Parenteral formulations of cb1 inhibitors and methods of use

Abstract

Provided herein are methods of treating cannabinoid-induced toxicity. Further provided herein are injectable compositions for treating acute cannabinoid overdose, poisoning, or acute cannabinoid-induced CNS depression. Further provided herein are methods of treating cannabinoid-induced toxicity in pediatric patients.

Description

PARENTERAL FORMULATIONS OF CB1 INHIBITORS AND METHODS OF USE CROSS-REFERENCE

[0001] This application claims the benefit of U.S. Provisional Application No.63 / 579,413, filed August 29, 2023, which is incorporated herein by reference in its entirety. BACKGROUND

[0002] The widespread use of Δ9-tetrahydrocannabinol (THC) and synthetic cannabinoids (SCs) has resulted in an increased number of emergency room visits secondary to symptoms of cannabinoid toxicity; this is especially notable after cannabis is legalized in a jurisdiction. A medical need therefore exists to treat THC and SC related-overdoses. BRIEF SUMMARY

[0003] Provided herein are formulations and methods for treating cannabinoid-related diseases or disorders. Provided herein are formulations and methods for treating cannabinoid toxicity via parenteral administration. Provided herein are formulations and methods for treating cannabinoid intoxication, cannabinoid overdose, or cannabinoid poisoning via parenteral administration. Provided herein are formulations and methods for treating acute cannabinoid intoxication (ACI), acute cannabinoid overdose (ACO), or cannabinoid poisoning via parenteral administration.

[0004] Provided herein are pharmaceutical compositions configured for parenteral administration comprising a compound having the structure:least one excipient, wherein the parenteral formulation comprises a nanosuspension, oil and water emulsion, liposome, or micelle. Further provided herein are pharmaceutical composition wherein Further provided herein are pharmaceutical composition wherein the parenteral formulation comprises a liposome. Further provided herein are pharmaceutical composition wherein the at least one excipient comprises a lipid. Further provided herein are pharmaceutical composition wherein the at least one excipient comprises a phospholipid. Further provided herein are pharmaceutical composition wherein the at least one excipient comprises a phosphatidylcholine. Further provided herein are pharmaceutical composition wherein the at least one excipient comprises a diacylglycerolphospholipid. Further provided herein are pharmaceutical composition wherein the at least one excipient comprises 1,2-distearoyl-sn-glycero-3-phospho-rac-glycerol (DSPG), cholesterol, hydrogenated soybean phosphatidylcholine (HSPC), 1-palmitoyl-2-oleoyl-sn-glycero-3- phosphocholine (POPC), phosphatidylcholine, dimyristoylphosphatidylglycerol (DMPG), or a salt thereof. Further provided herein are pharmaceutical composition wherein the formulation comprises at least two excipients selected from the group consisting of 1,2-distearoyl-sn-glycero-3- phospho-rac-glycerol (DSPG), cholesterol, hydrogenated soybean phosphatidylcholine (HSPC), 1- palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine (POPC), phosphatidylcholine, dimyristoylphosphatidylglycerol (DMPG) and any salts thereof. Further provided herein are pharmaceutical composition wherein the phosphatidylcholine is obtained from hen egg yolk, soybeans, Non-GMO Soybeans, sunflowers, or is synthetically produced. Further provided herein are pharmaceutical composition wherein the phosphatidylcholine has a purity of at least 80%. Further provided herein are pharmaceutical composition wherein the phosphatidylcholine has a purity of at least 94%. Further provided herein are pharmaceutical composition wherein the phosphatidylcholine is sold under the trade name LIPOID E 80 or LIPOID S 100 by Lipoid GmbH. Further provided herein are pharmaceutical composition wherein the ratio of compound to lipid is 1:5 to 1:25 (w / w). Further provided herein are pharmaceutical composition wherein the first excipient comprises Lipoid S 100 and the second excipient comprises DMPG, wherein the weight ratio of the first excipient to the second excipient is about 97:3. Further provided herein are pharmaceutical composition wherein the ratio of the first excipient to the second excipient is about 90:10 to about 99:1. T Further provided herein are pharmaceutical composition wherein the first excipient comprises HSPC, DMPC, phosphatidylcholine, DOPG, POPC, or a salt thereof. Further provided herein are pharmaceutical composition wherein the first excipient comprises HSPC, DMPC, soybean phosphatidylcholine, DOPG, POPC, or a salt thereof. Further provided herein are pharmaceutical composition wherein the second excipient comprises DSPG, DMPG, DMPC, or a salt thereof. Further provided herein are pharmaceutical composition wherein the pharmaceutical composition comprises about 10-50 mg / mL phospholipid. Further provided herein are pharmaceutical composition wherein the compound is present at about 0.5-10 mg / mL. Further provided herein are pharmaceutical composition wherein the compound is present at about 2mg / mL or about 3 mg / mL. Further provided herein are pharmaceutical composition wherein the pharmaceutical composition comprises a buffer. Further provided herein are pharmaceutical composition wherein the buffer comprises at least one phosphate. Further provided herein are pharmaceutical composition wherein the at least one phosphate comprises sodium phosphate dibasic, potassium phosphate monobasic, or a combination thereof. Further provided herein arepharmaceutical composition wherein the buffer comprises an excipient. Further provided herein are pharmaceutical composition wherein the buffer comprises a stabilizer. Further provided herein are pharmaceutical composition wherein the stabilizer comprises a sugar. Further provided herein are pharmaceutical composition wherein the sugar comprises sucrose, glucose, lactose, trehalose, or maltose. Further provided herein are pharmaceutical composition wherein the buffer has a pH of about 7-8. Further provided herein are pharmaceutical composition wherein the buffer is isotonic. Further provided herein are pharmaceutical composition wherein the pharmaceutical composition comprises an average particle size of no more than 200 nm. Further provided herein are pharmaceutical composition wherein the pharmaceutical composition comprises an average particle size of about 100-300 nm. Further provided herein are pharmaceutical composition wherein the pharmaceutical composition comprises a polydispersity index (PDI) of no more than 0.2. Further provided herein are pharmaceutical composition wherein the pharmaceutical composition comprises a polydispersity index (PDI) of about 0.1 to about 0.3. Further provided herein are pharmaceutical composition wherein the pharmaceutical composition is a solid. Further provided herein are pharmaceutical composition wherein the pharmaceutical composition is frozen. Further provided herein are pharmaceutical composition wherein the pharmaceutical composition is lyophilized. Further provided herein are pharmaceutical composition wherein the pharmaceutical composition is a liquid or solution. Further provided herein are pharmaceutical composition wherein the pharmaceutical composition is substantially free of crystals. Further provided herein are pharmaceutical composition wherein the pharmaceutical composition is substantially free of crystals as measured under light microscopy. Further provided herein are pharmaceutical composition wherein the pharmaceutical composition is substantially free of crystals after at least one week, one month, two months, six months, or at least a year. Further provided herein are pharmaceutical composition wherein the pharmaceutical composition is stable at room temperature for at least one week, one month, two months, six months, or at least a year. Further provided herein are pharmaceutical composition wherein the pharmaceutical composition is stable at no more than 0 degrees C for at least one week, one month, two months, six months, or at least a year. Further provided herein are pharmaceutical composition wherein the pharmaceutical composition is stable at no more than -20 degrees C for at least one week, one month, two months, six months, or at least a year. Further provided herein are pharmaceutical composition wherein the pharmaceutical composition is essentially unchanged at room temperature for at least one week, one month, two months, six months, or at least a year as measured by HPLC. Further provided herein are pharmaceutical composition wherein the pharmaceutical composition comprises no more than 5000 ppm residual solvent. Further provided herein are pharmaceutical composition wherein thepharmaceutical composition comprises no more than 5000 ppm residual ethanol. Further provided herein are pharmaceutical composition wherein the pharmaceutical composition comprises no more than 1500 ppm residual ethanol. Further provided herein are pharmaceutical composition wherein the parenteral formulation comprises a nanosuspension. Further provided herein are pharmaceutical composition wherein the at least one excipient comprises poloxamer 188, polyvinyl ketone (PVK) K17, PVK K30, or sodium deoxycholate. Further provided herein are pharmaceutical composition wherein the pharmaceutical composition comprises about 0.1-5% poloxamer 188. Further provided herein are pharmaceutical composition wherein the pharmaceutical composition comprises about 0.05-05% sodium deoxycholate. Further provided herein are pharmaceutical composition wherein the pharmaceutical composition comprises about 0.2-2% PVP K17 or PVP K30. Further provided herein are pharmaceutical composition wherein the compound is present at about 50-200 mg / mL. Further provided herein are pharmaceutical composition wherein the parenteral formulation comprises an oil and water emulsion. Further provided herein are pharmaceutical composition wherein the at least one excipient comprises an oil. Further provided herein are pharmaceutical composition wherein the excipient comprises soybean oil (SBO), Miglycol 812, olive oil, coconut oil, or a mixture thereof. Further provided herein are pharmaceutical composition wherein the pharmaceutical composition comprises soybean oil and at least one of coconut oil, olive oil, or Miglyol 812. Further provided herein are pharmaceutical composition wherein the pharmaceutical composition comprises about 5:1 to about 1:5 mixture of soybean oil to any one of coconut oil, olive oil, or Miglyol 812 Further provided herein are pharmaceutical composition wherein the compound is present at 5-20 mg / mL. Further provided herein are pharmaceutical composition wherein the parenteral formulation comprises micelles. Further provided herein are pharmaceutical composition wherein the parenteral formulation comprises a phospholipid. Further provided herein are pharmaceutical composition wherein the excipient comprises Miglyol 812, Lipoid E80, saline, or a combination thereof. Further provided herein are pharmaceutical composition wherein the pharmaceutical composition comprises about 0.5-3% Lipoid E80. Further provided herein are pharmaceutical composition wherein the compound is present at about 1-20 mg / mL. Further provided herein are pharmaceutical composition wherein the compound is present at about 1-5 mg / mL.

[0005] Provided herein are methods of treating a known or suspected acute cannabinoid toxicity in a subject in need thereof, the method comprising: administering to the subject a therapeutically- effective amount of a parenteral formulation of a compound having the structure:, wherein the parenteral formulation comprises a nanosuspension, oil and water emulsion, liposome, or micelle, and wherein treating improves one or more metrics associated with acute cannabinoid toxicity. Further provided herein are methods wherein the metric is measured by a healthcare provider or emergency responder. Further provided herein are methods wherein the metric is self-reported by the subject. Further provided herein are methods wherein the amount of compound administered to the subject is about 1 mg, about 5 mg, about 10 mg, about 15 mg, about 20 mg, about 30 mg or about 50 mg. Further provided herein are methods wherein the amount of compound administered to the subject is 1-200 mg, 1-10 mg, 1-25 mg, 5-20 mg, 10-50 mg, 10-30 mg, or 20-30 mg. Further provided herein are methods wherein the method further comprises administering 5-300 mg, 5-100 mg, or 10-30 mg of delta-9-tetrahydrocannabinol (THC) to the subject. Further provided herein are methods wherein the acute cannabinoid toxicity results from ingestion of an edible form of cannabis. Further provided herein are methods wherein the acute cannabinoid toxicity results from ingestion of a synthetic cannabinoid. Further provided herein are methods wherein the synthetic cannabinoid, edible form of cannabis, or THC is self- administered. Further provided herein are methods wherein the parenteral route of administration comprises intravenous (IV), intramuscular (IM), or subcutaneous (SC). Further provided herein are methods wherein the parenteral route of administration comprises intravenous (IV). Further provided herein are methods wherein intravenous (IV) comprises IV bolus, IV drip, or IV push. Further provided herein are methods wherein the pharmaceutical composition is delivered in a liquid volume of about 0.1-5 mL. Further provided herein are methods wherein the pharmaceutical composition is delivered in a liquid volume of about 50-1000 mL. Further provided herein are methods wherein the concentration the compound reaches a plasma concentration of at least 10, 25, 50, 100, 150, or at least 200 ng / mL within 10 minutes. Further provided herein are methods wherein the concentration the compound reaches a plasma concentration of at least 10, 25, 50, 100, 150, or at least 200 ng / mL within 5 minutes. Further provided herein are methods wherein the concentration the compound reaches a plasma concentration of at least 10, 25, 50, 100, 150, or at least 200 ng / mL within 2 minutes. Further provided herein are methods wherein the concentration the compound reaches a plasma concentration of at least 10, 25, 50, 100, 150, or at least 200 ng / mL within 60 seconds. Further provided herein are methods wherein the subject exhibits symptoms ofcannabinoid hyperemesis syndrome. Further provided herein are methods wherein the subject is experiencing one or more of nausea, vomiting, coughing, and choking. Further provided herein are methods wherein the subject is experiencing respiratory depression. Further provided herein are methods wherein the subject is experiencing anaphylactic shock. Further provided herein are methods wherein the subject is experiencing trauma or swelling to the face, mouth, throat, esophagus, or digestive tract. Further provided herein are methods wherein the subject is unwilling or unable to ingest an oral medicament. Further provided herein are methods wherein one or more symptoms of overdose are ameliorated in no more than 5 minutes. Further provided herein are methods wherein one or more symptoms of overdose are ameliorated in no more than 1 minute. Further provided herein are methods wherein the subject is a pediatric patient. Further provided herein are methods wherein the subject is selected from an adolescent, child, infant, or neonate. Further provided herein are methods wherein the patient is no more than 28 days, 2 years, 12 years, or 21 years old. Further provided herein are methods wherein the patient is 1-28 days old, 29 days to less than 2 years old, 2 years to less than 12 years old, or 12 years to less than 21 years old. Further provided herein are methods wherein the method further comprises monitoring the subject for improvement of cannabinoid overdose symptoms.

