26- 1102826385\4\AMERICAS wherein R² is r trans (E); m is an integer selected from 1 to 6; R³ is s 1, R³ is CH₃ or CH₂CH₃; and wherein R³ is H, there is no cis or trans at bond b; and wherein R^4a is a straight or branched substituted or unsubstituted alkyl or R^4a is alkoxyalkyl, akylamine, hydroxyalkyl, or hydroxyalkylamine, preferably wherein R^4a comprises from 1 to 12 carbons and optionally no more than 4 substituents, more preferably wherein R^4a comprises from 1 to 6 carbons and optionally no more than 2 substituents; wherein R² (E); m is an integer selected from 1 to 6; R³

is 1, R³ is CH3 or CH2CH3; and wherein R³ is H, there is no cis or trans at bond b; and wherein R^4a is a straight or branched substituted or unsubstituted alkyl or R^4a is alkoxyalkyl, akylamine, hydroxyalkyl, or hydroxyalkylamine, preferably wherein R^4a comprises from 1 to 12 carbons and optionally no more than 4 substituents, more preferably wherein R^4a comprises from 1 to 6 carbons and optionally no more than 2 substituents. [00116] Prodrugs useful in the compositions and methods of one or more embodiments of the present disclosure include, but are not limited to, the following prodrug of Formula G: -27- 1102826385\4\AMERICAS wherein R² is ans (E); m is an integer selected from 1 to 6; R³ is , , , , R³ is CH₃ or CH₂CH₃; and wherein R³ is H, there is no cis or trans at bond b. [00117] In one or more embodiments, the foregoing prodrugs may be advantageously formulated with a cyclodextrin, such as random methylated beta-cyclodextrin, 2-hydroxypropyl beta-cyclodextrin, or sulfobutyl ether beta-cyclodextrin. [00118] Prodrugs useful in the compositions and methods of one or more embodiments of the present disclosure include, but are not limited to, the following prodrug of Formula H: wherein R² (E); m is an integer selected

from 1 to 6; or m is 1, R³ is CH₃ or CH₂CH₃; and wherein R³ is H, there is no cis or trans at bond b. [00119] Prodrugs useful in the compositions and methods of one or more embodiments of the present disclosure include, but are not limited to, the following prodrug of Formula J: -28- 1102826385\4\AMERICAS

wherein R² is ; m is an integer selected from 1 to 6; R , , , , ³ is CH3 or CH2CH3; and wherein R³ is H, there is no cis or trans at bond b. [00120] Prodrugs useful in the compositions and methods of one or more embodiments of the present disclosure include, but are not limited to, the following prodrug of Formula K: wherein R² (E); m is an integer selected

from 1 to 6; or m R³ is CH3 or CH2CH3; and wherein R³ is H, there is no cis or trans at bond b. [00121] Additional prodrug strategies for the cannabinoid compounds described herein can be found in (H. Bundgard, Design of Prodrugs (Elsevier, Amsterdam, 1988), pp.7-9, 21-24). A discussion of prodrugs is provided in T. Higuchi et al., “Pro-Drugs as Novel Delivery Systems,” ACS Symposium Series, Vol. 14 and in E.B. Roche, ed., Bioreversible Carriers in Drug Design (American Pharmaceutical Association & Pergamon Press, 1987) the contents of which are hereby -29- 1102826385\4\AMERICAS incorporated in the entirety for all purposes and in particular for the cannabinoid prodrug compositions and formulations, and methods of making, using and/or administering such prodrug compositions described therein. [00122] In one or more embodiments, analogs or derivatives of these cannabinoids can be obtained by providing a precursor cannabinoid and further derivatization, e.g., by synthetic means. Non-natural cannabinoids include, but are not limited to, those described in United States Patent No. 9,394,267 to Attala et al.; United States Patent No. 9,376,367 to Herkenroth et al.; United States Patent No.9,284,303 to Gijsen et al.; United States Patent No.9,173,867 to Travis; United States Patent No. 9,133,128 to Fulp et al.; United States Patent No. 8,778,950 to Jones et al.; United States Patent No.7,700,634 to Adam-Worrall et al.; United States Patent No.7,504,522 to Davidson et al.; United States Patent No. 7,294,645 to Barth et al.; United States Patent No. 7,109,216 to Kruse et al.; United States Patent No. 6,825,209 to Thomas et al.; and United States Patent No.6,284,788 to Mittendorf et al. [00123] In some cases, protecting groups can be included in compounds used in methods according to the present disclosure or in compositions according to the present disclosure. The use of such a protecting group is to prevent subsequent hydrolysis or other reactions that can occur in vivo and can degrade the compound. Groups that can be protected include alcohols, amines, carbonyls, carboxylic acids, phosphates, and terminal alkynes. Protecting groups useful for protecting alcohols include, but are not limited to, acetyl, benzoyl, benzyl, ^-methoxyethoxyethyl ether, dimethoxytrityl, methoxymethyl ether, methoxytrityl, p-methoxybenzyl ether, methylthiomethyl ether, pivaloyl, tetrahydropyranyl, tetrahydrofuran, trityl, silyl ether, methyl ether, and ethoxyethyl ether. Protecting groups useful for protecting amines include carbobenzyloxy, p-methoxybenzylcarbonyl, t-butyloxycarbonyl, 9-fluorenylmethyloxycarbonyl, acetyl, benzoyl, benzyl, carbamate, p-methoxybenzyl, 3,4-dimethoxybenzyl, p-methoxyphenyl, tosyl, trichloroethyl chloroformate, and sulfonamide. Protecting groups useful for protecting carbonyls include acetals, ketals, acylals, and dithianes. Protecting groups useful for protecting carboxylic acids include methyl esters, benzyl esters, t-butyl esters, esters of 2,6-disubstituted phenols, silyl esters, orthoesters, and oxazoline. Protecting groups useful for protecting phosphate groups include 2-cyanoethyl and methyl. Protecting groups useful for protecting terminal alkynes include propargyl alcohols and silyl groups. Other protecting groups are known in the art. [00124] A compound of the present disclosure can be at least partially selective for binding to a CB2 cannabinoid receptor, CB1 cannabinoid receptor, TRPV receptor, GPR (G-protein- coupled receptor) 18, GPR 55, GPR 119, and/or other cellular receptors. In one or more embodiments, a compound of the present disclosure is selective for binding to one or more of a -30- 1102826385\4\AMERICAS CB2 cannabinoid receptor, CB1 cannabinoid receptor, TRPV receptor, GPR 18, GPR 55, and GPR 119. Pharmaceutical Compositions [00125] In one or more embodiments, provided herein is a pharmaceutical composition comprising a therapeutically effective amount of a compound of Formula I or a pharmaceutically acceptable salt thereof; and a pharmaceutically acceptable carrier. In one or more embodiments, the compound is a pharmaceutically acceptable salt. In one or more embodiments, the concentration of the compound in the pharmaceutical composition is from 1 to 30 µM in contact with the target neuron or target neuronal population. [00126] The pharmaceutical compositions described herein are typically formulated for administration. Accordingly, also described herein is a pharmaceutical composition comprising a Compound of Formula I or II, or any embodiments thereof, (e.g., 4-pentenyl-CBGA, a derivative thereof, or a combination thereof) formulated for administration with one or more pharmaceutically acceptable carrier(s), diluent(s), or excipient(s). The pharmaceutical compositions may be prepared by known procedures using well-known and readily available ingredients. [00127] Pharmaceutical compositions comprising the cannabinoid compounds of Formula I, II, and any embodiments thereof may be formulated for administration to a subject by one of a variety of standard routes, for example, intra-cerebroventricularly, intrathecally, intra-nasally, ocularly, orally, topically, parenterally, by inhalation or spray, rectally, or vaginally, in dosage unit containing conventional non-toxic pharmaceutically acceptable carriers, adjuvants, excipients and/or vehicles. [00128] The term parenteral as used herein includes in one or more embodiments subcutaneous injections, intradermal, intra-articular, intravenous, intramuscular, intravascular, intrasternal, intrathecal injection and infusion techniques. The pharmaceutical composition will typically be formulated in a format suitable for administration to the subject by the selected route, for example, as an injection, eyedrop, an ocular ophthalmic depot, a syrup, elixir, tablet, troche, lozenge, hard or soft capsule, pill, orally disintegrating film, intranasal spray, suppository, oily or aqueous suspension, dispersible powder or granule, emulsion, injectable, or solution. [00129] In one or more embodiments, the pharmaceutical compositions are formulated for administration via a systemic route, for example, intravenously, intramuscularly, intradermally, intraperitoneally, subcutaneously, or orally. [00130] Pharmaceutical compositions for intranasal administration may also be presented as aerosol. Pharmaceutical compositions for oromucosal spray use may also be presented as either buccal, sublingual, or oropharyngeal administration. Pharmaceutical compositions for sublingual use may also be presented as liquid tincture, lozenges, pastilles, tablets, troche, or as orally -31- 1102826385\4\AMERICAS disintegrating film applied under the tongue. Oral, mucosal, oromucosal sprays, intranasal, pulmonary, topical, and transdermal and other routes of administration for cannabinoids have been described (see for example, Bruni et al., Molecules, 23: 2478; doi:10.3390/molecules23102478 and WO2007032962A2). [00131] Pharmaceutical compositions intended for oral use may be prepared in either solid or fluid unit dosage forms. Fluid unit dosage form can be prepared according to procedures known in the art for the manufacture of pharmaceutical compositions and such pharmaceutical compositions may contain one or more agents selected from the group consisting of sweetening agents, flavoring agents, coloring agents, and preserving agents to provide pharmaceutically elegant and palatable preparations. An elixir can be prepared by using a hydroalcoholic (for example, ethanol) vehicle with suitable sweeteners such as sugar or saccharin, together with an aromatic flavoring agent, among other techniques for preparation. Suspensions can be prepared with an aqueous vehicle with the aid of a suspending agent such as acacia, tragacanth, methylcellulose and the like. [00132] Solid pharmaceutical compositions including, but not limited to, tablets, gels, or chews contain the active ingredient in admixture with non-toxic pharmaceutically acceptable excipients that are suitable for the manufacture of the same. These excipients may be for example, inert diluents, such as calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate: granulating and disintegrating agents for example, corn starch, or alginic acid: binding agents, for example starch, gelatin or acacia, and lubricating agents, for example magnesium stearate, stearic acid or talc and other conventional ingredients such as dicalcium phosphate, magnesium aluminum silicate, calcium sulfate, starch, lactose, methylcellulose, and functionally similar materials. The tablets may be uncoated, or they may be coated by known techniques. Among other reasons, a solid pharmaceutical composition that is coated such as a coated tablet can delay disintegration and absorption in the gastrointestinal tract and thereby provide a sustained action over an extended period. For example, a time delay material such as glyceryl monostearate or glyceryl distearate may be employed. [00133] Pharmaceutical compositions for oral use may also be presented as hard gelatin capsules wherein the active ingredient is mixed with an inert solid diluent, for example, calcium carbonate, calcium phosphate or kaolin, or as soft gelatin capsules wherein the active ingredient is mixed with water or an oil medium, for example peanut oil, medium chain triglyceride oil (MCTs oil), medium chain fatty acids (MCFAs), liquid paraffin, coconut oil, palm kernel oil, olive oil, or in some cases, peanut oil. Soft gelatin capsules are prepared by machine encapsulation of a slurry of the compound with an acceptable inert oil, such as vegetable oil, light liquid petrolatum, MCTs oil, MCFAs, coconut oil, palm kernel oil, peanut oil, or other inert oil. -32- 1102826385\4\AMERICAS [00134] Aqueous suspensions contain the active ingredient in admixture with one or more excipients suitable for the manufacture of aqueous suspensions. Such excipients include suspending agents, for example sodium carboxylmethylcellulose, methyl cellulose, hydropropylmethylcellulose, sodium alginate, polyvinylpyrrolidone, gum tragacanth and gum acacia; and dispersing or wetting agents such as naturally-occurring phosphatides (for example, lecithin), condensation products of an alkylene oxide with fatty acids (for example polyoxyethylene stearate), condensation products of ethylene oxide with long chain aliphatic alcohols (for example hepta-decaethyleneoxycetanol), condensation products of ethylene oxide with partial esters derived from fatty acids and a hexitol (for example, polyoxyethylene sorbitol monooleate), or condensation products of ethylene oxide with partial esters derived from fatty acids and hexitol anhydrides (for example polyethylene sorbitan monooleate). The aqueous suspensions may also contain one or more preservatives, for example ethyl, or n-propyl-p-hydroxy benzoate, one or more coloring agents, one or more flavoring agents or one or more sweetening agents, such as sucrose or saccharin. [00135] Oily suspensions may be formulated by suspending the active ingredient in a vegetable oil, for example peanut oil, olive oil, sesame oil or coconut oil, or in a mineral oil such as liquid paraffin. The oily suspensions may contain a thickening agent, for example beeswax, hard paraffin or cetyl alcohol. Sweetening agents such as those set forth previously herein, and flavoring agents may be added to provide palatable oral preparations. These pharmaceutical compositions may be preserved by the addition of an antioxidant such as ascorbic acid. [00136] Dispersible powders and granules suitable for preparation of an aqueous suspension by the addition of water provide the active ingredient in admixture with a dispersing or wetting agent, suspending agent and one or more preservatives. Suitable dispersing or wetting agents and suspending agents are exemplified by those already mentioned herein. Additional excipients, for example sweetening, flavoring and coloring agents, may also be present. [00137] Pharmaceutical compositions may also be in the form of oil-in-water emulsions. The oil phase may be a vegetable oil, for example olive oil or peanut oil, or a mineral oil, for example liquid paraffin, or mixtures of these. Suitable emulsifying agents may be naturally occurring gums, for example gum acacia or gum tragacanth, naturally occurring phosphatides, for example soybean, lecithin, and esters or partial esters derived from fatty acids and hexitol, anhydrides, for example sorbitan monooleate, and condensation products of such partial esters with ethylene oxide, for example polyoxyethylene sorbitan monooleate. The emulsions may also optionally contain sweetening and flavoring agents. [00138] The pharmaceutical compositions may be in the form of a sterile injectable aqueous or oleaginous suspension. Such suspensions may be formulated as known in the art using suitable -33- 1102826385\4\AMERICAS dispersing or wetting agents and suspending agents such as those mentioned previously herein. The sterile injectable preparation may also be a sterile injectable solution or a suspension in a non- toxic parentally acceptable diluent or solvent, for example as a solution in 1,3-butanediol. Other acceptable vehicles and solvents that may be employed include, for example, water, Ringer's solution, and isotonic sodium chloride solution. In addition, sterile, fixed oils