[0006] Provided herein are methods of manufacturing a pharmaceutical composition provided herein. Further provided herein are methods wherein the method comprises: preparing an organic phase; mixing the organic phase with an aqueous phase to generate a mixture; shearing the mixture; extruding the mixture; concentrating the mixture; and sterile-filtering the mixture. Further provided herein are methods wherein preparing the organic phase comprises: mixing the compound with a first excipient in a first solvent to generate a first solution; mixing a second excipient in a second solvent to generate a second solution; and combining the first solution and the second solution. Further provided herein are methods wherein the first solution is mixed at about room temperature. Further provided herein are methods wherein the second solution is mixed at about 40-60 degrees C. Further provided herein are methods wherein combining occurs at about room temperature. Further provided herein are methods wherein the aqueous phase comprises a buffer. Further provided herein are methods wherein shearing occurs at about 3000-5000 RPM with a square mixing screen. Further provided herein are methods wherein extruding comprises 1-2 passes through a 200 nm filter. Further provided herein are methods wherein concentrating comprises tangential flow filtration. Further provided herein are methods wherein the method further comprises freezing or lyophilizing after step (f).INCORPORATION BY REFERENCE

[0007] All publications, patents, and patent applications mentioned in this specification are herein incorporated by reference in their entireties to the same extent as if each individual publication, patent, or patent application was specifically and individually indicated to be incorporated by reference. DESCRIPTION OF THE DRAWINGS

[0008] The novel features of the present disclosure are set forth with particularity in the appended claims. An understanding of the features and advantages of the present disclosure may be obtained by reference to the following detailed description that sets forth illustrative embodiments, in which the principles of the present disclosure are utilized, and the accompanying drawings of which:

[0009] FIG.1 depicts two chromatograms, overlaid, showing the stability of the oil and water emulsion stability of ANEB-001 Lipoid E80-Miglyol 812N (1.2%w / v) 6mg / ml + blank, on Day 10, at 50°C. The x-axis is labeled Time (mins) from 0 to 9 at 1 unit intervals. The y-axis is mAU from - 100 to 500 at 100 unit intervals.

[0010] FIG.2 depicts a plot of two chromatograms, overlaid, showing the stability of the oil and water emulsion stability of ANEB-001 in Lipoid E80-Miglyol 812N (1.2%w / v), 6mg / ml + blank, Day 10, at 2-8°C. The x-axis is labeled Time (mins) from 0 to 9 at 1 unit intervals. The y-axis is mAU from -100 to 500 at 100 unit intervals.

[0011] FIG.3 depicts a plot of two chromatograms, overlaid, showing the stability of the oil and water emulsion stability of ANEB-001 in Lipoid E80-Miglyol 812N (1.2%w / v), 60mg / ml + blank, Day 10, at 50°C. The x-axis is labeled Time (mins) from 0 to 9 at 1 unit intervals. The y-axis is mAU from -100 to 500 at 100 unit intervals.

[0012] FIG.4 depicts a plot of two chromatograms, overlaid, showing the stability of the oil and water emulsion stability of ANEB-001 in Lipoid E80-Miglyol 812N (1.2%w / v), 60mg / ml + blank, Day 10, at 2-8°C. The x-axis is labeled Time (mins) from 0 to 9 at 1 unit intervals. The y-axis is mAU from -100 to 500 at 100 unit intervals.

[0013] FIG.5 depicts a plot of two chromatograms, overlaid, showing the stability of the oil and water emulsion stability of ANEB-001 in Lipoid E80-Miglyol 812N (1.2%w / v), 6 mg / ml + blank, Day 10, at 50°C. The x-axis is labeled Time (mins) from 0 to 9 at 1 unit intervals. The y-axis is mAU from -100 to 600 at 100 unit intervals.

[0014] FIG.6 depicts a plot of two chromatograms, overlaid, showing the stability of the oil and water emulsion stability of ANEB-001 in Lipoid E80-Miglyol 812N (1.2%w / v), 6 mg / ml + blank, Day 10, at 2-8°C. The x-axis is labeled Time (mins) from 0 to 9 at 1 unit intervals. The y-axis is mAU from -300 to 600 at 100 unit intervals.

[0015] FIG.7 depicts a plot of two chromatograms, overlaid, showing the stability of the oil and water emulsion stability of ANEB-001 in Lipoid E80-Miglyol 812N (1.2%w / v), 60mg / ml + blank, Day 14, at 50°C. The x-axis is labeled Time (mins) from 0 to 9 at 1 unit intervals. The y-axis is mAU from -100 to 600 at 100 unit intervals.

[0016] FIG.8 depicts a plot of two chromatograms, overlaid, showing the stability of the oil and water emulsion stability of ANEB-001 in Lipoid E80-Miglyol 812N (1.2%w / v), 60mg / ml + blank, Day 14, at 2-8°C. The x-axis is labeled Time (mins) from 0 to 9 at 1 unit intervals. The y-axis is mAU from -300 to 500 at 100 unit intervals.

[0017] FIG.9 depicts a plot of PSD (particle size distribution) analysis: 10% ANEB-001 in 1% PVP k17 and 0.15% Na Deoxy suspension (5⁰C; T1-week). The x-axis is labeled Diameter (microns) from 0.010 to 5000 at log10 unit intervals. The left y-axis is q (%) from 0 to 12 at 2 unit intervals. The right y-axis is undersize (%) from 0 to 100 at 10 unit intervals.

[0018] FIG.10 depicts a plot of PSD analysis: 10% ANEB-001 in 1% PVP k17 and 0.15% Na Deoxy suspension (25⁰C; T1-week). The x-axis is labeled Diameter (microns) from 0.010 to 5000 at log10 unit intervals. The left y-axis is q (%) from 0 to 12 at 2 unit intervals. The right y-axis is undersize (%) from 0 to 100 at 10 unit intervals.

[0019] FIG.11 depicts a plot of PSD analysis: 10% ANEB-001 in 1% PVP k17 and 0.20% Na Deoxy suspension 40 mg / mL (5⁰C; T1-week). The x-axis is labeled Diameter (microns) from 0.010 to 5000 at log10 unit intervals. The left y-axis is q (%) from 0 to 12 at 2 unit intervals. The right y- axis is undersize (%) from 0 to 100 at 10 unit intervals.

[0020] FIG.12 depicts a plot of PSD analysis: 10% ANEB-001 in 1% PVP k17 and 0.20% Na Deoxy suspension 40 mg / mL (25⁰C; T1-week). The x-axis is labeled Diameter (microns) from 0.010 to 5000 at log10 unit intervals. The left y-axis is q (%) from 0 to 12 at 2 unit intervals. The right y-axis is undersize (%) from 0 to 100 at 10 unit intervals.

[0021] FIG.13 depicts a PSD analysis: 10% ANEB-001 in 1% PVP k17 and 0.20% Na Deoxy suspension 100 mg / mL (5⁰C; T1-week). The x-axis is labeled Diameter (microns) from 0.010 to 5000 at log10 unit intervals. The left y-axis is q (%) from 0 to 12 at 2 unit intervals. The right y- axis is undersize (%) from 0 to 100 at 10 unit intervals.

[0022] FIG.14 depicts a plot of PSD analysis: 10% ANEB-001 in 1% PVP k17 and 0.20% Na Deoxy suspension 100 mg / mL (25⁰C; T1-week). The x-axis is labeled Diameter (microns) from 0.010 to 5000 at log10 unit intervals. The left y-axis is q (%) from 0 to 12 at 2 unit intervals. The right y-axis is undersize (%) from 0 to 100 at 10 unit intervals.

[0023] FIG.15 depicts a plot of compound 1 (ANEB-001) plasma pharmacokinetics for IV Bolus and IV infusion for a liposomal formulation (IV bolus, squares; IV infusion, circles) and emulsionformulation (triangles) of compound 1. The y-axis is labeled ANEB-001 concentration in plasma (ng / mL) from 1 to 10,000 at log10 unit intervals and the x-axis is labeled time (h) from 0 to 6 at 1 hour intervals.

[0024] FIG.16 depicts a plot of compound 1 (ANEB-001) plasma pharmacokinetics for IM administration for a liposomal formulation (squares), a nanosuspension formulation (inverted triangles) and an emulsion formulation (circles) of compound 1. The y-axis is labeled ANEB-001 concentration in plasma (ng / mL) from 1 to 1000 at log10 unit intervals and the x-axis is labeled time (h) from 0 to 24 at 6 hour intervals.

[0025] FIG.17 depicts a plot of compound 1 (ANEB-001) plasma pharmacokinetics for IM, IV and SC administration for a liposomal formulation (IV, squares; IM, triangles; SC, inverted triangles), of compound 1. The y-axis is labeled ANEB-001 concentration in plasma (ng / mL) from 1 to 10,000 at log10 unit intervals and the x-axis is labeled time (h) from 0 to 6 at 1 hour intervals.

[0026] FIG.18 depicts a plot of compound 1 (ANEB-001) plasma pharmacokinetics for IV administration for a liposomal formulation (squares) and an emulsion formulation (circles) of compound 1. The y-axis is labeled ANEB-001 concentration in plasma (ng / mL) from 1 to 10,000 at log10 unit intervals and the x-axis is labeled time (h) from 0 to 24 at 6 hour intervals.

[0027] FIG.19 depicts a plot of compound 1 (ANEB-001) plasma pharmacokinetics for IV (circles) and IM (inverted triangles) administration for an emulsion formulation of compound 1. The y-axis is labeled ANEB-001 concentration in plasma (ng / mL) from 1 to 10,000 at log10 unit intervals and the x-axis is labeled time (h) from 0 to 24 at 6 hour intervals.

[0028] FIG.20 depicts a plot of compound 1 (ANEB-001) plasma pharmacokinetics for IV (squares), SC (inverted triangles), IV infusion (diamonds) and IM administration (triangles) for an emulsion formulation of compound 1. The y-axis is labeled ANEB-001 concentration in plasma (ng / mL) from 1 to 10,000 at log10 unit intervals and the x-axis is labeled time (h) from 0 to 6 at 1 hour intervals. DETAILED DESCRIPTION

[0029] Provided herein are compositions and methods of treating cannabinoid toxicity. In some embodiments, cannabinoid toxicity comprises acute or chronic toxicity. In some embodiments, cannabinoid toxicity comprises acute cannabinoid overdose, acute cannabinoid poisoning, acute cannabinoid-induced CNS depression, or other cannabinoid-related toxicity. Further provided herein are metrics and assessments for identifying cannabinoid toxicity, and measuring amelioration of cannabinoid toxicity after treatment. Further provided herein are methods of treating acute cannabinoid toxicity caused by ingestion or inhalation of an edible form of cannabis.In some instances, ingestion or inhalation is intentional or accidental. In some instances, compositions and methods provided herein are used to treat pediatric patients. Cannabinoid Intoxication

[0030] Provided herein are methods for treating acute cannabinoid overdose via parenteral administration. Provided herein are metrics for measuring cannabinoid intoxication. In some instances, cannabinoid intoxication occurs from ingestion of an edible form of cannabis, cannabis extract, or synthetic cannabinoid. In some instances, metrics are used for determining if a patient is intoxicated with a cannabinoid. In some instances, metrics are used by healthcare providers to determine if a cannabinoid overdose treatment is provided. In some instances, metrics are used to measure the effect of treatment on a patient suffering from cannabinoid intoxication. In some instances, metrics are obtained at a first time before administration of a treatment (i.e., pre- administration) and later obtained at a second time after administration of the treatment. Changes in metrics in some instances guides treatment decisions (e.g., releasing the patient, providing a follow up dose of a CB1 inhibitor, or other action). Metrics may generally comprise physical measurements, self-reported assessments, or answers to other written or verbal questions (e.g., cognitive measurements). Any number of metrics may be used with the methods described herein, such as 1, 2, 3, 4, 5, 10, 15, 20, or more than 50 metrics. Metrics in some instances are compared to baseline or threshold levels established for a particular patient or patient population. In some instances, baseline or threshold levels take into consideration age, weight, sex, or other factor. In some instances, administration of a treatment (e.g., Compound 1) to a patient suffering from cannabinoid intoxication results in at least 5%, 10%, 15%, 20%, 25%, 30%, 40%, 50%, 75%, 100%, 200%, or more than 200% improvement in a metric relative to a baseline value. In some instances, improvements are defined as a metric’s value trending closer to a baseline value (e.g., sobriety). In some instances, administration of a treatment (e.g., Compound 1) to a patient suffering from cannabinoid intoxication results in about 5%, 10%, 15%, 20%, 25%, 30%, 40%, 50%, 75%, 100%, 200%, or about 200% improvement in a metric relative to a baseline value. In some instances, administration of a treatment (e.g., Compound 1) to a patient suffering from cannabinoid intoxication results in 5-200%, 5-100%, 5-80%, 5-50%, 5-25%, 10-200%, 10-100%, 10-75%, 20- 200%, 20-100%, 20-75%, 50-300%, 50-200%, 50-100%, 75-300%, 100-300%, or 150-300% improvement in a metric relative to a baseline value. In some instances, the improvement is realized no more than 8, 6, 5, 4, 3, 2.5, 2, 1.5, 1.2, 1.0, 0.8, or 0.5 hours after treatment. Metrics may be defined categorically (e.g., high, medium, or low), or on a continuous scale (e.g., VAS).