may be employed as a solvent or suspending medium. Various bland fixed oils known to be suitable for this purpose may be employed including non-natural mono- or diglycerides. In addition, fatty acids such as oleic acid find use in the preparation of injectables. Adjuvants such as local anesthetics, preservatives and buffering agents may also optionally be included in the injectable solution or suspension. [00139] Other pharmaceutical compositions and methods of preparing pharmaceutical compositions are known in the art and are described, for example, in “Remington: The Science and Practice of Pharmacy” (formerly “Remington’s Pharmaceutical Sciences”); Gennaro, A., Lippincott, Williams & Wilkins, Philadelphia, Pa. (2003). [00140] The concentration of the compound (e.g., 4-pentenyl-CBGA) in the pharmaceutical composition will vary depending on the condition to be treated and/or the mode of administration. Methods of Use [00141] In one or more embodiments, provided herein is a method of treating a patient with a neuronal disorder, the method comprising administering a therapeutically effective amount of a compound of Formula I, or a pharmaceutically acceptable salt thereof; or administering a therapeutically effective amount of a pharmaceutical composition comprising a compound of Formula I, or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier. [00142] Described herein are methods of protecting a neuron from neurodegeneration, as well as methods for stimulating neuritogenesis, e.g., by promoting neurite elongation and/or restoring neurite formation. In general, the methods include contacting an affected population of neurons with a therapeutically effective amount of a compound of Formula I, a single stereoisomer or mixture of stereoisomers thereof, a pharmaceutically acceptable salt thereof, a derivative thereof, prodrugs thereof, or combinations thereof. The method can be an in vitro method. Alternatively, the method can be a method performed at least partially in vivo, such as by administering a neuroprotective composition to a subject. The administering can be performed by intranasal, sublingual, systemic (intravenous injection) or localized (intracerebroventricular or subcutaneous injections). The administering can be performed by a localized administration method that is non-invasive. For example, localized administration may be directly to brain. -34- 1102826385\4\AMERICAS [00143] In one or more embodiments, the compound is administered for a period of less than twenty weeks. In one or more embodiments, the compound is administered for a period of less than 19, 18, 17, 16, 15, 14, 13, 12, 11, 10, 9, 8, 7, or 6 weeks. In one or more embodiments, the compound is administered for a period of about one to sixteen weeks. In one or more embodiments, the compound is administered for a period of about one to twelve weeks. In one or more embodiments, the compound is administered for a period of about one to eight weeks. In one or more embodiments, the compound is administered for a period of about one to four weeks. In one or more embodiments, such as to treat a neurodegenerative disease such as AD, PD, ALS, HD, MS the compound will be administered for an extended period, such as for several years, or for the remaining life of the patient. The compound may be administered biweekly, weekly, two times per week, three times per week every other day, daily, twice per day, or three times per day. [00144] The cannabinoid compound may be administered to treat the brain of a subject in need of treatment to protect brain neurons. For example, the subject may have received an “insult” affecting the brain nerves, such as a physical injury. As another example, the subject may have received a diagnosis of AD (pre-clinical stage) or may be suffering from the mild to severe clinical symptoms of AD. If the cannabinoid compound is administered to protect neurons, such as brain neurons, then the cannabinoid compound can be administered at a dosage that provides a peak (e.g., Cmax), median (e.g., steady state), or trough (e.g., Ctrough), preferably peak, neuroprotective effective concentration of the cannabinoid compound (e.g., 4-pentenyl-CBGA or a pharmaceutically acceptable salt thereof, a derivative thereof, prodrugs thereof, or combinations thereof) in contact with the target neuron or target neuronal population. In one or more embodiments, the target neuron is a brain neuron. In one or more embodiments, the target neuron is a peripheral neuron. In one or more embodiments, the target neuron is a central neuron. [00145] In one or more embodiments, the neuroprotective effective concentration of the cannabinoid compound (e.g., 4-pentenyl-CBGA or a pharmaceutically acceptable salt thereof, a derivative thereof, prodrugs thereof, or combinations thereof) in contact with the target neuron or target neuronal population is less than about 30 µM, less than about 25 µM, less than about 20 µM, less than about 15 µM, less than about 14 µM, less than about 13 µM, less than about 12 µM, less than about 11 µM, less than about 10 µM, less than about 5 µM, less than about 1.5 µM, less than about 0.5 µM or less than about 0.15 µM. In one or more embodiments, the neuroprotective effective concentration of the cannabinoid compound (e.g., 4-pentenyl-CBGA or a pharmaceutically acceptable salt thereof, a derivative thereof, prodrugs thereof, or combinations thereof) in contact with the target neuron or target neuronal population is from greater than about 0.15 µM to less than about 30 µM, or from greater than 0.15 µM to less than 30 µM, or from at least about 0.15 µM to less than about 30 µM, or from at least 0.15 µM to less than 30 µM, is from -35- 1102826385\4\AMERICAS greater than about 0.15 µM to less than about 25 µM, or from greater than 0.15 µM to less than 25 µM, or from at least about 0.15 µM to less than about 25 µM, or from at least 0.15 µM to less than 25 µM, from greater than about 0.15 µM to less than about 20 µM, or from greater than 0.15 µM to less than 20 µM, or from at least about 0.15 µM to less than about 20 µM, or from at least 0.15 µM to less than 20 µM, or from greater than about 0.15 µM to less than about 15 µM, or from greater than 0.15 µM to less than 15 µM, or from at least about 0.15 µM to less than about 15 µM, or from at least 0.15 µM to less than 15 µM, 0.15 µM to less than about 10 µM, or from greater than 0.15 µM to less than 10 µM, or from at least about 0.15 µM to less than about 10 µM, or from at least 0.15 µM to less than 10 µM, 0.15 µM to less than about 5 µM, or from greater than 0.15 µM to less than 5 µM, or from at least about 0.15 µM to less than about 5 µM, or from at least 0.15 µM to less than 5 µM. [00146] In one or more embodiments, the amount of a cannabinoid compound (e.g., 4-pentenyl-CBGA or a pharmaceutically acceptable salt thereof, a derivative thereof, prodrugs thereof, or combinations thereof) sufficient to inhibit or slow the progression of neurodegenerative disease is an amount that results in a concentration of about 0.15 µM to about 15 µM, from about 0.15 µM to about 10 µM, from about 0.15 µM to about 7.5 µM, or from about 0.15 µM to about 5 µM in contact with the neuron. In one or more embodiments, the amount of a cannabinoid compound (e.g., 4-pentenyl-CBGA or a pharmaceutically acceptable salt thereof, a derivative thereof, prodrugs thereof, or combinations thereof) sufficient to inhibit or slow the progression of neurodegenerative disease is an amount that results in a concentration of about 0.5 µM to about 15 µM, from about 0.5 µM to about 10 µM, from about 0.5 µM to about 7.5 µM, or from about 0.5 µM to about 5 µM in contact with the neuron. [00147] In one or more embodiments, for i.c.v. administration in a neurodegenerative disease indication (e.g., to treat AD), the i.c.v. dose can be from about 11 µg to about 1.4 mg, from about 11 µg to about 1.0 mg, from about 11 µg to about 0.5 mg, from about 11 µg to about 0.25 mg, from about 11 µg to about 0.125 mg, from about 5.5 µg to about 1.0 mg, from about 5.5 µg to about 0.5 mg, from about 5.5 µg to about 0.25 mg or from about 5.5 µg to about 0.125 mg applied to the brain (in vitro), such as in the form of an injectable formulation. The dose can be repeated, e.g., biweekly, weekly, two times per week, three times per week, every other day, daily, or twice a day. In one or more embodiments, for i.c.v. administration in a neurodegenerative disease indication (e.g., to AD), the brain dose can be from 1.1 µg to about 0.14 mg, from 1.1 µg to about 0.10 mg, from 1.1 µg to about 0.05 mg from 1.1 µg to about 0.025 mg or from 1.1 µg to about 0.0125 mg applied to the brain, such as in the form of an i.c.v. injection or via pump. The dose can be repeated, e.g., biweekly, weekly, two times per week, three times per week, every other day, daily, or twice a day. -36- 1102826385\4\AMERICAS [00148] In one or more embodiments, a systemic dose level (concentration of cannabinoid compound in a composition according to one or more embodiments) is from 5 to 50 mg/kg (e.g., for intraperitoneal injection in a mouse). In one or more embodiments, a systemic dose level is from about 1 mg/kg to about 50 mg/kg, such as from 1 mg/kg to 50 mg/kg (e.g., for intraperitoneal injection in a mouse). In one or more embodiments, the systemic dose level (e.g., for intraperitoneal injection in a mouse) is from about 5 mg/kg to about 50 mg/kg, from about 10 mg/kg to about 50 mg/kg, from about 5 mg/kg to about 40 mg/kg, from about 10 mg/kg to about 40 mg/kg, from about 15 mg/kg to about 40 mg/kg, from about 20 mg/kg to about 40 mg/kg, from about 30 mg/kg to about 40 mg/kg, from about 5 mg/kg to about 30 mg/kg, from about 10 mg/kg to about 30 mg/kg, from about 15 mg/kg to about 30 mg/kg, from about 20 mg/kg to about 30 mg/kg, from about 5 mg/kg to about 20 mg/kg, from about 10 mg/kg to about 50 mg/kg, or from about 5 mg/kg to about 10 mg/kg. [00149] In one or more embodiments, the systemic dose level (e.g., for intraperitoneal injection in a mouse) is in a range with a lower limit selected from any one of 1, 5, 10, 15, 20, 25, 30, 35, 40, or 45 mg/kg; and an upper limit selected from any one of 5, 10, 15, 20, 25, 30, 35, 40, 45, or 50 mg/kg; where the lower limit and the upper limit form a mathematically allowable range. [00150] In one or more embodiments, a systemic dose level is from 0.8 to 4.5 mg/kg (e.g., for intraperitoneal injection in a human). In one or more embodiments, a systemic dose level is from about 0.5 mg/kg to about 6 mg/kg, such as from 0.5 mg/kg to 6 mg/kg (e.g., for intraperitoneal injection in a human). In one or more embodiments, the systemic dose level (e.g., for intraperitoneal injection in a human) is from about 0.6 mg/kg to about 5 mg/kg, from about 0.8 mg/kg to about 5 mg/kg, from about 0.6 mg/kg to about 4.5 mg/kg, from about 0.8 mg/kg to about 4.5 mg/kg, from about 1 mg/kg to about 4.5 mg/kg, from about 2.0 mg/kg to about 4.5 mg/kg, from about 3.5 mg/kg to about 4.5 mg/kg, from about 0.6 mg/kg to about 4 mg/kg, from about 0.8 mg/kg to about 4 mg/kg, from about 1 mg/kg to about 4 mg/kg, from about 2 mg/kg to about 4 mg/kg, from about 3 mg/kg to about 4 mg/kg, from about 0.6 mg/kg to about 3.5 mg/kg, from about 0.8 mg/kg to about 3.5 mg/kg, from about 1 mg/kg to about 3.5 mg/kg, or from about 2 mg/kg to about 3.5 mg/kg. [00151] In one or more embodiments, the systemic dose level (e.g., for intraperitoneal injection in a human) is in a range with a lower limit selected from any one of 0.5, 0.6, 0.7, 0.8, 0.85, 0.9, 0.95, 1.0, 1.5, 2.0, 2.5, or 3.0 mg/kg; and an upper limit selected from any one of 1.0, 1.5, 2.0, 2.5, 3.0, 3.5, 4.0, 4.5, 5.0, 5.5, or 6.0 mg/kg; where the lower limit and the upper limit form a mathematically allowable range. [00152] In one or more embodiments, the cannabinoid compound, or a formulation thereof, is administered to a subject having AD. In one or more embodiments, the cannabinoid compound, or -37- 1102826385\4\AMERICAS a formulation thereof, is administered to a subject having ALS, HD, PD, or MS. In one or more embodiments, the cannabinoid compound, or a formulation thereof, is administered to a subject having mild to severe symptoms of AD. [00153] The cannabinoid compound may be administered to treat a subject in need of treatment to protect peripheral neurons. For example, the subject may have received an insult affecting one or more peripheral nerves, such as a physical injury. As another example, the subject may have a disease or condition characterized by peripheral nerve degeneration. PNS disorders outside the brain and spinal cord that would benefit from the present disclosure also include entrapment neuropathy, such as carpal tunnel syndrome; brachial plexus injury, such as that seen in a motorcycle upper extremity traction injury; and direct open traumatic injury. Peripheral nerve disorders distort or interrupt the messaging between the brain and the rest of the body and can affect one nerve or many nerves. Some are the result of other diseases, like diabetic nerve problems. Others, like Guillain-Barre syndrome, happen after a virus infection. Still others are from nerve compression, like carpal tunnel syndrome or thoracic outlet syndrome. In some cases, like complex regional pain syndrome and brachial plexus injuries, the problem begins after an