[0031] Physical measurements may be used to measure cannabinoid intoxication. In some instances, physical measurements are made directly on the patient. In some instances, physicalmeasurements are taken in response to specific actions or tasks given to the patient to complete. In some instances, physical measurements comprise measurement of body movement. In some instances, body movement comprises body sway or eye movement. In some instances, eye movement comprises Saccadic movement, adaptive tracking, or smooth pursuit. In some instances, body sway comprises antero-posterior sway. In a non-limiting measurement method, body sway is measured by a pot string meter (celesco). In a non-limiting measurement method, body sway is measured by a pot string meter based on the Wright ataxiameter (Bowdle, et al.). In an exemplary protocol with a string attached to the waist, all body movements over a period of time are integrated and expressed as mm sway. Subjects are instructed to wear a pair of comfortable, low-heeled shoes on each session. Before starting a measurement, subjects are asked to stand still and comfortable, with their feet approximately 10 cm part and their hands in a relaxed position alongside the body and eyes closed. Subjects may not talk during the measurement. The total period of body-sway measurement in some instances is two minutes. Physical measurements in some instances comprise heart rate, body temperature, blood pressure, or other physical measurement. In some instances, metrics comprise one or more of eye opening response, best motor response, and best verbal response. In some instances, administration of a treatment (e.g., Compound 1) to a patient suffering from cannabinoid intoxication results in at least 5%, 10%, 15%, 20%, 25%, 30%, 40%, 50%, 75%, 100%, 200%, or more than 200% improvement in a physical measurement relative to a baseline value. In some instances, improvements are defined as a metric’s value trending closer to a baseline value (e.g., sobriety). In some instances, administration of a treatment (e.g., Compound 1) to a patient suffering from cannabinoid intoxication results in about 5%, 10%, 15%, 20%, 25%, 30%, 40%, 50%, 75%, 100%, 200%, or about 200% improvement in a physical measurement relative to a baseline value. In some instances, administration of a treatment (e.g., Compound 1) to a patient suffering from cannabinoid intoxication results in 5-200%, 5-100%, 5-80%, 5-50%, 5-25%, 10- 200%, 10-100%, 10-75%, 20-200%, 20-100%, 20-75%, 50-300%, 50-200%, 50-100%, 75-300%, 100-300%, or 150-300% improvement in a physical measurement relative to a baseline value. In some instances, the improvement is realized no more than 8, 6, 5, 4, 3, 2.5, 2, 1.5, 1.2, 1.0, 0.8, or 0.5 hours after treatment.

[0032] Cognitive metrics may also be obtained for use with the methods described herein. Cognitive metrics in some instances are obtained by self-report via verbal interrogation of a subject, or by subject’s responses to a questionnaire. In some instances, questions are answered by the subject, and another party (healthcare provider, family member, emergency responder, or other third party) fills out the questionnaire. In some embodiments, a metric is measured by a healthcare provider or emergency responder. In some embodiments, a metric is measured by self-reporting.Questions may address any aspect of cognition experienced by the subject, including but not limited to intoxication, anxiety, alertness, mood, or internal / external perception. In some instances, questions are directed to one or more of orientation of person, place, time, and situation. In some instances, questions are directed to levels of the Glasgow coma scale. In some instances, treatment with CB1 inhibitors described herein (e.g., compound 1) improves a Glasgow coma metric by at least one level. In some instances, questions are directed to one or more of alertness / fuzzy / clearheaded, coordinate / clumsy, lethargic / energetic, contented / discontented, troubled / tranquil, mentally slow / quick witted, tense / relaxed, attentive / dreamy, drowsy, calm / excited, strong / feeble, incompetent / proficient, happy / sad, antagonistic / friendly, interested / bored, withdrawn / sociable, self-centered / outward going or depressed / elated. In some instances, metrics comprise measurement of working memory. In some instances, working memory is measured using an n-back test. In some instances, the n-back test comprises a zero back, one back, or two back test. In some instances, cognitive metrics are measured using a VAS (visual analog scale) measurement system. In some instances, VAS comprises choosing a position along a line wherein each end of the line comprises an opposing / opposite feeling or state (e.g., troubled vs. tranquil, calm vs. excited). In some instances, a metric comprises the distance along the line that is chosen. In some instances, the distance on the line is measured in metric units (e.g., centimeters or millimeters) or in English units (e.g., inches). In some instances, measurements comprise use of one or more questions from the sixteen questions of the Bond and Lader test. In some instances, measurements comprise use of one or more questions from the Bond and Lader test. In some instances, measurements comprise use of four or more questions from the Bond and Lader test. In some instances, measurements comprise use of six or more questions from the Bond and Lader test. In some instances, measurements comprise use of Bowdle scales. In some instances, administration of a treatment (e.g., Compound 1) to a patient suffering from cannabinoid intoxication results in about 5%, 10%, 15%, 20%, 25%, 30%, 40%, 50%, 75%, 100%, 200%, or about 200% improvement in a cognitive measurement relative to a baseline value. In some instances, administration of a treatment (e.g., Compound 1) to a patient suffering from cannabinoid intoxication results in 5-200%, 5-100%, 5-80%, 5-50%, 5-25%, 10-200%, 10-100%, 10-75%, 20- 200%, 20-100%, 20-75%, 50-300%, 50-200%, 50-100%, 75-300%, 100-300%, or 150-300% improvement in a cognitive measurement relative to a baseline value. In some instances, the improvement is realized no more than 8, 6, 5, 4, 3, 2.5, 2, 1.5, 1.2, 1.0, 0.8, or 0.5 hours after treatment.Compound 1

[0033] As described herein, Compound 1 (ANEB-001) refers to (R)-N-(tert-butyl)-3-((4- chlorophenyl)(2-(trifluoromethyl)phenyl)methoxy)azetidine-1-carboxamide, which has the chemical structure as shown below:p , a stereoisomer thereof or a pharmaceutically acceptable solvate or hydrate thereof.

[0034] Compound 1 is a CB1 modulator. CB1 modulators, such as a CB1 inhibitor, are useful in the treatment of various conditions and disorders, including but not limited to acute drug and cannabis overdose and cannabis use disorder.

[0035] The preparation and uses of Compound 1 have been previously described (see, Example 81 of US 7,504,522, which is incorporated by reference).

[0036] In some embodiments, compounds herein can include all stereoisomers, enantiomers, diastereomers, mixtures, racemates, atropisomers, and tautomers thereof.

[0037] In some embodiments, as disclosed herein, Compound 1 is crystalline.

[0038] As used herein, “crystalline form,” “polymorph,” “Form,” and “form” may be used interchangeably herein, and are meant to include all crystalline and amorphous forms of the compound, including, for example, polymorphs, pseudopolymorphs, salts, solvates, hydrates, unsolvated polymorphs (including anhydrates), conformational polymorphs, and amorphous forms, as well as mixtures thereof, unless a particular crystalline or amorphous form is referred to. Compounds of the present disclosure include crystalline and amorphous forms of those compounds, including, for example, polymorphs, pseudopolymorphs, solvates, hydrates, unsolvated polymorphs (including anhydrates), conformational polymorphs, and amorphous forms of the compounds, as well as mixtures thereof. In some embodiments, the crystalline form is a single solid state form. In some instances, method described herein comprises treatment with a crystalline form of Compound 1.

[0039] In some embodiments, additional compounds may be used alternatively, or in addition to Compound 1 in the parenteral (e.g., liposomal or other) formulations described herein. In some embodiments, the additional compounds comprise a CB1 modulator. In some embodiments, theCB1 modulator is a CB1 inhibitor. In some embodiments, the CB1 inhibitor comprises antagonist, inverse agonist, or reverse agonist. In some embodiments, the CB1 inhibitor comprises rimonabant, taranabant, MK-0364, AM251, AM1387, AM4113, cannabigerol, ibipinabant, otenabant, surinabant, tetrahydrocannabivarin and virodamine, TM-38837, AM6545, or a CB1 targeting- antibody. In some embodiments, the CB1 inhibitor comprises methylphosphonofluoridic acid 5,8,11,14-eicosatetraenyl ester (MAFP, CAS 188404-10-6), NESS 0327 (8-chloro-1-(2,4- dichlorophenyl)-1,4,5,6-tetrahydro-N-1-piperidinyl-benzo[6,7]cyclohepta[1,2-c]pyrazole-3- carboxamide, CAS 494844-07-4), AM-251 (CAS 183232-66-8), LY-320135 (CAS 176977-56-3), AM 281 (CAS 202463-68-1), MJ 15 (CAS 944154-76-1), amauromine (CAS 88360-87-6), AM 404 (183718-77-6), virodhamine hydrochloride (443129-35-9), NIDA-41020 (CAS 502486-89-7), SLV 319 (CAS 362519-49-1), URB447 (CAS 1132922-57-6), falcarinol (CAS 4117-12-8), CB-25 (CAS 869376-63-6), O-1821 (35482-50-9), or AVE-1625 (drinabant, CAS 358970-97-5. In some instances, the CB1 modulator comprises rimonabant, taranabant, surinabant or drinabant.

[0040] Provided herein are compounds having the structure of formula (I): whereinR1is aryl or heteroaryl; R2is alkyl, aryl or heteroaryl; R3is alkyl, aryl, heteroaryl, NR9R10, OR15, or NR16C(O)R17; Y is C═O, C═S, SO2, or (CR7R8)p; R7and R8are independently selected from H and lower alkyl; R9is selected from H, alkyl, aryl, heteroaryl, and non-aromatic heterocyclic groups, or together with R10forms a saturated 4, 5, 6, or 7 membered ring optionally containing an additional heteroatom selected from N and O; R10is selected from H and lower alkyl, or together with R9forms a saturated 4, 5, 6, or 7 membered ring optionally containing an additional heteroatom selected from N and O; R11and R12are independently selected from H and lower alkyl; R15is selected from alkyl and aryl; R16is selected from H and lower alkyl; R17is selected from alkyl, aryl and heteroaryl; m is 1 or 2;n is 1 or 2; and p is 1, 2, 3 or 4.

[0041] In some embodiments, R1and / or R2is substituted with 1 to 3 substituents. In some embodiments, R1and / or R2is substituted with 1 or 2 substituents. In one embodiment, R1and R2are independently selected from a group -A(R4)(R5)(R6), where A is an aryl or heteroaryl ring, and where A may be selected from phenyl, naphthyl, thienyl, furanyl, pyrrolyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, oxazolyl, isooxazolyl, pyridyl, pyrazinyl, pyrimidinyl, quinolinyl, isoquinolinyl, benzofuranyl and isobenzofuryl. In some embodiments, one of R1and R2is aryl and the other is heteroaryl, or both R1and R2are aryl. In some embodiments, both R1and R2are monocyclic. In this embodiment, R4, R5, and R6are independently selected from hydrogen, halo, alkyl (including haloalkyl), thioalkyl, alkoxy (including haloalkoxy), alkylsulfonyl, amino, mono- and di-alkyl amino, mono- and di-aryl amino, alkylarylamino, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, NR14C(O)R19, NR14SO2R20, COOR19, OC(O)R20, CONR13R14and SO2NR13R14, wherein R13and R14are independently selected from hydrogen and alkyl or may form a 5 or 6 membered ring optionally containing 1 or 2 additional heteroatoms selected from N, O and S; and R19is selected from H, alkyl, aryl and heteroaryl and R20is selected from alkyl, aryl and heteroaryl. The groups R1and R2may be the same or different, and in one embodiment are different. In some embodiments, R3is NR9R10. In some embodiments, R3is NR9R10, and R9and R10are independently lower alkyl or hydrogen. In some embodiments, Y is C═O. In some embodiments, Y is C═O and R3is NR9R10. In some embodiments, R3is NR9R10, R9is lower alkyl, and R10is hydrogen.