injury. Some peripheral nerve disorders are hereditary. A group of hereditary disorders, such as hereditary sensory and autonomic neuropathies (HSANs) are caused by PNS dysfunction. One such disorder, familial dysautonomia, is caused by mutation of the IKBKAP gene. [00154] The cannabinoid compound may be administered to treat a subject in need of treatment to protect central neurons. For example, the subject may have received an insult affecting neurons in the central nervous system (CNS). As another example, the subject may have a disease or condition characterized by central nerve degeneration. [00155] The method may include or further include administering a second active agent simultaneously or sequentially in combination with the cannabinoid compound provided herein. In some cases, the second active agent is a therapeutic agent for the treatment of Alzheimer’s Disease. [00156] The pharmaceutical composition can contain additional active agents. In one or more embodiments, the pharmaceutical composition can contain 4-pentenyl-CBGA, or a pharmaceutically acceptable salt thereof, a derivative thereof, prodrugs thereof, or combinations thereof, and an additional cannabinoid or a terpenoid. In one or more embodiments, the pharmaceutical composition can contain an additional active pharmaceutical agent for treatment of AD, PD, ALS, HD and MS or an additional active pharmaceutical agent for treatment of neurodegenerative disease. [00157] Currently, different classes of therapeutic agents are used for treatment and reversal of AD, including, but not limited to: FDA-approved medications available for AD that are designed to relieve symptoms such as memory loss for a limited time. These drugs, including Aricept, -38- 1102826385\4\AMERICAS Exelon, Razadyne, Galantamine, Donepezil, Tacrine and Rivastigmine are acetylcholinesterase inhibitors that increase levels of acetylcholine, a neurotransmitter that sends signals from one brain cell to another. [00158] Namenda works by regulating the activity of neurotransmitter glutamate. Namzaric combines the two approaches. None of these drugs can stop damage to brain cells; they may alleviate memory issues for a short time by regulating neurotransmitters. There are currently > 120 potential drugs in clinical trials designed to treat the underlying causes of Alzheimer’s, rather than its symptoms. J147, an experimental anti-aging mitochondrial ATP synthase modulator, is promising. Nonetheless, any therapeutic agent appropriate for treating AD may be used in concert with the compound of any one of Formulas I, II, B3, C2, C3, C4, D5, E6, and F7. Nonetheless, any therapeutic agent appropriate for treating AD may be used in concert with the compound of Formula I, a pharmaceutically acceptable salt thereof, a derivative thereof, prodrugs thereof, or combinations thereof. [00159] In one or more embodiments, the pharmaceutical compositions described herein, e.g., containing 4-pentenyl-CBGA or a pharmaceutically acceptable salt thereof, a derivative thereof, prodrugs thereof, or combinations thereof allow a lower dose, or less frequent dosing, of one or more therapeutic agents for the treatment of AD. [00160] The compounds of Formula I, II, or any embodiments thereof may be also administered to stimulate neuritogenesis in a patient in need thereof. Neuritogenesis ensures proper synaptogenesis, axon guidance, and neuronal function, and can play a role in ischemic stroke (Arvidsson et al., 2002; Zhanget al., 2004) as well as spinal cord injuries that result in axonal injury or degeneration of neurites. Improper neuritogenesis also underlies a variety of neurodevelopmental disorders such as (Cellular and Molecular Life Sciences (2020) 77:1511– 1530) schizophrenia, Down syndrome, and autism spectrum disorder (ASD). Degeneration and loss of spinal motor neurons can also cause progressive and fatal motor neuron diseases such as amyotrophic lateral sclerosis (ALS), primary lateral sclerosis, and spinal muscular atrophy. Also contemplated herein is the use of the subject compounds, compositions, and methods in regenerative therapies for motor neuron diseases (Cells 2020, 9(4), 934; https://doi.org/10.3390/cells9040934), as well as chronic hearing loss, tinnitus, hyperacusis, presbycusis, or balance disorders associated with cochlear synaptopathy and vestibular synaptopathy. EXAMPLES Example 1: Protection of Differentiated SH-SY5Y Neuronal Cells -39- 1102826385\4\AMERICAS [00161] Cell Culture and Differentiation: The SH-SY5Y human neuronal cell line was derived from neuroblastoma established from a metastatic bone tumor (patient with neuroblastoma). The cells were maintained in DMEM:F-12 culture medium supplemented with 10% FBS and 1% Antibiotic-Antimycotic penicillin/streptomycin (growth medium) at 37°C in a humidified atmosphere of 5% CO2. To induce neuronal differentiation of SH-SY5Y cells, culture media was replaced by a growth medium containing Retinoic Acid (RA) for 5 days at 37°C in a humidified atmosphere of 5% CO2. [00162] Compounds and Dosing Formulations for Animal Studies: 4-pentenyl-CBGA was prepared by biosynthesis. Briefly, 5-hexenoic acid was “fed” to a strain of Saccharomyces cerevisiae engineered to convert the acid analog to 4-pentenyl-olivetolic acid. The olivetolic acid analog was recovered from the culture medium by extraction with ethylacetate. The 4-pentenyl-oliveltolic acid was then “fed” to a strain of S. cerevisiae engineered to overproduce the geranyl-diphosphate precursor (GPP) and to express a heterologous gene encoding a prenyltransferase. The bioconversion strain converted the olivetolic acid analog to 4- pentenyl-CBGA which was recovered from the yeast cells by ethyl acetate extraction and purified by preparative reverse phase HPLC.4-pentenyl-CBGA can be synthesized by chemical synthesis. [00163] A stock solution of 4-pentenyl CBGA in 100% DMSO was diluted in 10% Tween and 80% PBS to attain a desired formulation concentration at about 10% DMSO concentration for intraperitoneal administration. This resulted in the compound 4-pentenyl-CBGA in formulation with the Vehicle Control (VC): about 10% DMSO, 10% Tween and 80% Phosphate Buffer Saline. [00164] For a day’s injection, DMSO stock solution was diluted in Tween, vortex mixed followed by addition of PBS buffer to the mixture to produce sufficient volume of formulation for administration. This was followed by vortex mixing for 30 seconds or more at the highest setting of the mixer. [00165] For In vitro studies, ethanol (100%) was used as the solvent to prepare stock solutions (10 mM) (e.g., for CBGA, CBGVA, and 4-pentenyl-CBGA). Amyloid-beta stock solution (1 mM) was prepared in ammonium hydroxide (NH₄OH). Treatments were prepared directly in the control medium (DMEM:F12 + 5% FBS+1% Antibiotic-Antimycotic) by using appropriate stock solutions. Treatment concentrations for CBGA and CBGVA were prepared at 5 µM, 10 µM, 15 µM, and 20 µM. Treatment concentrations for 4-pentenyl-CBGA were prepared at 5 µM, 10 µM, 15 µM, 20 µM, and 25 µM. [00166] Evaluation of Cytotoxicity and Neuroprotection: Evaluation of neuroprotection and cytotoxicity on differentiated SH-SY5Y human neuronal cells was carried out by MTT (3-(4,5- dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) assay. Initially, cytotoxicity and -40- 1102826385\4\AMERICAS neuroprotection were evaluated for the compounds tested in a primary screen assay without the presence of cytotoxicity inducing insult agents. Subsequently, compounds tested with “border- line” cytotoxicity were selected and advanced to a secondary screen by further evaluation in the presence of insult-inducing cytotoxic agents such as Amyloid-beta (Aβ1-42) peptide. The Retinoic Acid (RA) differentiated SH-SY5Y neuronal cells were seeded onto 96-well plates (10,000 cells/well) in DMEM:F12 complete medium. Cells were differentiated for 5 days in the presence of RA. Post-differentiation cells were treated with Aβ1-42 (24 hrs.) and the compounds in the tests and were processed for MTT assay. [00167] MTT Assay: For the MTT assay, differentiated SH-SY5Y neuronal cells were treated with the compounds tested at various concentrations for 24 hrs. in the presence of Aβ1-42 peptide at 5 µM, and processed to determine cytotoxicity. Briefly, 5 mg/mL of methylthiazolyldiphenyl- tetrazolium bromide (Sigma-Aldrich) stock solution was prepared in PBS. Following treatment of SH-SY5Y neuronal cells with the compounds tested for 24 h, the cells were incubated with 20 μL of MTT stock solution in 200 μL DMEM for 2 hrs. at 37 °C. Following subsequent washes with PBS, 200 μL of isopropanol was added to the well(s). The resulting change in color from dissolving formazan salt was immediately quantified using a spectrophotometer (BMG Labtech) at a wavelength of 570 nm. The data were normalized to Amyloid beta containing 0.5% NH₄OH and 0.25% Ethanol and presented as % Cell Death. The results are illustrated in FIGS.1 and 2. [00168] As shown in FIG.1, 4-pentenyl-CBGA and CBGA conferred effective neuroprotection against Aβ1-42 induced cytotoxicity insult on SH-SY5Y neuronal cells. FIG. 1 illustrates comparison of the neuroprotective effects of CBGA versus 4-pentenyl-CBGA versus CBGVA on differentiated SH-SY5Y cells from the Aβ1-42 induced cytotoxicity at 5 µM. Concurrent exposure with CBGA at 10 µM, 15 µM, and 20 µM concentrations protected cells from Aβ1-42 induced insult. Concurrent exposure with 4-pentenyl-CBGA at 10 µM, 15 µM, and 20 µM concentrations protected cells from Aβ1-42 induced insult in a dose dependent manner. CBGVA did not confer neuroprotection against Aβ1-42 induced cytotoxicity insult on SH-SY5Y neuronal cells at 10 µM or 15 µM and induced cytotoxicity. However, concurrent exposure with CBGVA 20 µM concentration slightly protected cells from Aβ1-42 induced insult. [00169] As shown in FIG. 2a, 1-pentenyl-CBGA conferred effective neuroprotection against Aβ1-42 induced cytotoxicity insult on SH-SY5Y neuronal cells at 5 µM, 10 µM, and 15 µM in a dose dependent manner; however, 1-pentenyl-CBGA resulted in cytotoxicity at 20 µM and 25 µM. As shown in FIG. 2b, 4-pentenyl-CBGA provided neuroprotection against Aβ1-42 induced cytotoxicity insult on SH-SY5Y neuronal cells at 10 µM, 15 µM, 20 µM, and 25 µM, and was dose dependent up to 15 µM. -41- 1102826385\4\AMERICAS [00170] Overall, these data indicate that a beneficial therapeutic range for 4-pentenyl-CBGA against Aβ1-42 insult is about 10 µM to about 25 µM (or greater); 1-pentenyl-CBGA against Aβ1-42 insult is about 5 µM to about 15 µM. These results suggest that the location of the double bond in R² of the compound of Formula I may play a role in neuroprotection. For comparison, these data indicated that a beneficial therapeutic range for CBGA against Aβ1-42 insult is about 10 µM to about 20 µM (or greater). Example 2: Impact of a compound of Formula I on neuritogenesis [00171] Neuritogenesis includes, among other things, maturing an adult neuron and passing on its connection to connect to another neuron. Thus, neuritogenesis differentiates mature neurons from general neuronal growth. Changes in neurite length following treatment with a compound of Formula I in a dose dependent manner was determined. In WO2022082313A1, it was determined that CBGA in a dose dependent manner significantly increased the neuritogenesis in SH-SY5Y cells. To initiate neuronal differentiation, cells were plated on culture dishes pre-coated with Matrigel (10 mg/mL; BD Bio-science, San Jose, CA, USA) and grown for 5 days in a medium containing Retinoic acid (10 µM, Sigma; St. Louis, MO, USA). SH-SY5Y cells (control) were treated with 4-Pent-CBGA (5 µM-15 µM) for 24 hrs. All experiments were carried out using cells within passages 14–22. Post-treatment, Phase-contrast photomicrographs of SH-SY5Y cells were obtained using Leica Microscope using a 10× objective. Multiple images of the cells were analyzed for total neurite length. Briefly, we used the NeuronJ plugin of ImageJ software to detect the neurite length, and the neurites were traced to quantify their respective lengths. For statistical analysis, approximately 100-150 cells were analyzed from multiple images, and the average of the total neurite length per image was denoted as neurite length. The results are illustrated in FIG.3. [00172] As shown in FIG.3, in the present study it was determined that 4-pentenyl-CBGA, improved neuritogenesis in SH-SY5Y cells compared to CBGA at 5 µM, 10 µM, and 15 µM. Although the difference is small as shown in FIG. 3, neurites only grow to a certain length in the tested in vitro system. For example, the growth of neurites in the tested in vitro system is also small, to the extent that small differences are sufficient to identify neuritogenesis. Example 3: Presence of a compound of Formula I in vivo, brain and plasma [00173] 4-Pent-CBGA concentrations in plasma and brain samples were assayed by HQP-liquid chromatography-mass spectrometry (HQP-LC-MS) using an Exion LC-AD liquid chromatograph coupled to a Sciex7500QQQ mass spectrometer. A total of 9 male 10-weeks-old B6.Cg-Tg mice received a single intraperitoneal injection of 40mg/kg dose. 2 animals were dosed with a control vehicle (10% DMSO and 10% Tween in 80% Phosphate Buffer Saline). Animals were euthanized, -42- 1102826385\4\AMERICAS and brain tissue and blood were collected after 30 mins, 75 mins and 240 mins post IP injection (n = 3). Blood samples were processed immediately to isolate plasma and stored at -80 °C until analysis. Plasma and Brain samples were processed for further bioanalytical analysis. As shown in FIG. 4, 4-pentenyl-CBGA was at ratio of about 0.55 (brain/plasma) 30 minutes after administration. The ratio of 4-pentenyl-CBGA in the brain compared to plasma decreased to a range from about 0.30 to about 0.35, 75 minutes after administration. The ratio of 4-pentenyl-CBGA in the brain compared to plasma decreased to about 0.25, 240 minutes after administration. Example 4: Behavioral tests in vivo [00174] In vivo study design: For in vivo experiments, TG mice (5XFAD transgenic male mice) were purchased from JAX/MMRRC and housed at the MBF, UBC. TG mice display AD pathologies such as rapid β-amyloid plaque deposition, neurodegeneration, and cognitive dysfunction. 