[0042] In some embodiments of a compound of Formula (I) where R4, R5, and R6are selected from halo. In some embodiments, the halo group is fluoro, chloro, bromo or iodo. In some embodiments, the halo group is chloro or bromo. In some embodiments, R4, R5, and R6are selected from alkyl, thioalkyl, alkoxy and alkylsulfonyl. In some embodiments, R4, R5, and R6are selected from lower alkyl. In some embodiments, R4, R5, and R6are selected from methyl and ethyl. Where R4, R5, and R6are selected from haloalkyl, the alkyl is in some embodiments methyl, and the R4, R5, or R6group is trifluoromethyl. Where R4, R5, and R6are selected from haloalkoxy, the alkyl is in some embodiments methyl and the R4, R5, or R6group is trifluoromethoxy or difluoromethoxy. In some embodiments, one or two of R4, R5, and R6are hydrogen. In some embodiments, at least one of the R1and R2groups has a non-hydrogen substituent in the ortho-position(s) relative to the point of attachment to the [—CH—O—] group. The R1or R2groups may independently have one or two non-hydrogen substituents in said ortho position(s). Preferred ortho-substituents include halo and haloalkyl, as described herein. In some embodiments, ortho-substituents are chloro and trifluoromethyl. In some embodiments, if —Y—R3is —C(O)NH(alkyl) then: R1and / or R2isselected from heteroaryl; and / or m and / or n is 2; and / or R11and / or R12is lower alkyl. In some embodiments, if —Y—R3is —C(O)NH(alkyl) then: R1and / or R2is selected from aryl, and m and n are 1.

[0043] In some embodiments of a compound of Formula (I) where R13and R14form a 5- or 6- membered ring, the ring is 6-membered. In some embodiments, the ring is saturated or partially saturated. In some embodiments where the ring contains additional heteroatoms, such as N and O. In some embodiments, there are 0 or 1 additional heteroatoms.

[0044] In some embodiments of a compound of Formula (I), R1is selected from aryl. In some embodiments, R2is selected from aryl or heteroaryl. In some embodiments, R3is selected from NR9R10. In an alternative embodiment R3is selected from alkyl, aryl and heteroaryl. In some embodiments, Y is selected from C═O, C═S and SO2. Where Y is selected from (CR7R8)p, then R7and / or R8in some embodiments are hydrogen or methyl, and p is 1 or 2. Where Y is SO2, R3is in some embodiments selected from alkyl, aryl and heteroaryl. Where Y is (CR7R8)p, in some embodiments p is 1, and R3is selected from alkyl, aryl, heteroaryl. In some embodiments, R9is selected from piperidinyl (such as 1-piperidinyl) and morpholinyl (such as 4-morpholinyl). In some embodiments, R9is cyclic, such as aryl or heteroaryl, and the R9group may be substituted with one or more substituent groups. In some embodiments, R9is substituted with halo, nitro, or alkoxy haloalkyl.

[0045] In some embodiments of a compound of Formula (I), the ring formed by NR9R10may be substituted, and substituents include hydroxy, methoxy, mono- and di-alkyl amino and alkoxycarbonyl. In one embodiment (hereinafter referred to as embodiment (i)), R9is selected from aryl, heteroaryl and a non-aromatic heterocyclic group, and R10is selected from H and lower alkyl. In an alternative embodiment (hereinafter referred to as embodiment (ii)), R9is selected from alkyl and R10is selected from lower alkyl. In a further alternative embodiment hereinafter referred to as embodiment (iii)), R9and R10form a 4, 5, 6, or 7-membered ring, or a 5, 6, or 7-membered ring, optionally containing an additional heteroatom selected from N and O.

[0046] In some embodiments of a compound of Formula (I), m is 1 and / or n is 1. In some embodiments, both m and n are 1. Where m is 2, the R11groups may be the same or different, but at least one of the R11groups in the (CHR11)2 moiety is hydrogen. Where n is 2, the R12groups may be the same or different, but at least one and optionally both of the R12groups in the (CHR12)2moiety is / are hydrogen. In some embodiments, R11and R12are independently selected from hydrogen and methyl. In some embodiments, at least one of R11and R12is hydrogen. In some embodiments, R15is selected from alkyl, such as lower alkyl (substituted or unsubstituted). In some embodiments, R15is selected from aryl, such as phenyl (substituted or unsubstituted). In one embodiment, R15isselected from lower alkyl, benzyl and phenyl. In some embodiments, R16is hydrogen. In some embodiments, R17is lower alkyl, aryl, or heteroaryl, and in one embodiment is aryl.

[0047] Provided herein are compounds having the structure of formula (Ia)or a pharmaceutically acceptable salt or prodrug thereof, wherein R1and R2are independently selected from aryl or heteroaryl; and R9is hydrogen or alkyl; wherein at least one of R1and R2has a non-hydrogen substituent in the ortho-position(s) thereof relative to the point of attachment to the [—CH—O—] group.

[0048] Provided herein are compounds having the structure of formula (Ia)or a pharmaceutically acceptable salt or prodrug thereof, wherein R1and R2are independently selected from aryl; and R9is hydrogen or alkyl; wherein at least one of R1and R2has a non-hydrogen substituent in the ortho-position(s) thereof relative to the point of attachment to the [—CH—O—] group.

[0049] In the compounds of formula (I) or (Ia), R1and R2are independently selected from substituted or unsubstituted phenyl or naphthyl. In some embodiments, R1and R2are independently selected from phenyl or naphthyl having 1 to 3 substituents. In one embodiment the substituent groups are selected from halogen and haloalkyl. In some embodiments, R1and R2are selected from mono-cyclic aromatic groups.

[0050] In some embodiments of the compounds of formula (I) or (Ia), R1and R2are independently selected from a group of formula (II):whereinR4, R5, and R6are independently selected from hydrogen, halo, alkyl (including haloalkyl), thioalkyl, alkoxy (including haloalkoxy), alkylsulfonyl, amino, mono- and di-alkyl amino, mono- and di-aryl amino, alkylarylamino, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, NR14C(O)R19, NR14SO2R20, COOR19, OC(O)R20, CONR13R14and SO2NR13R14, R13and R14are independently selected from hydrogen and alkyl or form a 5 or 6 membered ring optionally containing 1 or 2 additional heteroatoms selected from N, O, and S; R19is selected from H, alkyl, aryl and heteroaryl, and R20is selected from alkyl, aryl and heteroaryl.

[0051] In some embodiments of the compounds of formula (I) or (Ia), the groups R1and R2in are the same or different, and in one embodiment are different. Where R4, R5, and R6are selected from halo, the halo group is in some embodiments fluoro, chloro, bromo or iodo. Where R4, R5and R6are selected from alkyl, thioalkyl, alkoxy and alkylsulfonyl, the alkyl is in some embodiments lower alkyl. Where R4, R5, and R6are selected from aminoalkyl, alkylaminoalkyl and dialkylaminoalkyl, the alkyl is selected from methyl and ethyl. Where R4, R5, and R6are selected from dialkylaminoalkyl, the dialkylamino fragment is in some embodiments selected from cyclicamino, such as morpholino and piperazino. Where R4, R5, and R6are selected from haloalkyl, the alkyl is in some embodiments methyl, and the R4, R5, or R6group is trifluoromethyl. Where R4, R5, and R6are selected from haloalkoxy, the alkyl is in some embodiments methyl and the R4, R5, or R6group is selected from trifluoromethoxy or difluoromethoxy. In some embodiments, one or two of R4, R5, and R6are hydrogen. At least one of the R1and R2groups has a non-hydrogen substituent in the ortho-position(s). The R1or R2groups in some embodiments independently have one or two non-hydrogen substituents in the ortho position(s) relative to the point of attachment to the [—CH—O—] group. Preferred ortho-substituents include halo and haloalkyl, as described herein. In some embodiments, ortho-substituents are chloro and trifluoromethyl. Where R13and R14form a 5- or 6-membered ring, the ring in some embodiments is 6-membered. Where the ring contains additional heteroatoms, in some embodiments, these are N and / or O. In some embodiments, there are 0 or 1 additional heteroatoms. In some embodiments, R13and R14are independently hydrogen or alkyl.

[0052] In some embodiments of the compounds of formula (I) or (Ia), R9is selected from hydrogen or alkyl. In some embodiments, R9is alkyl. In some embodiments, R9is selected from methyl, ethyl, propyl, sec-butyl, or tert-butyl. The alkyl group in some embodiments are substituted or unsubstituted, and in one embodiment is substituted. In some embodiments, one or two substituent groups are present. In some embodiments, substituents are hydroxy, alkoxy, thioalkyl, amino, mono- and dialkyl amino, alkoxycarbonyl, aryl, and heterocyclic groups including both heteroaryland non-aromatic heterocyclic groups. Where R9is an acyclic alkyl group, in some embodiments it is substituted by a cyclic alkyl group; and where R9is a cyclic alkyl group in some embodiments it is substituted by an acyclic alkyl group. Where the substituent group is heteroaryl, in some embodiments the heteroaryl is a 5- or 6-membered ring containing one or more N, O, or S atoms, such as thiophenyl, furanyl, isoxazolyl, thiazolyl and benzothiophenyl. Other substituent groups in some embodiments include dihydrobenzofuranyl, dihydrobenzodioxinyl, tetrahydrofuranyl, pyrrolidinyl, oxopyrrolindyl and benzodioxolyl.

[0053] In one embodiment of a compound of formula (I), R3has the structure: —(CHR9)n(CH2)mCR10R11R12wherein n is 0 or 1; m is 0, 1, 2 or 3; R9, R10, R11, and R12are selected from hydrogen, alkyl, hydroxy, alkoxy, thioalkyl, amino, mono- and di-alkyl amino, alkoxycarbonyl and R13; wherein R13is selected from aryl, heteroaryl and non-aromatic heterocyclic optionally substituted by one or more groups selected from alkyl, halogen, alkoxy, oxo, aryl, heteroaryl and non-aromatic heterocycle.

[0054] In some embodiments of Formula (I) or (Ia), m is 0 or 1 or 2. In some embodiments, m is 0 or 1. In some embodiments, n is 0. In some embodiments, n is 1 and m is 1. In one embodiment, at least one or two of R10, R11, and R12are selected from hydrogen. In a further embodiment, at least two of R10, R11, and R12are selected from methyl. In a further embodiment, R9is selected from cyclic alkyl, including cyclopentyl, cyclohexyl, norbornanyl and adamantyl. In some embodiments, R9groups are tertiary butyl, sec-butyl, isobutyl, isopropyl, n-propyl and ethyl.

[0055] In some embodiments, the CB1 antagonist of Formula (I) or (Ia) is ((R)-(+)-N-tert-butyl-3- [(4-chloro)phenyl-(2-trifluoromethyl)phenyl]methoxyazetidine-1-carboxamide (Compound ANEB- 001). In some embodiments, the CB1 antagonist is ((S)-(-)-N-tert-butyl-3-[(4-chloro)phenyl-(2- trifluoromethyl)phenyl]methoxyazetidine-1-carboxamide. In some embodiments, the CB1 antagonist is (N-tert-butyl-3-[(4-chloro)phenyl-(2-trifluoromethyl)phenyl]methoxyazetidine-1- carboxamide. In some embodiments, the CB1 antagonist is Cannabigerol. In some embodiments, the CB1 antagonist is ibipinabant. In some embodiments, the CB1 antagonist is otenabant. In some embodiments, the CB1 antagonist is tetrahydrocannabivarin. In some embodiments, the CB1 antagonist is virodhamine. In some embodiments, the CB1 inverse agonist is rimonabant. In some embodiments, the CB1 inverse agonist is taranabant. In some embodiments, the CB1 inverse agonist is surinabant or drinabant. In some embodiments, a composition or formulation describedherein comprises two or more CB1 inhibitors. In some embodiments, the CB1 inhibitor is a neutral antagonist. In some instances, the CB1 inhibitors comprise one or more substitutions at the phenyl groups that function as effective neutral antagonists of CB1.

[0056] In some instances, a CB1 inhibitor comprises a structure of formula (Ia), wherein R1and R2are substituted aromatic groups, and R3is an optionally substituted C1-C6 alkyl group. In some instances, R3is tert-butyl. In some instances, R3is isopropyl. In some instances, R3is sec-butyl. In some instances, R1is a substituted aromatic group. In some instances, R1is an optionally substituted phenyl group. In some instances, R1is a phenyl group substituted with a halogen (e.g., F, Cl, Br, I). In some instances, R1is a phenyl group substituted with Cl. In some instances, R1is a phenyl group para substituted in (4-position) with a halogen (e.g., F, Cl, Br, I). In some instances, R1is a 4-chlorophenyl group. In some instances, R2is a substituted aromatic group. In some instances, R2is an optionally substituted phenyl group. In some instances, R2is a phenyl group substituted with a C1-C5 alkyl group. In some instances, R2is a phenyl group substituted with a C1- C5trifluoroalkyl group. In some instances, R2is a phenyl group substituted with a trifluoromethyl group. In some instances, R2is a phenyl group ortho substituted in (4-position) with a C1-C5 trifluoroalkyl group. In some instances, R2is a 2-trifluoromethylphenyl group. In some embodiments, the CB1 inhibitor is compound ANEB-001, having the following structure:. Methods of producing ANEB-001 and related compounds (and enantiomers thereof) are known in the art (see Example 81 of US 7,504,522 which is incorporated by reference). In some embodiments, the CB1 inhibitor has the structure:. In some embodiments, the CB1 inhibitor has the structure:.

[0057] In some embodiments, a CB1 inhibitor is a compound of Table 1. Table 1

[0058] In some embodiments, the additional compounds herein can include all stereoisomers, enantiomers, diastereomers, mixtures, racemates, atropisomers, and tautomers thereof.

[0059] In some embodiments, as disclosed herein, the additional compounds are crystalline. Compositions and Formulations

[0060] In another aspect, the present disclosure provides compositions, including pharmaceutical compositions and injectable compositions.

[0061] Pharmaceutical Compositions

[0062] In one aspect, the present disclosure provides a pharmaceutical composition comprising the (R)-N-(tert-butyl)-3-((4-chlorophenyl)(2-(trifluoromethyl)phenyl)methoxy)azetidine-1- carboxamide, and at least one pharmaceutically acceptable excipient.

[0063] In some embodiments, Compound 1 (or polymorphs thereof) are formulated into pharmaceutical compositions. In specific embodiments, pharmaceutical compositions are formulated in a conventional manner using one or more physiologically acceptable carriers comprising excipients and auxiliaries which facilitate processing of the active compounds / polymorphs into preparations which can be used pharmaceutically. Proper formulation is dependent upon the route of administration chosen. Any pharmaceutically acceptable techniques, carriers, and excipients are used as suitable to formulate the pharmaceutical compositions described herein: Remington: The Science and Practice of Pharmacy, Nineteenth Ed (Easton, Pa.: Mack Publishing Company, 1995); Hoover, John E., Remington’s Pharmaceutical Sciences, Mack Publishing Co., Easton, Pennsylvania 1975; Liberman, H.A. and Lachman, L., Eds., Pharmaceutical Dosage Forms, Marcel Decker, New York, N.Y., 1980; and Pharmaceutical Dosage Forms and Drug Delivery Systems, Seventh Ed. (Lippincott Williams & Wilkins1999).

[0064] In some embodiments, the present disclosure provides pharmaceutical compositions comprising Compound 1 and a pharmaceutically acceptable diluent(s), excipient(s), or carrier(s). In certain embodiments, the pharmaceutical compositions include Compound 1 or polymorphs thereof.

[0065] A pharmaceutical composition, as used herein, refers to a mixture of Compound 1 with other chemical components, such as carriers, stabilizers, diluents, dispersing agents, suspending agents, thickening agents, and / or excipients. In certain embodiments, the pharmaceuticalcomposition facilitates the administration of the polymorphs to an organism. In some embodiments, in practicing the methods of treatment or use as described herein, therapeutically effective amounts of Compound 1 or polymorphs thereof are administered in a pharmaceutical composition to a subject having a condition or disorder to be treated. In specific embodiments, the subject is a human. In certain embodiments, therapeutically effective amounts vary depending on the severity of the condition or disorder, the age and relative health of the subject and other factors. Compound 1 or polymorphs thereof described herein are used singly or in combination with one or more therapeutic agents as components of mixtures.

[0066] In some embodiments, the polymorphs of Compound 1 are subjected to spray drying prior to being formulated.

[0067] In some embodiments, the pharmaceutical composition is formulated for oral, parenteral, inhalation, intravenous (IV), intramuscular (IM), or subcutaneous (SC) administration. In some instances, pharmaceutical composition is formulated for intravenous (IV) administration. In some instances, intravenous (IV) comprises IV bolus, IV drip, or IV push. In some embodiments, the pharmaceutical composition is delivered in a liquid volume of 0.1-5 mL, 0.1-4, 0.1-3, 0.1-2, 0.1-1, 0.1-0.5, 0.5-5 mL, 0.5-4, 0.5-3, 0.5-2, 0.5-1, 1-5 mL, 1-4, 1-3, or 1-2 mL. In some embodiments, the pharmaceutical composition is delivered in an IV liquid volume of 10-1000 mL, 10-500 mL, 10-400 mL, 10-300 mL, 10-200 mL, 10-100 mL, 10-50 mL, 100-1000 mL, 100-500 mL, 200-500 mL, 200-1000 mL, 500-1000 mL, or 750-1000 mL.

[0068] In some embodiments, the pharmaceutical composition is formulated to deliver a therapeutically effective amount of the (R)-N-(tert-butyl)-3-((4-chlorophenyl)(2- (trifluoromethyl)phenyl)methoxy)azetidine-1-carboxamide in no more than 10 minutes. In some embodiments, the pharmaceutical composition is formulated to deliver a therapeutically effective amount of (R)-N-(tert-butyl)-3-((4-chlorophenyl)(2-(trifluoromethyl)phenyl)methoxy)azetidine-1- carboxamide in no more than 5 minutes. In some embodiments, the pharmaceutical composition is formulated to deliver a therapeutically effective amount of (R)-N-(tert-butyl)-3-((4- chlorophenyl)(2-(trifluoromethyl)phenyl)methoxy)azetidine-1-carboxamide in no more than 2 minutes. In some embodiments, the pharmaceutical composition is formulated to deliver a therapeutically effective amount of (R)-N-(tert-butyl)-3-((4-chlorophenyl)(2- (trifluoromethyl)phenyl)methoxy)azetidine-1-carboxamide in no more than 1 minute. In some embodiments, the pharmaceutical composition is formulated to deliver a therapeutically effective amount of (R)-N-(tert-butyl)-3-((4-chlorophenyl)(2-(trifluoromethyl)phenyl)methoxy)azetidine-1- carboxamide in no more than 30 seconds. In some embodiments, the pharmaceutical composition is formulated to deliver a therapeutically effective amount of (R)-N-(tert-butyl)-3-((4-chlorophenyl)(2-(trifluoromethyl)phenyl)methoxy)azetidine-1-carboxamide in no more than 10 seconds. In some embodiments, the pharmaceutical composition is formulated to deliver a therapeutically effective amount of (R)-N-(tert-butyl)-3-((4-chlorophenyl)(2- (trifluoromethyl)phenyl)methoxy)azetidine-1-carboxamide in 10-120, 10-100, 10-75, 10-60, 10-45, 10-30, 10-15, 20-120, 20-100, 20-75, 20-60, 20-45, 20-30, 30-120, 30-100, 30-75, 30-60, 30-45, 45-120, 45-100, 45-75, 45-60, 60-120, 60-100, 60-75, 75-120, or 100-120 minutes.

[0069] In one embodiment, Compound 1 or polymorphs thereof are formulated in an aqueous solution. In one embodiment, Compound 1 or polymorphs thereof are formulated in an aqueous solution for parenteral injection. In other embodiments, Compound 1 or polymorphs thereof are formulated for transmucosal administration. In still other embodiments, wherein the one or more polymorphs described herein are formulated for other parenteral injections, appropriate formulations include aqueous or nonaqueous solutions. In specific embodiments, such solutions include physiologically compatible buffers and / or excipients.

[0070] In still other embodiments, the polymorphs described herein are formulated for parental injection, including formulations suitable for bolus injection or continuous infusion. In specific embodiments, formulations for injection are presented in unit dosage form (e.g., in ampoules) or in multi-dose containers. Preservatives are, optionally, added to the injection formulations. In still other embodiments, the pharmaceutical composition of a polymorph of Compound 1 is formulated in a form suitable for parenteral injection as sterile suspension, solution, or emulsion in oily or aqueous vehicles. Parenteral injection formulations optionally contain formulatory agents such as suspending, stabilizing and / or dispersing agents. In specific embodiments, pharmaceutical formulations for parenteral administration include aqueous solutions of the active polymorphs in water-soluble form. In additional embodiments, suspensions of the active polymorphs are prepared as appropriate oily injection suspensions. Suitable lipophilic solvents or vehicles for use in the pharmaceutical compositions described herein include, by way of example only, fatty oils such as sesame oil, or synthetic fatty acid esters, such as ethyl oleate or triglycerides, or liposomes. In certain specific embodiments, aqueous injection suspensions contain substances which increase the viscosity of the suspension, such as sodium carboxymethyl cellulose, sorbitol, or dextran. Optionally, the suspension contains suitable stabilizers or agents which increase the solubility of the polymorphs to allow for the preparation of highly concentrated solutions. Alternatively, in other embodiments, the active ingredient is in powder form for constitution with a suitable vehicle, e.g., sterile pyrogen-free water, before use. Alternatively, in other embodiments, a powder comprises a lyophilized form.

[0071] In certain embodiments, pharmaceutical compositions are formulated in any conventional manner using one or more physiologically acceptable carriers comprising excipients and auxiliaries which facilitate processing of the active polymorphs into preparations which can be used pharmaceutically. Proper formulation is dependent upon the route of administration chosen. Any pharmaceutically acceptable techniques, carriers, and excipients are optionally used as suitable. Pharmaceutical compositions comprising Compound 1 or polymorphs thereof are manufactured in a conventional manner, such as, by way of example only, by means of conventional mixing, dissolving, granulating, dragee-making, levigating, emulsifying, encapsulating, entrapping or compression processes.

[0072] Pharmaceutical compositions include at least one pharmaceutically acceptable carrier, diluent, or excipient and at least one polymorph of Compound 1 described herein as an active ingredient. The active ingredient is in acid-free or base-free form, or in a pharmaceutically acceptable salt form. All tautomers of the compounds described herein are included within the scope of the compounds presented herein. Additionally, the compounds described herein encompass unsolvated as well as solvated forms with pharmaceutically acceptable solvents such as water, ethanol, and the like. The solvated forms of the compounds presented herein are also considered to be disclosed herein. In addition, the pharmaceutical compositions optionally include other medicinal or pharmaceutical agents, carriers, adjuvants, such as preserving, stabilizing, wetting or emulsifying agents, solution promoters, salts for regulating the osmotic pressure, buffers, and / or other therapeutically valuable substances.

[0073] Methods for the preparation of compositions, comprising Compound 1 or polymorphs thereof described herein include formulating the polymorphs with one or more inert, pharmaceutically acceptable excipients or carriers to form a solid, semi-solid or liquid. Solid compositions include, but are not limited to, powders, tablets, dispersible granules, capsules, cachets, and suppositories. Liquid compositions include solutions in which a compound is dissolved, emulsions comprising a compound, or a solution containing liposomes, micelles, or nanoparticles comprising a compound as disclosed herein. Semi-solid compositions include, but are not limited to, gels, suspensions, and creams. The form of the pharmaceutical compositions described herein include liquid solutions or suspensions, solid forms suitable for solution or suspension in a liquid prior to use, or as emulsions. These compositions also optionally contain minor amounts of nontoxic, auxiliary substances, such as wetting or emulsifying agents, pH buffering agents, isotonizing agents, and so forth.

[0074] In some embodiments, pharmaceutically acceptable carriers or excipients for formulations described herein may comprise one or more polymers. In some embodiments, the pharmaceuticallyacceptable carrier is a polymer. Examples of polymers suitable for oral, buccal, intranasal, transdermal, thin-film, suppository or other administration include biocompatible and biodegradable polymers. Further examples of biocompatible polymers include natural or synthetic polymers such as polystyrene, polylactic acid, polyketal, butadiene styrene, styreneacrylic-vinyl terpolymer, polymethylmethacrylate, polyethylmethacrylate, polyalkylcyanoacrylate, styrene- maleic anhydride copolymer, polyvinyl acetate, polyvinylpyridine, polydivinylbenzene, polybutyleneterephthalate, acrylonitrile, vinylchloride-acrylates, polycaprolactone, poly(alkyl cyanoacrylates), poly(lactic-co-glycolic acid), and the like. In some instances, the carrier is Labrasol. In some instances, the carrier is methyl cellulose. In further embodiments, the pharmaceutically acceptable carrier comprises one or more biodegradable polymers. Use of biodegradable polymers provides the advantages of using a formulation that will eventually disintegrate, which facilitates release of the benzofuran compound and elimination of the carrier in vivo. However, benzofuran compounds can also be released from the matrix of non-biodegradable polymers as a result of gradual efflux from channels within the polymer matrix, including those formed by soluble materials included in the polymer matrix.

[0075] Examples of biodegradable polymers include polylactide polymers include poly(D,L- lactide)s; poly(lactide-co-glycolide) (PLGA) copolymers; polyglycolide (PGA) and polydioxanone; caprolactone polymers; chitosan; hydroxybutyric acids; polyanhydrides and polyesters; polyphosphazenes; and polyphosphoesters. In some instances, the biodegradable polymer for use in the nanoparticles is poly-(D,L-lactide-co-glycolide).

[0076] In some instances, a PLGA copolymer comprises a lactide to glycolide ratio of 10:90, 20:80, 30:70, 40:60, or 50:50.