5 weeks old mice were acclimatized to the light and dark cycle and began administration of the respective vehicle and/or a compound of Formula I at 8 weeks of age. Mice were treated three times per week for 8 weeks, followed by two times per week for an additional 5 weeks, and the Behavior Tests were conducted at week 21. In these tests, n = 4 to 6 per group. [00175] The compound 4-Pent-CBGA (stock solution 125mg/ml) was formulated in 10% DMSO and 10% Tween in 80% Phosphate Buffer Saline (6.25mg/ml). A total of 7 male 8-week-old B6.Cg-Tg mice received repeat doses of 4-Pent-CBGA [10mg/kg (low) and 40mg/kg (high)] intraperitoneally (two times per week or three times per week) for three months. 7 male WT mice and 7 TG mice were also dosed with the vehicle control. Between 4-5 months of age, wild-type (WT) control and TG mice underwent a sequence of behavioural tests encompassing open-field (OFT), elevated-plus maze (EPM), novel object recognition (NORT), and acoustic startle response assessments. These tests were designed to establish a comprehensive baseline relevant to the experimental timeline. [00176] Behavior Test 1: open field-single enclosure (basal and locomotor activity) [00177] To determine a basal and locomotor activity baseline, control (normal. wild-type), and TG mice were observed after being placed in an open field-single enclosure. The open field served as a tool to evaluate anxiety-like responses in mice resulting from exposure to an unsheltered, expansive area. This open-field apparatus was constructed from a plexiglass square (72 x 72 cm) bordered by walls that were 36 cm in height. Mice were positioned in one corner of this space, allowing them to navigate the area for a duration of 7 minutes. Indicators of anxiety-like reactions, such as the duration spent in the field's centre were documented. The movement of mice was recorded and analyzed using a video-tracking system (ezTrack). The control mice were observed -43- 1102826385\4\AMERICAS near the walls through testing and were observed less near the center at a proportion of 0.06 relative time. The TG mice were observed near the center of the enclosure at a proportion of 0.14 relative time. Next, 4-pent-CBGA (low) treated TG mice were tested, which were observed near the center at a proportion of from about 0.08 to about 0.1 relative time. The 4-pent-CBGA (high) TG mice were tested and were observed near the center at a proportion of from about 0.04 to about 0.06 relative time. These results are shown in FIG.5b. N: Control = 5; TG = 5; 4-pent-CBGA (low) = 6; 4-pent-CBGA (high) = 4.5XFAD mice: male, age: 4.5 months. Error bar: standard error of the mean (SEM). [00178] From these tests, the results show that mice treated with 4-pentenyl-CBGA improved basal and locomotor activity compared to the TG mice in a dose dependent manner. Additionally, TG mice treated with 4-pentenyl-CBGA (high) met or exceeded the results displayed by the healthy control mice. Without being bound by theory, these tests indicate that the TG mice treated with 4-pentenyl-CBGA (high) mice displayed the same or increased anxiety-like behavior compared to the control. Whereas the TG mice displayed less anxiety-like behavior. [00179] Behavior Test 2: elevated plus maze test (anxiety-related behavior) [00180] An elevated plus maze was used to determine effects of compounds of Formula I on anxiety-related behavior. This maze comprised four arms (an arm measuring 30 x 5 cm) radiating from a central square (5 x 5 cm). The structure stood 45 cm above the ground. Two of these arms were surrounded by side barriers that stood 15 cm tall (termed closed arms), whereas the other two were devoid of any walls (referred to as open arms). During a session, mice were positioned at the maze's centre, facing an open arm, and were allowed to traverse the maze for a span of 7 minutes. Observations related to anxiety-like behavior, such as the duration spent in the open vs closed arms, were noted. The movement of mice was recorded and analyzed using a video-tracking system (ezTrack). Control mice (normal, wild-type) and TG mice were observed after being placed on the platform. The control mice moved toward the closed arms (protected, closed in sides) of the enclosure. Thus, the control mice (normal, wild-type) were observed on the open arm of the elevated maze at a proportion of about 0.15 relative time. The untreated TG mice were observed in the open arm at a proportion of from about 0.2 to about 0.25 relative time. The 4-pent-CBGA (low) treated TG mice were tested and were observed on the open arm at a proportion of about 0.15 relative time. The 4-pent-CBGA (high) treated TG mice were tested and were observed on the open arm at a proportion of from about 0.1 to about 0.15 relative time. These results are shown in FIG.6b. N: Control = 6; TG = 4; 4-pent-CBGA (low) = 6; 4-pent-CBGA (high) = 4.5XFADF mice; male; age: 4.5 months. -44- 1102826385\4\AMERICAS [00181] These results show that TG mice treated with 4-pentenyl-CBGA increased anxiety- related behavior to match or exceed the healthy control group compared to the untreated TG group. Dose dependent improvements were observed. [00182] Behavior Test 3: 2-hour new object recognition (cognitive function and memory) [00183] To determine the effects of a compound of Formula I on short and long-term memory impairments in TG mice, a novel object recognition test (NORT) was conducted. The mice were placed in an open, transparent box containing two identical objects for ten minutes, allowing familiarization with the objects to take place. Observations were recorded and are shown in FIG.7b (Control old). The short-term memory assessment was conducted two hours later. During this stage, the mice were once again placed in the box for five minutes, with one of the objects they were familiar with and a novel object. Observations were recorded and are shown in FIG. 7b (Control new). The tests with the new object were performed with control mice (norma, wild-type; “Control NEW”), untreated TG mice (“TG NEW”), 4-pent-CBGA (low) treated TG mice, and 4-pent-CBGA (high) treated TG mice; observations were recorded and are shown in FIG. 7b. N: Control = 6; TG = 4; 4-pent-CBGA (low) = 6; 4-pent-CBGA (high) = 4.5XFAD mice: male, age: 4.5 months. Error bar: SEM. Untreated TG mice demonstrated no preference for new objects (number of visits); however, the total time spent at new objects was lower compared to control (normal, wild-type) mice. [00184] The Control OLD group spent the same amount of time at objects in the environment, about 1.0 relative time compared to previous control with the old. The Control NEW group spent more time at the new object in the environment than the old object, or about 1.6 relative time compared to Control OLD. The untreated TG group (TG NEW) spent less time at the new object compared to the control group at the new object; the TG group (untreated) spent about 1.2 relative time compared to Control OLD. In other words, the TG mice (untreated) had little or no preference between an old or new object. When the new object was placed into the treated group environments, 4-pent-CBGA (low) treated TG mice performed similarly to Control OLD (about 1.0 relative time compared to Control OLD), and 4-pent-CBGA (high) treated TG mice performed similarly to the healthy control new mice (Control NEW) (about 1.4 relative time compared to control old). [00185] These results show that control (wild-type) mice (Control NEW) prefer new objects compared to the untreated TG mice (TG NEW). Without wanting to be bound by theory, this observed behavior may be due to the mice’s exploratory nature. The untreated TG mice (TG NEW) demonstrated a lower preference for new objects as the total time spent at new objects was lower compared to control (wild-type) mice (Control NEW). The 4-pent-CBGA (high) treated TG mice had similar behavior as the wild-type mice (Control OLD). Thus, it was observed that an increased -45- 1102826385\4\AMERICAS dose of 4-pent-CBGA (high) mice versus 4-pent-CBGA (low) mice improved cognitive and function and memory (post 2 hours exposure). [00186] Behavior Test 3: 24-hour new object recognition (cognitive function and memory) [00187] The cognitive function and memory test was conducted twenty-four hours after the initial familiarization (of the object at time zero). The mice were reintroduced to the box, which contained the original object along with a novel object, different from the one used in the short- term memory assessment. Memory was measured as the preference in the amount of time spent exploring the novel object over the amount of time spent exploring the old object (novel object preference). Exploration was defined as when the mouse paused and sniffed the object. The results are illustrated in FIG.8b. The tests with the new object were performed with control mice (healthy, wild-type), untreated TG mice, 4-pent-CBGA (low) treated TG mice, and 4-pent-CBGA (high) treated TG mice; observations were recorded and are shown in FIG.8b. N: Control = 6; TG = 4; 4-pent-CBGA (low) = 4; 4-pent-CBGA (high) = 3.5XFAD mice: male, age 4.5 months. Error bar: SEM. Untreated TG mice demonstrated no preference for new objects in terms of number of visits; however, time spent at object(s) decreased. [00188] The Control OLD group spent the same amount of time at objects in their environment, about 1.0 relative time compared to previous control with the old. The Control NEW group spent more time at the new object in the environment compared to the old object, or from about 1.2 to about 1.4 relative time compared to Control OLD. The untreated TG group spend less time at the new object compared to the control group at the new object (Control NEW); the untreated TG group spent from about 0.8 to about 1.0 relative time compared to Control OLD. In other words, the untreated TG mice had little or no preference between an old or new object. When the new object was placed into the treated group environments, both 4-pent-CBGA (low) and 4-pent-CBGA (high) TG mice performed similarly to the Control NEW mice (from about 1.2 to about 1.4 relative time compared to Control OLD). [00189] These results reaffirm that healthy wild-type mice prefer new objects compared to the untreated TG mice. The untreated 5XFAD (TG) mice demonstrated a lower preference for new objects as the total time spent at new objects was lower compared to healthy wild-type mice. The 4-pent-CBGA (low) and 4-pent-CBGA (high) TG mice remembered the object they had observed before the new object was placed in their environment and they exhibited similar behavior as the healthy wild-type mice. Thus, it was observed that that TG mice treated with 4-pentenyl-CBGA in dosage ranges from 10 to 40 mg/kg improved cognitive and function and memory (post 24 hours exposure). -46- 1102826385\4\AMERICAS [00190] Behavior Test 4: acoustic startle (sound awareness) [00191] To determine the effects of hearing loss in conjunction with Alzheimer’s, a pre-pulse inhibition or acoustic startle (sound awareness) test was performed. Pre-pulse inhibition of the acoustic startle reflex is a tool that measures detection thresholds in animals that are awake. In these tests, hearing loss correlated with neuronal loss. The acoustic startle test was employed to assess the startle response to an auditory signal and to evaluate sensorimotor gating, known as pre- pulse inhibition. Mice were placed in a compact holding chamber within the larger startle device. Following this, they were exposed to auditory cues ranging from 70-120 dB to elicit a startle reaction, which was determined based on their movements. Pre-pulse inhibition was ascertained using pairs of sound cues, where a less intense sound immediately came before a more intense one. A demonstration of pre-pulse inhibition was when mice exhibited a diminished startle to the subsequent sound compared to their reaction to the same sound when presented by itself. The mice underwent a singular testing session lasting 16 minutes, during which 32 trials featuring varied auditory signals were executed. Hearing dysfunction was measured as the maximum startle response (Vmax), and the percent pre-pulse inhibition (PPI), calculated using the formula 100 − [(Vmax of PPI trials/Vmax of startle alone trials) × 100]. The results are illustrated in FIG.9. [00192] As shown in FIG. 9, untreated TG mice tested at about 25-30% PPI (78 