[0077] Functionalized poly (D,L-lactide)s can also be used as biodegradable polymers in the nanoparticles described herein. Examples of functionalized poly(D,L-lactide)s include poly(L- lactide), acrylate terminated; poly(L-lactide), amine terminated; poly(L-lactide), azide terminated; poly(L-lactide), 2-bromoisobutyryl terminated; poly(L-lactide), 2-bromoisobutyryl terminated; poly(L-lactide) 4-cyano-4-[(dodecylsulfanylthiocarbonyl)sulfanyl]pentonate; poly(L-lactide) N-2- hydroxyethylmaleimide terminated; poly(L-lactide) 2-hydroxyethyl, methacrylate terminated; poly(L-lactide), propargyl terminated; or poly(L-lactide), thiol terminated.

[0078] Other biodegradable polymers that can be used in the nanoparticles include AB - 38 -eblock copolymers such as poly(ethylene glycol) methyl ether-block-poly(D,L-lactide); poly(ethylene glycol) methyl ether-block-poly(lactide-co-glycolide) PEG; poly(ethylene glycol)- block-poly(.epsilon.-caprolactone) methyl ether PEG; and polypyrrole-block-poly(caprolactone). Further biodegradable polymers include ABA triblock copolymers such as polylactide-block-poly(ethylene glycol)-block-polylactide PLA; poly(lactide-co-glycolide)-block-poly(ethylene glycol)-block-poly(lactide-co-glycolide); poly(lactide-co-caprolactone)-block-poly(ethylene glycol)-block-poly(lactide-co-caprolactone); polycaprolactone-block-polytetrahydrofuran-block- polycaprolactone; and polyglycolide-block-poly(ethylene glycol)-block-polyglycolide PEG.

[0079] Biodegradable polymers also include various natural polymers. Examples of natural polymers include polypeptides including those modified non-peptide components, such as saccharide chains and lipids; nucleotides; sugar-based biopolymers such as polysaccharides; cellulose; carbohydrates and starches; dextrans; lignins; polyamino acids; adhesion proteins; lipids and phospholipids (e.g., phosphorylcholine). In some embodiments, the polymer is a cellulose derivative such as hydroxypropyl methylcellulose polymers. Hydroxypropyl methyl cellulose (HPMC) is a non-ionic cellulose ether made through a series of chemical processes, with the natural polymer cellulose as the raw material. The product is a non-ionic cellulose ether in the shape of white powder, odorless and tasteless. HPMC is also known as hypromellose, is a methylcellulose modified with a small amount of propylene glycol ether groups attached to the anhydroglucose of the cellulose.

[0080] Useful pharmaceutical compositions also, optionally, include solubilizing agents to aid in the solubility of a polymorph of Compound 1. The term “solubilizing agent” generally includes agents that result in formation of a micellar solution or a true solution of the agent. Certain acceptable nonionic surfactants, for example polysorbate 80, are useful as solubilizing agents, as can ophthalmically acceptable glycols, polyglycols, e.g., polyethylene glycol 400, and glycol ethers. In some instances, solubilizing agents comprise poloxamers, Solutol HS 10, Cremophor EL, or other solubilizing agent. In some instances, solubilizing agents are described in Strickley, Robert G. "Solubilizing excipients in oral and injectable formulations." Pharmaceutical research 21 (2004): 201-230, which is incorporated by reference.

[0081] Furthermore, useful pharmaceutical compositions optionally include one or more pH adjusting agents or buffering agents, including acids such as acetic, boric, citric, lactic, phosphoric, and hydrochloric acids; bases such as sodium hydroxide, sodium phosphate, sodium borate, sodium citrate, sodium acetate, sodium lactate and tris-hydroxymethylaminomethane; and buffers such as citrate / dextrose, sodium bicarbonate and ammonium chloride. Such acids, bases and buffers are included in an amount required to maintain pH of the composition in an acceptable range.

[0082] Additionally, useful compositions also, optionally, include one or more salts in an amount required to bring osmolality of the composition into an acceptable range. Such salts include those having sodium, potassium or ammonium cations and chloride, citrate, ascorbate, borate, phosphate,bicarbonate, sulfate, thiosulfate, or bisulfite anions; suitable salts include sodium chloride, potassium chloride, sodium thiosulfate, sodium bisulfite and ammonium sulfate.

[0083] Still other useful compositions include one or more surfactants to enhance physical stability or for other purposes. Suitable nonionic surfactants include polyoxyethylene fatty acid glycerides and vegetable oils, e.g., polyoxyethylene (60) hydrogenated castor oil; and polyoxyethylene alkylethers and alkylphenyl ethers, e.g., octoxynol 10, octoxynol 40. Pharmaceutical Compositions for Parenteral Delivery

[0084] In some embodiments, Compound 1 is formulated into an injectable composition. In some embodiments, the injectable composition comprises (R)-N-(tert-butyl)-3-((4-chlorophenyl)(2- (trifluoromethyl)phenyl)methoxy)azetidine-1-carboxamide, or the pharmaceutical composition described herein, an opioid antagonist, and a benzodiazepine antagonist. In some embodiments, the benzodiazepine antagonist is flumazenil. In some embodiments, the opioid antagonist is naloxone or naltrexone. In some embodiments, the opioid antagonist is samidorphan. In some embodiments, the opioid antagonist is naltrexone. In some embodiments, the injectable composition is formulated in a single dose injectable device.

[0085] Provided herein are pharmaceutical compositions configured for parenteral administration. In some instances, parenteral formulations comprise a compound having the structure:. In some instances, parenteral formulations comprise a compound having the structure:and at least one excipient. In some instances, parenteral formulations comprise a nanosuspension, oil and water emulsion, liposome, or micelles. Parenteral formulations in some instances are administered by intravenous (IV), intramuscular (IM), or subcutaneous (SC) methods.

[0086] Oil in water emulsions

[0087] Parenteral formulations may comprise an oil and water emulsion. In some instances, the at least one excipient comprises an oil. In some instances, the excipient comprises soybean oil (SBO), Miglyol 812, olive oil, coconut oil, or a mixture thereof. In some instances, the pharmaceutical composition comprises soybean oil and at least one of coconut oil, olive oil, or Miglyol 812. In some instances, the pharmaceutical composition comprises a 10:1 to 1:10, 5:1 to 1:5, 3:1 to 1:3, 2:1 to 1:2: or 1.5:1 to 1:5 mixture of soybean oil to any one of coconut oil, olive oil, or Miglyol 812. In some instances, the compound is present at 1-20, 2-20, 3-20, 5-20, 8-20, 10-20, 15-20, or 20-50 mg / mL. In some instances, the compound is present at less than 3, 2, 1.5, 1, or 0.5 mg / mL.

[0088] Micelles

[0089] Parenteral formulations may comprise micelles. In some instances, the parenteral formulation comprises micelles. In some instances, the parenteral formulation comprises a mixed micelle formulation. In some instances a parenteral formulation comprises a phospholipid and at least one bile salt. In some instances, a bile salt comprises sodium deoxycholate or sodium glycocholate. In some instances, the parenteral formulation comprises a phospholipid. In some instances, the excipient comprises Miglycol 812, Lipoid E80, saline, or a combination thereof. In some instances, the pharmaceutical composition comprises 0.1-5%, 0.2-5%, 0.5-3%, 0.8-3%, 0.5- 1.5%, 1-3%, 1.5-3%, or 2-3%, Lipoid E80. In some instances, the compound is present at 1-20, 2- 20, 3-20, 5-20, 8-20, 10-20, 15-20, or 20-50 mg / mL. In some instances, the compound is present at less than 3, 2, 1.5, 1, or 0.5 mg / mL.

[0090] Liposomes

[0091] Parenteral formulations may comprise liposomes. A liposome can have a similar structure, but is usually formed from a double layer of surfactant or amphiphilic molecules (e.g., a lipid bilayer) ) encapsulating one or more aqueous compartments. In some instances, a liposome comprises an inner aqueous compartment portion, a middle portion, and an outer shell composed of a phospholipid bilayer. For example, the inner portion is relatively hydrophilic, the middle portion (e.g., the outer shell of the liposome, formed by the bilayer structure of the surfactant or amphiphilic molecules mainly phospholipids) which inner domain (formed by the fatty acid parts of the phospholipids) is relatively hydrophobic or lipophilic, and the exterior to the liposome is an aqueous or a hydrophilic environment. In some embodiments, the liposomes are dispersed an aqueous or a hydrophilic environment.

[0092] The inner portion, if present within an entity, contains a liquid, and in all cases, the liquid is aqueous. In some cases, the liquid contains saline or a salt solution in water. Optionally, the liquid can contain a drug or other pharmaceutical agent (e.g., Compound 1). In some cases, the liquid contains an isotonic solution in water. In some cases, the liquid contains a sugar solution inwater. In some cases, sugar comprises glucose, sucrose, lactose, trehalose, and maltose, or other sugar.

[0093] In some instances, the parenteral formulation comprises a liposome. In some instances, the at least one excipient comprises a phospholipid. In some instances, the pharmaceutical composition comprises 10-50, 10-40, 10-30, 20-50, 20-40, 20-30, 25-45, 30-50, or 40-50 mg / mL phospholipid. In some instances, the at least one excipient comprises Lipoid S100 or dimyristoylphosphatidylglycerol (DMPG). In some instances, the excipient comprises Lipoid S100 and DMPG. In some instances, the excipient comprises soybean phosphatidylcholine and 1,2 dimyristoylphosphatidylglycerol. In some instances, a phosphatidylcholine is sold under the trade name LIPOID E 80 or LIPOID S 100 by Lipoid GmbH. In some instances, the Compound 1 is present at 0.1-15, 0.5-10, 0.8-10, 0.5-15, 0.5-3, 0.8-3, 0.8-2, 0.8-5, 0.5-3, 5-15, or 10-15 mg / mL in the liposomal formulation. In some instances, the Compound 1 is present about 0.1, 0.2, 0.3, 0.5, 0.8, 1.0, 1.2, 1.5, 1.7, 2.0, 2.2, 2.5, 2.8, 3, 3.1, 3.2, 3.3, or about 3.5 mg / mL in the liposomal formulation. Phospholipids (e.g., phosphatidylcholine) may be obtained from different sources. In some instances, phospholipids are obtained from hen egg yolk, soybeans, Non-GMO Soybeans, sunflowers, or are synthetically produced. In some instances, phosphatidylcholine is obtained from hen egg yolk, soybeans, Non-GMO Soybeans, sunflowers, or is synthetically produced. Liposomal formulations may comprise a ratio of compound / drug (e.g., Compound 1) to lipid (e.g., phospholipid). In some embodiments, the ratio of compound to lipid is 1:5 to 1:25, 1:5 to 1:50 (w / w), 1:1 to 1:25, 1:2 to 1:25, 2:1 to 1:25, 1:5 to 1:25, 1:10 to 1:25, or 1:10 to 1:20. In some embodiments, the ratio of compound to lipid is about 2:1, 1:1, 1:1.5, 1:2, 1:5, 1:7, 1:10, 1:12, 1:15, 1:17, 1:20, 1:25, or about 1:50.

[0094] In some embodiments, the phospholipids comprise diacyl-phospholipids. In some embodiments, the phospholipids comprises phosphatidylcholine, or phosphatidylethanolamine,. The company Lipoid Gmbh (https: / / lipoid.com / en / product-finder / ) produces a variety of phospholipids products suitable for formulations described herein, which includes but not limited to Lipoid 16:1 / 18:1, Lipoid S 100, DMPG NA, Lipoid P 75, Lipoid S 80, Lipoid S, Lipoid R, Lipoid E, Lipoid E 100j, and Lipoid E PG / DSPG. Synthetic DA-PLs, such as Lipoid PC, Lipoid PE, Lipoid PG, Lipoid PA, Lipoid PS are also in some embodiments used in the liposomal formulations described herein.

[0095] In some instances, a phospholipid is a substantially pure compound. In some instances, a phospholipid is less than 100% pure. In some instances, a phospholipid comprises at least 40, 50, 60, 70, 80, 90, 94, 96, 97, or at least 98% phosphatidylcholine (w / w). In some instances, a phospholipid comprises at least 40, 50, 60, 70, 80, 90, 94, 96, 97, or at least 98%phosphatidylethanolamine (w / w). In some instances, a phospholipid comprises at least 40, 50, 60, 70, 80, 90, 94, 96, 97, or at least 98% hydrogenated phosphatidylcholine, (w / w). In some instances, a phospholipid comprises at least 40, 50, 60, 70, 80, 90, 94, 96, 97, or at least 98% sphingomyelin, (w / w). In some instances, a phospholipid comprises at least 40, 50, 60, 70, 80, 90, 94, 96, 97, or at least 98% phosphatidylglycerol, (w / w), or a salt thereof (e.g., sodium or potassium salt). In some instances, the balance comprises additional phospholipids. In some instances, a liposomal formulation comprises one or more of CAS Reg. Nos.: 8001-17-0, 93685-90-6, 97281-44-2, 97281- 50-0, 92347-24-5, 85187-10-6, 97281-45-3, 8030-76-0, 97281-47-5, 92128-87-5, 97281-48-6, 28319-77-9, 9008-30-4, 97281-49-7, 18194-24-6, 63-89-8, 816-94-4, 4235-95-4, 51779-95-4, 26853-31-6, 67232-80-8, 67232-81-9, 200880-42-8, 67254-28-8, 208070-86-8, 998-07-2, 923-61- 5, 1069-79-0, 4004-05-1, 70614-14-1, 169051-60-9, 384835-59-0, 147867-65-0, 384835-61-4, 132172-61-3, 538-23-8, 8001-22-7, 73398-61-5, 8016-13-5, 112-80-1, and 143-19-1. In some instances, a liposomal formulation comprises at least 40, 50, 60, 70, 80, 90, 94, 96, 97, or at least 98% of one or more of CAS Reg. Nos.: 8001-17-0, 93685-90-6, 97281-44-2, 97281-50-0, 92347- 24-5, 85187-10-6, 97281-45-3, 8030-76-0, 97281-47-5, 92128-87-5, 97281-48-6, 28319-77-9, 9008-30-4, 97281-49-7, 18194-24-6, 63-89-8, 816-94-4, 4235-95-4, 51779-95-4, 26853-31-6, 67232-80-8, 67232-81-9, 200880-42-8, 67254-28-8, 208070-86-8, 998-07-2, 923-61-5, 1069-79-0, 4004-05-1, 70614-14-1, 169051-60-9, 384835-59-0, 147867-65-0, 384835-61-4, 132172-61-3, 538- 23-8, 8001-22-7, 73398-61-5, 8016-13-5, 112-80-1, and 143-19-1. In some instances, a phospholipid comprises one or more of lecithin, phosphatidylcholine, phosphatidylethanolamine, phosphatidylglycerol, sphingomyelin, phosphatidylcholine, hydrogenated, sn-glycero-3- phosphocholine, 1,2-dimyristoyl-sn-glycero-3-phosphocholine, 1,2-dipalmitoyl-sn-glycero-3- phosphocholine, 1,2-distearoyl-sn-glycero-3-phosphocholine, 1,2-dioleoyl-sn-glycero-3- phosphocholine, 1.2- dioleoylphosphatidylcholine, 1,2 dierucoyl-sn-glycero-3-phosphocholine, 1- palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine, 1,2-dimyristoyl-sn-glycero-3-phospho-rac- glycerol, sodium salt, 1,2-dipalmitoyl-sn-glycero-3-phospho-rac-glycerol, sodium salt, 1,2- distearoyl-sn-glycero-3-phospho-rac-glycerol, sodium salt, 1,2-dioleolyl-sn-glycero-3-phospho-rac- glycerol, sodium salt, 1-palmitoyl-2-oleoyl-sn-glycero-3-phospho-rac-glycerol, sodium salt, 1,2- dimyristoyl-sn-glycero-3-phosphoethanolamine, 1,2-dipalmitoyl-sn-glycero-3- phosphoethanolamine, 1,2-distearoyl-sn-glycero-3-phosphoethanolamine, 1,2-dioleoyl-sn-glycero- 3-phosphoethanolamine, 1,2-dioleoyl-sn-glycero-3-phospho-l-serine, sodium salt, 1,2-dipalmitoyl- sn-glycero-3-phosphate, monosodium salt, n-(carbonyl-methoxypolyethylene glycol-2000)-1,2- dimyristoyl-sn-glycero-3-phosphoethanolamine, sodium salt, n-(carbonyl-methoxypolyethylene glycol-2000)-1,2-distearoyl-sn-glycero-3-phosphoethanolamine, sodium salt, n-(carbonyl-methoxypolyethylene glycol-5000)-1,2-dipalmitoyl-sn-glycero-3-phosphoethanolamine, sodium salt1,2-dioleoyloxy-3-trimethylammonium-propane chloridetricaprylin, soybean oil, medium-chain triglycerides, fish oil, and oleic acid. In some embodiments, a parenteral formulation comprises at least one excipient selected from 1,2-distearoyl-sn-glycero-3-phospho-rac-glycerol (DSPG), cholesterol, hydrogenated soybean phosphatidylcholine (HSPC), 1-palmitoyl-2-oleoyl-sn-glycero- 3-phosphocholine (POPC), 1-palmitoyl, 2-oleoylphosphatidylglycerol, 1,2 dioleoylphosphatidylserine, phosphatidylcholine, dimyristoylphosphatidylglycerol (DMPG), or a salt thereof.

[0096] Liposomal formulations may comprise a combination of two or more excipients (e.g., phospholipids). In some embodiments, a parenteral formulation comprises at least two excipients selected from 1,2-distearoyl-sn-glycero-3-phospho-rac-glycerol (DSPG), cholesterol, hydrogenated soybean phosphatidylcholine (HSPC), 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine (POPC), phosphatidylcholine, dimyristoylphosphatidylglycerol (DMPG), or a salt thereof. In some embodiments, the ratio of the first excipient to the second excipient is 50:50 to 99:1, 60:40 to 99:1, 70:30 to 99:1, 80:20 to 99:1, 90:10 to 99:1, or 95:99:1. In some embodiments, the first excipient comprises HSPC, DMPC, phosphatidylcholine, DOPG, POPC, or a salt thereof. In some embodiments, the second excipient comprises DSPG, DMPG, DMPC, or a salt thereof.

[0097] Parenteral formulations of liposomes may comprise two excipients. In some instances, formulations comprise phospholipids. In some embodiments, formulations comprise two phospholipids. In some embodiments, the first lipid is zwitterionic with net neutral charge at pH 7. In some embodiments, the second lipid is negatively charged at pH 7. In some embodiments, the first lipid and the second lipid are at 37 °C in the liquid crystalline state. Without being bound by theory, liquid crystalline state in some embodiments comprises a physical state of the phospholipids at which the fatty acid chains are mobile and flexible. In some embodiments, the relevant transition temperature is called the “liquid to crystalline phase transition temperature”- below the lipids are in the mobile liquid crystalline state, above in the rigid gel state). In some embodiments, the first lipid and the second lipid comprise phospholipids with two esterified fatty acid chains (defined as diacyl-phospholipids). In some cases, a formulation comprises a phospholipid with a phase transition temperature above 37°C (e.g., DPPC or DSPC or hydrogenated soybean PC for uncharged lipids and DPPG or DSPG for charged lipids) is used in combination with other lipids such as cholesterol useful as component of the liposomes described herein. In some embodiments, the first lipid and the second lipid are parenteral grade and are available from reputed phospholipid vendors for large scale development and production of a pharmaceutical drug product. In some embodiments, a first lipid and a second lipid are independently selected from POPC (1-palmitoyl,2-oleoylphosphatidylcholine), DOPC (1.2- dioleoylphosphatidylcholine), DMPC (1.2- dimyristoylphksphatidylcholine), POPG (1-palmitoyl, 2-oleoylphosphatidylglycerol), POPG (1- palmitoyl, 2-oleoylphosphatidylglycerol) ammonium or sodium salt, DOPG (1,2 dioleoylphosphatidylglycerol), DOPG (1,2 dioleoylphosphatidylglycerol), ammonium or sodium salt, DOPS (1,2 dioleoylphosphatidylserine), DOPS (1,2 dioleoylphosphatidylserine) sodium salt, Lipoid S 100, DMPG, egg phosphatidylglycerol, or egg phosphatidylglycerol ammonium or sodium salt. In some embodiments, a first lipid is selected from soybean phosphatidylcholine with at least 96 % PC content (Lipoid S 100), Egg yolk PC with 70 - 100 % PC content (examples LIPOID E 80, Lipoid E 100j, Soybean PC with at least 70 up to 98 % PC content (example Lipoid S 75), POPC (1-palmitoyl, 2-oleoylphosphatidylcholine), DOPC (1.2- dioleoylphosphatidylcholine), or DMPC (1.2-dimyristoylphksphatidylcholine). In some embodiments, a second lipid is selected from DMPG (1,2 dimyristoylphosphatidylglycerol) (Lipoid DMPG), Egg phosphatidylglycerol, ammonium or sodium salt, POPG (1-palmitoyl, 2- oleoylphosphatidylglycerol), ammonium or sodium salt, DOPG (1,2 dioleoylphosphatidylglycerol) ammonium or sodium salt, DOPS (1,2 dioleoylphosphatidylserine) sodium salt. In some embodiments, the first lipid comprises soybean phosphatidylcholine with at least 96 % PC content (e.g., Lipoid S 100), In some embodiments, the second lipid comprises DMPG (1,2 dimyristoylphosphatidylglycerol) (Lipoid DMPG).

[0098] In some embodiments, a phospholipid used herein comprises a natural (e.g. egg yolk, soybean, rapeseed) or synthetic or semi-synthetic phospholipid (described in the catalogue of Avanti Polar Lipid (https: / / avantilipids.com / product-category / phospholipids). In some instances, a phospholipid comprises one or more of the following properties (a)-(h): (a) possessing two esterified fatty acids to the glycerol backbone of the phospholipids; (b) wherein the two fatty acids comprise a mixture of different fatty acids or two identical fatty acids, which yield at 37°C a liquid crystalline state of the phospholipid; (c) wherein said fatty acids may be saturated, mono unsaturated or polyunsaturated; (d) wherein said fatty acids have a chain length ranging from C2-C32; (e) wherein the polar head group of said un-charged phospholipids is choline (for example, a first lipid) or ethanolamine; (f) wherein said un-charged phospholipids (for example, a first lipid) is a sphingomyelin; (g) wherein the polar head group of the negatively charged phospholipid is selected from the group of inositol, glycerol, and serine (for example, a second lipid); and (h) wherein the negatively charged phospholipid (for example, a second lipid), is a phosphatidic acid or a cardiolipin.

[0099] In some embodiments, the phospholipids comprise a negative charge. It has been observed that, in some cases, a pharmaceutical composition disclosed herein comprising negatively charged phospholipids exerts a stronger anti-calcium effect than neutral charged phospholipids at pH values of about 7. Thus, in some embodiments, the phospholipids are negatively charged. In some embodiments, the phospholipids is lecithin. In some embodiments, the phospholipids is phosphatidylglycerol. In aqueous medium diacyl-phospholipids normally form liposomes. The participation of surfactant in the formation of vesicles increases the curvature, which results in liposomes with smaller diameter or results in thermodynamically stable micelles. The addition of surfactant, such as monoacyl-phospholipids or bile salt, reduces the viscosity of the formulation. Thus, in one embodiment, the pharmaceutical composition comprises Compound 1, or a pharmaceutically acceptable salt thereof, diacyl-phospholipids and at least one surfactant, preferably one surfactant. In some embodiments, the at least one surfactant is monoacyl- phospholipids. In some embodiments, the at least one surfactant is bile salt. In some embodiments, the at least one surfactant is vitamin E TPGS. In some embodiments, the pharmaceutical composition comprises diacyl- phospholipids and monoacyl-phospholipids. Typically, the molar ratio between monoacyl-phospholipids and diacyl-phospholipids is from at least about 1:20 to up to about 1:4, to up to about 1:3, to up to about 1:2, to up to about 1:1. In some embodiments, the pharmaceutical composition comprises diacyl- phospholipids and at least one bile salt, preferably one bile salt. Typically, the molar ratio between diacyl-phospholipids and the bile salt is from about 3:1 to about 1:3, from about 2:1 to about 1:2 and more typically about 1:1.

[0100] In some embodiments, the pharmaceutical composition comprises diacyl- phospholipids, monoacyl-phospholipids and at least one bile salt. Suitable bile salts include, but not limited to, sodium cholate, sodium deoxycholate, sodium chenodeoxycholate, sodium lithocholate, sodium ursodeoxycholate, sodium hyodeoxycholate, glycine conjugated sodium glycocholate, sodium glycodeoxycholate, sodium glycochenodeoxycholate, sodium glycoursodeoxycholate, taurine conjugated sodium taurocholate, sodium taurodeoxycholate, sodium taurochenodeoxycholate. In some embodiments, the bile salt is selected from a group consisting of sodium taurocholate sodium taurodeoxycholate sodium taurochenodeoxycholate sodium glycocholate, sodium glycodeoxycholate and sodium glycochenodeoxycholate. In some embodiments, the bile salt is selected from a group consisting of sodium cholate, sodium deoxycholate, sodium glycocholate, sodium taurocholate, and sodium taurodeoxycholate. In some embodiments, the bile salt is sodium taurocholate. In some embodiments, the bile salt is sodium glycocholate. Alternatively, bile salts exist in abundance in gastric intestinal tract, which could interact with the DA-PL released from the composition to form micelles or small sized liposomes even if the composition itself does notcomprise bile salt. In some embodiments, the phospholipid is soybean phosphatidylcholine or monoacyl-phospholipids. Lipoid LPC 80 contains 70%-80% of monoacyl-phospholipids, while the rest is mainly diacyl-phospholipids. In some embodiments, the pharmaceutical composition comprises phospholipids, wherein phospholipids is predominantly lyso-phospholipids. Used in this context, the term “predominantly” is understood that the molar ratio between monoacyl- phospholipids and diacyl-phospholipids is from at least about 1:1 to up to about 2:1, to up to about 3:1, to up to about 4:1, to up to about 5:1.