decibel “dB” sound pressure level “SPL”) compared to control mice that tested at about 50-55% PPI (78 dB SPL) in these experiments.4-pent-CBGA (low) mice and 4-pent-CBGA (high) TG mice tested at about 40-50% PPI (78 dB SPL). In sum, TG mice when treated with 4-pentenyl-CBGA showed improvement in startle response, which implicated a reduction in neuronal loss in brain olfactory zones. N = 4-6 animals in a group. Error bar: SEM. Example 5: RNA sequence profile [00193] To determine whether an RNA sequence profile of the brain samples complimented the behavioral results with 4-pentenyl-CBGA, several genes related to Alzheimer’s disease were found to be altered statistically significant and observed for changes (e.g., upregulation, downregulation, etc.). [00194] Methodology: RNA Isolation and Quality Control: Total RNA was extracted from the cortical brain tissues using the Qiagen RNeasy Kit (Qiagen, Hilden, Germany) according to the manufacturer's instructions. Quality control assessments for RNA integrity and purity were performed using Agilent 2100 bioanalyzer. Samples with an RNA Integrity Number (RIN) of 9 or greater were used. [00195] RNA-seq library prep and Transcriptome Analysis: The mRNA libraries were prepared using Illumina® Stranded mRNA library prep kit (cat# 20040534). The miRNA libraries were -47- 1102826385\4\AMERICAS prepared using OTTR cDNA library construction kit. The libraries were sequenced using a high- throughput Illumina sequencing platform, NextSeq 550 system, to generate paired-end reads (2 x 150bp). The quality of the reads was controlled using FastQC tool. Reads were mapped to the genome (UCSC hg38) using TopHat2, and the transcripts were quantified using Cufflinks. Differential expression (DE) analysis was performed using Cuffdiff2 to identify AD-related genes that are differentially expressed between control (healthy, wild-type) mice, untreated TG mice, and 4-Pent-CBGA treated TG mice. Based on the evidence implicating specific toxicogenomics targets, genes involved in inflammation and neuronal health were performed. [00196] Pathway Enrichment Analysis: GSEA was used to perform the Gene Set Enrichment Analysis on the differentially expressed genes to detect enriched biological and cellular pathways. [00197] The RNA in these sequence profiles correlated to inflammatory genes and neuronal health. When untreated TG mice were tested, RNA associated with inflammation were found in greater concentrations (upregulated) compared to control (healthy, wild-type). In untreated TG mice, RNA associated with neuronal health were found in lesser concentrations (downregulated) compared to control (healthy, wild-type). In other words, the control mice retained genes and RNA production of the wild type whereas the untreated TG mice displayed RNA production similar to Alzheimer’s disease. [00198] In TG mice that were treated with 4-pentenyl-CBGA (4-pent-CBGA (low) mice and 4-pent-CBGA (high) mice), the RNA sequence profile showed that inflammation pathways were downregulated (downregulation of inflammation markers), and that neuronal health pathways were upregulated (upregulation of neuronal functional markers) compared to untreated TG mice. Specifically, proinflammatory genes were elevated and neuronal function genes were reduced for the untreated TG group compared to control (normal wild-type) mice. For the 4-pent-CBGA (low) group, pro-inflammatory genes were reduced compared to TG. For the 4-pent-CBGA (high) group, the pro-inflammatory genes were reduced and neuronal function genes were elevated compared to untreated TG. These data are consistent with behavioral study data. These results may also show that neurological pathways were preserved in the 4-pent-CBGA treated mice. [00199] It was confirmed that the results of the behavioral tests described in Example 4 were supported by the RNA sequence profile studies. Example 6: GFAP levels in brain [00200] GFAP is associated with inflammatory response in Alzheimer’s disease. For example, when ß-Amyloid is present, glial cells are activated and an inflammatory response releases GFAP in the brain. In these studies, the concentration of glial fibrillary acidic protein level (GFAP) in the brain was compared between the control mice (normal, wild-type), untreated TG mice, -48- 1102826385\4\AMERICAS 4-pent-CBGA (low) treated TG mice, and 4-pent-CBGA (high) treated TG mice. Post-treatment, mice brains were collected and dissected to separate cortical regions. Tissue was washed in cold phosphate buffer saline (PBS) and lysed using lysis buffer (10% v/v) containing a protease- phosphatase inhibitor mixture (1% v/v). The homogenates were centrifuged, supernatants were collected, and the protein concentration was determined using the Bio-Rad protein assay (Bio-Rad Laboratories, Mississauga, ON, Canada). Whole cortical tissue lysates (15 μgs protein) were solubilized in Laemmli sample buffer (Bio-Rad Laboratories, Mississauga, ON, Canada) containing 5% β-mercaptoethanol were fractionated on SDS-PAGE and transferred onto a nitrocellulose membrane. The membranes were blocked with 5% skim milk in Tris-buffered saline with 0.2% Tween 20 for 1 hr at RT and incubated overnight with GFAP antibody (1:500). Post- incubation, the membranes were washed and incubated with species-specific (HRP)-conjugated secondary antibody (1:1000) for 2 hours at room temperature (RT). The membranes were washed and developed with HRP-chemiluminescence substrates and photographed using FluorChem software (Alpha Innotech, San Jose, CA, USA) on the Alpha Innotech imaging system. β-actin (1:5000) was used as the loading control, and densitometric analysis was performed using the FluorChem software. The results (FIG. 10) showed that 4-pentenyl-CBGA administered to TG mice reduced GFAP concentration in the brain in a dose dependent manner. Example 7: ß-Amyloid concentration in cortex [00201] The concentration of ß-Amyloid in the cortex was compared between the control mice (normal, wild-type), untreated TG mice, 4-pent-CBGA (low) treated TG mice, and 4-pent-CBGA (high) treated TG mice. Post in vivo treatment, mice brains were collected and dissected to separate cortical regions. Tissue was washed in cold PBS and lysed using lysis buffer (10% v/v) containing a protease-phosphatase inhibitor mixture (1% v/v). The homogenates were centrifuged, supernatants were collected, and the protein concentration was determined using the Bio-Rad protein assay (Bio-Rad Laboratories, Mississauga, ON, Canada). ELISA was performed as per the manufacturer's instructions (FastScan™ β-Amyloid (1-40) ELISA Kit #20882). Briefly, 50 μL of sample or Positive Control was added to the corresponding well, followed by the Antibody Cocktail (50 μL). The plate was incubated for 1 hour at RT on a plate shaker set to 400 rpm. Post incubation, the plate was washed three times, and 100 μL of TMB Substrate was added to a well, followed by 100 μL of STOP Solution to end the reaction. The plate was read at 450 nm within 30 min after adding STOP Solution using a spectrophotometer (BMG Labtech). The results were normalized to the control as shown in FIG.11. It was shown that TG mice treated with 4-pentenyl- CBGA reduced the ß-Amyloid concentration in the cortex in a dose dependent manner. Further, -49- 1102826385\4\AMERICAS treated 4-pent-CBGA (low) and 4-pent-CBGA (high) groups may show less accumulation of ß-Amyloid in the mice brain. Example 8: PS19 Tau model [00202] Longer-term studies includes behavioral tests to determine, e.g., cognitive function and memory, and additional biological (molecular) endpoints. An appropriate Alzheimer’s disease in- vivo model such as PS19 mice (also known as B6;C3-Tg(Prnp-MAPT*P301S)PS19Vle/J; The Jackson Lab: Stock# 008169) is used. These animals at age groups 1-3 months represent the stages with no plaques or NFTs formation, whereas animals aged 3 - 6 months display tau seeding activity and further tau aggregation as an early phenotype in this model (Holmes et al., 2014). Moreover, cognitive impairment, including spatial learning and memory impairment (Takeuchi et al., 2011), motor deficits progress, and paralysis at 7 to 10 months are observed as well (Yoshiyama et al., 2007). [00203] For the administration of cannabinoids, sex and age-matched genotype and their wild- type littermate (age group 1-3 months) receive intraperitoneal (i.p.) injections or oral gavage of optimum cannabinoid doses every alternate day for 3-6 months. [00204] Cannabinoid-injected PS19 and wild-type mice at the ages of 6 and 9 months are used to compare behavioral changes (spatial learning and memory) and motor responses associated with the progressive transition of AD pathogenesis. [00205] To establish a functional and pathological correlation between AD and the endocannabinoid system, Tau hyperphosphorylation and CB1R/CB2R expression in cortical and hippocampal tissue extracts are analyzed using ELISA, immunohistochemistry, and Western blots in 3, 6, and 9-month-old control and cannabinoid-infused PS19 and wild-type mice. [00206] For evaluating neuro-inflammation, hippocampal cytokines IL-1β, IL-6, and TNFα levels as well as microgliosis in 3, 6, and 9-month-old pS19 mice and age-matched wild type (WT) mice treated with vehicle or 4-pent-CBGA are determined by using ELISA analysis. [00207] For neuritogenesis as an indicator of functional integration of neurons into the hippocampal trisynaptic circuit as well as the recovery of NFT-damaged neurons under in wild- type and AD transgenic mice, RNAseq analysis is performed to determine the changes in the expression of genes such as CLDN11, ATP8B1, ITGA3, CD9, CRIM1 and NTN4 etc. Moreover, the expression of microtubule-binding proteins such as Synaptophysin Lis-1, DCX, and Map2c that help bundle the microtubules in growing neurites is determined by immunofluorescence immunity chemistry in the mice brain sections. Example 9: Receptor interaction studies -50- 1102826385\4\AMERICAS [00208] The interaction of 4-pentenyl-CBGA with different receptors was assessed by various assay methods. [00209] The interaction of 4-pentenyl-CBGA with the CB1 and CB2 receptors using cAMP as an assay marker was assessed using the HitHunter(R) cAMP assay. Briefly, cAMP Hunter cell lines expressing either the CB1 or the CB2 receptor were assessed via the DiscoverX HitHunter cAMP XS+ assay. To assess agonist behavior (Gs agonist format), cells were incubated with sample to induce a response, media was aspirated and replaced with HBSS/Hepes buffer containing cAMP XS+ Ab reagent, then 5 µL of 4X sample was added to the cells and incubated at 37 ^oC or room temperature for 30 or 60 minutes with a vehicle concentration of 1%. To assess agonist behavior (Gi agonist format), cells were incubated in the presence of EC80 forskolin to induce a response, media was aspirated and replaced with HBSS/Hepes buffer containing cAMP XS+ Ab reagent, then 5 µL of 4X sample with 4X EC80 forskolin was added to the cells and incubated at 37 ^oC or room temperature for 30 or 60 minutes with a vehicle concentration of 1%. To assess antagonist behavior, cells were pre-incubated with sample followed by an agonist challenge at the EC80 concentration, media was aspirated and replaced with HBSS/Hepes buffer containing cAMP CS+ Ab reagent, then 5 µL of 4X of the sample compound was added to the cells and incubated at 37 ^oC or room temperature for 30 minutes, followed by addition of 5 µL of EC80 agonist and incubation at 37 ^oC or room temperature for 30 or 60 minutes with a vehicle concentration of 1%. For GI coupled GPCRs, EC80 forskolin was included in the antagonist assay. For signal detection for either assay, 20 µL of cAMP XS+ ED/CL lysis cocktail was added and incubated for one hour followed by addition of 20 µL cAMP CS+ EA reagent and incubation at room temperature for 3 hours. Microplates were read for chemiluminescent detection. [00210] The interaction of 4-pentenyl-CBGA with the CB1 and CB2 receptors using Arrestin as an assay marker was assessed using the PathHunter(R) β-Arrestin assay from Eurofins DiscoverX Corp. [00211] The interaction of 4-pentenyl-CBGA with PPARγ, PPARα and PPARδ was assessed using the PathHunter(R) Nuclear Hormone Receptor Protein Interaction (Pro) assay. Briefly, for agonist determination, PathHunter NHR cell lines were incubated with sample, then 5 µL of 5X sample was added to the cells and incubated at 37 ^oC or room temperature for 3-16 hours with a final vehicle assay concentration of 1%. For antagonist determination, cells were pre-incubated with antagonist followed by agonist challenge at the EC80 concentration, then 5 µL of 5X sample was added to the cells and incubated at 37 ^oC or room temperature for 60 minutes with a final vehicle assay concentration of 1%, followed by addition of 5 µL of EC80 agonist in assay buffer and incubation at 37 ^oC or room temperature for 3-16 hours. Assay signal was generated by addition -51- 1102826385\4\AMERICAS of 12.5 or 15 µL of PathHunter detection reagent cocktail and incubation for one hour at room temperature followed by microplate reading for chemiluminescent detection. [00212] Data on receptor interactions using Eurofins Bioassays are provided in Table 1 as follows: Table 1: 4-pentenyl-CBGA Receptor Interaction Data Receptor Assay Type Agonist EC50 Antagonist IC50 (µM) (µM) [0021

e es g y, ese a a s o a -pe e y- s a seec e as 1R and CB2R agonist for the cAMP signaling pathway, with a strong bias for CB2R. However, it is neither a CB1R or CB2R agonist nor an antagonist for the ß-arrestin signaling pathway. In addition, it is a PPARγ agonist but a PPARα and δ antagonist. [00214] Previously, CBGA has been shown to be a strong CB1R agonist for the cAMP signaling pathway and a weak agonist for the ß-arrestin signaling pathways, whereas a weak agonist of CB2R for both the cAMP and the ß-arrestin signaling pathways. Furthermore, CBGA is a PPARα and PPARγ agonist. THC has been shown to be a strong CB1R and CB2R agonist for the ß-arrestin signaling pathway. THC is also a strong CB1R agonist but a weak CB2R agonist for the cAMP signaling pathway. THC is also a PPARγ agonist. Relative to THC, CBD is a weak CB1R and CB2R agonist for both cAMP and the ß-arrestin signaling pathways and a PPARγ agonist. (Navarro et al. Pharmacological Research.2020; 159:104940; O'Sullivan et al. BBRC.2005;337(3):824–831; Khosropoor et al. Phytomedicine 2023; 114:154771). [00215] These data and disclosure demonstrate a compound of Formula I that can be systemically delivered across the blood-brain-barrier, potentially by oral ingestion; demonstrates, in vitro, neuroprotection and neurogenesis; and demonstrates, in vivo, improvements in locomotion, cognition, memory, reduced neuroinflammation, and increased neuronal functional improvement. In addition, 4-pentenyl-CBGA demonstrates decreased cytotoxicity. -52- 1102826385\4\AMERICAS * * * [00216] The inventions illustratively described herein can suitably be practiced in the absence of any element or elements, limitation or limitations not specifically disclosed herein. Thus, for example, the terms “comprising,” “including,” “containing,” etc. shall be read expansively and without limitation. Additionally, the terms and expressions employed herein have been used as terms of description and not of limitation, and there is no intention in the use of such terms and expressions of excluding any equivalents of the future shown and described or any portion thereof, and it is recognized that various modifications are possible within the scope of the invention claimed. [00217] Thus, it should be understood that although the present invention has been specifically disclosed by preferred embodiments and optional features, modification and variation of the inventions herein disclosed can be resorted by those skilled in the art, and that such modifications and variations are considered to be within the scope of the inventions disclosed herein. The inventions have been described broadly and generically herein. Each of the narrower species and sub-generic groupings falling within the scope of the generic disclosure also form part of these inventions. This includes the generic description of each invention with a proviso or negative limitation removing any subject matter from the genus, regardless of whether or not the excised materials specifically resided therein. [00218] In addition, where features or aspects of an invention are described in terms of the Markush group, those skilled in the art will recognize that the invention is also thereby described in terms of any individual member or subgroup of members of the Markush group. It is also to be understood that the description herein is intended to be illustrative and not restrictive. Many embodiments will be apparent to those of in the art upon reviewing the description herein. The scope of the invention should, therefore, be determined not with reference to the description herein but should instead be determined with reference to the appended claims, along with the full scope of equivalents to which such claims are entitled. The disclosures of all articles and references, including patent publications, are incorporated herein by reference. -53- 1102826385\4\AMERICAS

Claims

What is claimed is: 1. A method of treating a patient with a neuronal disorder, a method of protecting a neuron from neurodegeneration, or a method of inducing neuritogenesis, the method comprising administering a therapeutically effective amount of a compound of Formula I, or a pharmaceutically acceptable salt thereof; or administering a therapeutically effective amount of a pharmaceutical composition comprising a compound of Formula I, or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier, wherein the compound of Formula I is according to: ;

R³ is H, CH₃, or CH₂CH₃, provided that when m is 1, R³ is CH₃ or CH₂CH₃; and wherein R³ is H, there is no cis or trans at bond b.

2. The method of claim 1, wherein the compound of Formula I is a compound of Formula II:

or a pharmaceutically acceptable salt thereof.

3. The method of claim 1 or 2, wherein R² contains a total of 4, 5, 6, 7, or 8 carbon atoms.

4. The method of any one of claims 1 to 3, wherein R² contains a total of 5, 6, 7, or 8 carbon atoms.

5. The method of any one of claims 1 to 4, wherein R² contains a total of 5 carbon atoms.

6. The method of any one of claims 1 to 5, wherein R³ is H.

7. The method of any one of claims 1 to 5, wherein R³ is CH3. -54- 1102826385\4\AMERICAS

8. The method of any one of claims 1 to 5, wherein R³ is CH2CH3.

9. The method of any one of claims 1 to 8, wherein bond b in R² is trans.

10. The method of any one of claims 1 to 8, wherein bond b in R² is cis.

11. The method of claim 1, wherein the compound of Formula (I) is selected from the group consisting of: OH O or

12. The method of claim 1, wherein the compound of Formula (I) is selected from the group consisting of:

or a pharmaceutically acceptable salt thereof.

13. The method of claim 1, wherein the compound of Formula (I) is: OH O O^H ; or a pharmaceutically

14. The method of any one of claims 1-13, wherein the compound of Formula (I) or (II) is not a pharmaceutically acceptable salt.

15. The method of any one of claims 1-13, wherein the compound of Formula (I) or (II) is a pharmaceutically acceptable salt thereof.

16. The method of any one of claims 1 to 15, wherein the method comprises inducing neuritogenesis.

17. A pharmaceutical composition comprising a therapeutically effective amount of a compound of Formula I:

or a pharmaceutically acceptable salt thereof; and a pharmaceutically acceptable carrier; wherein, wherein

m is an integer selected from 1 to 6; and R³ is H, CH3, or CH2CH3, provided that when m is 1, R³ is CH3 or CH2CH3; and wherein R³ is H, there is no cis or trans at bond b.

18. The pharmaceutical composition of claim 17, wherein the compound of Formula I is a compound of Formula II: -56- 1102826385\4\AMERICAS or a pharmaceutically acceptable salt thereof.

19. The pharmaceutical composition of claim 17 or 18, wherein R² contains a total of 4, 5, 6, 7, or 8 carbon atoms.

20. The pharmaceutical composition of any one of claims 17 to 19, wherein R² contains a total of 5, 6, 7, or 8 carbon atoms.

21. The pharmaceutical composition of any one of claims 17 to 20, wherein R² contains a total of 5 carbon atoms.

22. The pharmaceutical composition of any one of claims 17 to 21, wherein R³ is H.

23. The pharmaceutical composition of any one of claims 17 to 21, wherein R³ is CH3.

24. The pharmaceutical composition of any one of claims 17 to 21, wherein R³ is CH2CH3.

25. The pharmaceutical composition of any one of claims 17 to 24, wherein bond b in R² is trans.

26. The pharmaceutical composition of any one of claims 17 to 24, wherein bond b in R² is cis.

27. The pharmaceutical composition of claim 17, wherein the compound of Formula (I) is selected from the group consisting of: OH O

7); or a pharmaceutically

28. The pharmaceutical composition of claim 17, wherein the compound of Formula (I) is selected from the group consisting of: OH O OH O or a

29. The pharmaceutical composition of claim 17, wherein the compound of Formula (I) is: OH O ; or a pharmaceutically

30. The pharmaceutical composition of any one of claims 17 to 29, wherein the compound of Formula (I) or (II) is not a pharmaceutically acceptable salt.

31. The pharmaceutical composition of claim 17 to 29, wherein the compound of Formula (I) or (II) is a pharmaceutically acceptable salt.

32. The pharmaceutical composition of any one of claims 17 to 31, wherein the concentration of the compound is from 1 to 30 µM in contact with the target neuron or target neuronal population.

33. The pharmaceutical composition of any one of claims 17 to 31, wherein the concentration of the compound is systemic concentration from about 0.5 mg/kg to about 6 mg/kg.

34. The method of any one of claims 1-16, wherein the neuronal disorder is Alzheimer’s disease. -58- 1102826385\4\AMERICAS

35. The method of any one of claims 1-16 and 34, wherein a therapeutically effective amount of a pharmaceutical composition according to any one of claims 17 to 33 is administered. -59- 1102826385\4\AMERICAS