[0101] In one embodiment, the pharmaceutical composition comprises Compound 1 or a pharmaceutically acceptable salt thereof, phospholipids and at least one co-solvent. Co-solvent is miscible with water and can increase the solubilization of the drug. Preferably the co-solvent is pharmaceutically acceptable.

[0102] Pharmaceutical compositions (e.g., those containing liposomes) may comprise a buffer as disclosed herein. In some embodiments, the buffer comprises a pH of 6-8, 6-7, 7-8, or 7-9. In some embodiments, the buffer is isotonic and isohydric. In some embodiments, the buffer comprises a sugar. In some embodiments, the buffer is isotonic. In some embodiments, the buffer comprises sucrose. In some embodiments, the buffer comprises an isotonizing agent. In some embodiments, the buffer comprises a sugar. In some embodiments, the buffer comprises saline, glucose, sucrose, lactose, trehalose, and maltose, or other sugar. In some embodiments, the buffer comprises a phosphate buffer. In some embodiments, the buffer comprises sodium phosphate dibasic, potassium phosphate monobasic, or a combination thereof.

[0103] Pharmaceutical compositions provided herein may comprise liposome particles of defined size. In some instances, particles comprise an average particle size of 100-500, 100-400, 100-300, 100-250, 100-200, 150-500, 150-400, 150-300, 150-250, 150-200, 175-300, 175-250, 175-200, 200-500, 200-400, 200-300, or 300-500 nm. In some instance, particles comprise an average particle size of no more than 500, 400, 300, 275, 250, 225, 200, 190, 180, 175, 170, 160, 150, or no more than 140 nm. In some instance, particles comprise a PDI of no more than 0.05, 0.1, 0.14, 0.15, 0.16, 0.17, 0.18, 0.19, 0.2, 0.25, 0.3, 0.35, 0.4 or no more than 0.5. In some embodiments, liposomes comprise average particle sizes enabling passage through a 0.22 micron pore size filter for sterilization purposes.

[0104] Pharmaceutical compositions may be used immediately, or prepared for storage. In some instances, a parenteral formulations (e.g., liposomal formulation) is stored as a solid. In some instances, a parenteral formulations (e.g., liposomal formulation) is frozen. In some instances, a parenteral formulations (e.g., liposomal formulation) is stored as a lyophilized powder. In some instances, a parenteral formulations (e.g., liposomal formulation) is stored as a liquid or solution. Insome instances, a parenteral formulations (e.g., liposomal formulation) is stored at a temperature of no more than 30, 25, 20, 15, 10, 5, 4, 0, -5, -10, -15, -20, or no more than -40 degrees C. In some embodiments, parenteral formulations are stored under inert gas or under vacuum. In some embodiments, parenteral formulations are stored under nitrogen or argon.

[0105] Pharmaceutical compositions disclosed herein may comprise advantageous properties for storage. In some embodiments, formulations (e.g., liposomes) comprise increased chemical and physical stability. In some embodiments, formulations (e.g., liposomes) are stable in terms of average particle size and chemical degradation. In some embodiments, pharmaceutical compositions are stable at room temperature for at least one week, two weeks, three weeks, one month, two months, three months, four months, five months, six months, eight months, ten months, a year, two years, or at least three years. In some embodiments, the pharmaceutical composition is stable at 2-8 degrees C for at least one week, two weeks, three weeks, one month, two months, three months, four months, five months, six months, eight months, ten months, a year, two years, or at least three years. In some embodiments, the pharmaceutical composition is stable at no more than 4 degrees C for at least one week, two weeks, three weeks, one month, two months, three months, four months, five months, six months, eight months, ten months, a year, two years, or at least three years. In some embodiments, the pharmaceutical composition is stable at no more than 0 degrees C for at least one week, two weeks, three weeks, one month, two months, three months, four months, five months, six months, eight months, ten months, a year, two years, or at least three years. In some embodiments, the pharmaceutical composition is stable at no more than -10 degrees C for at least one week, two weeks, three weeks, one month, two months, three months, four months, five months, six months, eight months, ten months, a year, two years, or at least three years. In some embodiments, the pharmaceutical composition is stable at no more than -20 degrees C for at least one week, two weeks, three weeks, one month, two months, three months, four months, five months, six months, eight months, ten months, a year, two years, or at least three years. In some embodiments, the pharmaceutical composition is essentially unchanged at no more than 20, 4, 0, -10, or -20 degrees C for at least one week, two weeks, three weeks, one month, two months, three months, four months, five months, six months, eight months, ten months, a year, two years, or at least three years as measured by HPLC. In some embodiments, the pharmaceutical composition is essentially unchanged at no more than -20 degrees C for at least one week, two weeks, three weeks, one month, two months, three months, four months, five months, six months, eight months, ten months, a year, two years, or at least three years as measured by HPLC. In some embodiments, the pharmaceutical composition comprises no more than 0.1, 0.2, 0.5, 0.7, or no more than 1% degradation at no more than 20, 4, 0, -10, or -20 degrees C for at least one week, twoweeks, three weeks, one month, two months, three months, four months, five months, six months, eight months, ten months, a year, two years, or at least three years as measured by HPLC. In some embodiments, the pharmaceutical composition comprises no more than 0.1, 0.2, 0.5, 0.7, or no more than 1% Compound 1 degradation at no more than 20, 4, 0, -10, or -20 degrees C for at least one week, two weeks, three weeks, one month, two months, three months, four months, five months, six months, eight months, ten months, a year, two years, or at least three years as measured by HPLC. In some embodiments, the pharmaceutical composition comprises no more than 0.1, 0.2, 0.5, 0.7, or no more than 1% Compound 1 and phospholipid degradation at no more than 20, 4, 0, - 10, or -20 degrees C for at least one week, two weeks, three weeks, one month, two months, three months, four months, five months, six months, eight months, ten months, a year, two years, or at least three years as measured by HPLC. In some embodiments, the pharmaceutical composition comprises no more than 0.1, 0.2, 0.5, 0.7, or no more than 1% phospholipid degradation at no more than 20, 4, 0, -10, or -20 degrees C for at least one week, two weeks, three weeks, one month, two months, three months, four months, five months, six months, eight months, ten months, a year, two years, or at least three years as measured by HPLC. In some embodiments, formulations prevent or reduce crystallization, which may negatively affect parenteral administration. In some embodiments, the pharmaceutical composition is substantially free of crystals. In some embodiments, the pharmaceutical composition is substantially free of crystals as measured under light microscopy. In some embodiments, the pharmaceutical composition is substantially free of crystals after at least one week, one month, two months, six months, or at least a year. In some embodiments, the pharmaceutical composition is substantially free of crystals after at least 1, 2, 3, 4, 5, 6, or more than 6 freeze-thaw cycles.

[0106] Pharmaceutical compositions disclosed herein may have a high purity (e.g., purity of Compound 1). In some embodiments, the purity of a pharmaceutical compositions is at least 90, 92, 94, 95, 96, 97, 98, 99, 99.5, 99.8, 99.9, or at least 99.95% pure. In some embodiments, a pharmaceutical compositions is essentially free of solvents or other impurities. In some embodiments, a pharmaceutical compositions comprises no more than 10,000, 7500, 5000, 4000, 3000, 2000, 1000, or no more than 500 ppm residual solvent. In some embodiments, solvent comprises an alcohol, ether, ketone, aldehyde, amide, amine, alkane, or haloalkane solvent. In some embodiments, the solvent comprises methanol, ethanol, or chloroform.

[0107] Nanosuspensions

[0108] Parenteral formulations may comprise a nanosuspension. In some instances, the parenteral formulation comprises a nanosuspension. In some instances, the at least one excipient comprises poloxamer 188, polyvinyl ketone (PVK) K17, PVK K30, or Sodium Deoxycholate. In someinstances, the at least one excipient comprises a wetting agent for a nanoparticle formulation. In some instances, the wetting agent comprises poloxamer 188, polyvinyl ketone (PVK) K17, PVK K30, or sodium deoxycholate. In some instances, the pharmaceutical composition comprises 0.1- 5%, 0.1-4, 0.1-3, 0.1-2, 0.1-1, 0.2-0.6, 0.3-0.5, 0.5-5, 0.5-3, 0.5-2, 0.5-1.5, 1-5, 1-4, 1-3, 1-2, 2-5, or 2-7% poloxamer 188. In some instances, the pharmaceutical composition comprises 0.01-0.5, 0.02- 0.5, 0.05-0.5, 0.05-0.4, 0.05-0.3, 0.05-0.2, 0.05-0.1, 0.1-0.5, 0.2-0.5 or 0.3-0.5% sodium deoxycholate. In some instances, the pharmaceutical composition comprises 0.1-3, 0.2-2, 0.3-3, 0.5-3, 1-3, 1.5-3, 2-3, or 0.5-3% PVP K17 or PVP K30. In some instances, the compound is present at 20-200, 20-150, 20-100, 25-150, 25-100, 50-150, 50-200, 75-200, 75-200, 100-200, or 150-300 mg / mL. Methods of Making Compound 1 and Polymorphic Forms Thereof

[0109] In another aspect, the present disclosure provides methods of making Compound 1 or polymorphs thereof:p , or a pharmaceutically acceptable solvate or hydrate thereof.

[0110] The preparation and uses of Compound 1 have been previously described (see, Example 81 of US 7,504,522, which is incorporated by reference in its entirety).

[0111] The preparation of polymorphs of Compound 1 has been previously described (see, US 11,795,146, which is incorporated by reference in its entirety). Methods of Treatment

[0112] Methods provided herein may comprise measurement of one or more metrics followed by treatment with compounds described herein (e.g., Compound 1). In some instances, parenteral formulations provided herein are uniquely suited to treat subjects that are unable to receive treatment using alternative methods of administration (e.g., oral), or require amelioration of symptoms faster than provided by other routes of administration.

[0113] In one aspect, the present disclosure provides a method of treating known or suspected acute drug overdose reaction in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of (R)-N-(tert-butyl)-3-((4-chlorophenyl)(2-(trifluoromethyl)phenyl)methoxy)azetidine-1-carboxamide, or the pharmaceutical composition as described herein. Provided herein are methods of treating a known or suspected acute cannabinoid toxicity in a subject in need thereof, the method comprising: administering to the subject a therapeutically-effective amount of a compound having the structure:. In some instances, the method comprises parenteral administration.

[0114] In some embodiments, the subject shows signs of an acute cannabinoid overdose. In some embodiments, the acute cannabinoid overdose is caused by a compound from the Cannabis genus. In some embodiments, the acute cannabinoid overdose is caused by a synthetic cannabinoid. In some embodiments, the acute cannabinoid overdose is caused by oral ingestion of cannabinoids or synthetic cannabinoids. In some embodiments, the acute cannabinoid overdose is caused by oral ingestion of cannabinoids or synthetic cannabinoids. In some embodiments, the synthetic cannabinoid is capable of binding to the Cannabinoid (CB1) receptor.

[0115] A subject may be unwilling or physically unable to be administered an oral formulation. This could include inability to swallow, unconsciousness, or age limitations. In some embodiments, the subject shows signs of cannabinoid hyperemesis syndrome. In some instances, the subject shows signs of vomiting. In some instances, parenteral administration is used to treat subjects showing symptoms of cannabinoid hyperemesis syndrome and / or vomiting. In some instances, parenteral administration is used to treat subjects showing symptoms of nausea, vomiting, coughing, and choking.

[0116] In some embodiments, parenteral administration is used to treat subjects showing symptoms of cannabis toxicity / poisoning (e.g., pediatric patients). In some instances, parenteral administration is used to treat subjects showing neurologic, cardiovascular, gastrointestinal, ocular, respiratory, or other cannabinoid toxicity symptom. In some instances, parenteral administration is used to treat subjects showing symptoms of cannabis-induced CNS depression. In some instances, parenteral administration is used to treat subjects showing symptoms of CNS depression, respiratory depression, drowsiness / lethargy, ataxia, tachycardia, agitation, confusion tremors, seizures, and coma. In some instances, parenteral administration is used to treat subjects showing symptoms of anaphylactic shock. In some instances, parenteral administration is used to treatsubjects experiencing trauma or swelling to the face, mouth, throat, esophagus, or digestive tract. In some instances, respiratory depression is caused by synthetic cannabinoids. In some instances, respiratory depression is caused by another drug in the patient’s system, such as an opiate. In some instances, parenteral administration is used to treat acute cannabis (or cannabinoid)-induced CNS depression.

[0117] Provided herein are methods of treating cannabinoid overdose in pediatric patients. In some embodiments, a pediatric patient comprises an adolescent, child, infant, or neonate. In some embodiments, the patient is no more than 28 days, 2 years, 12 years, or 21 years old. In some embodiments, the patient is 1-28 days old, 29 days to less than 2 years old, 2 years to less than 12 years old, or 12 years to less than 21 years old. In some embodiments, the method further comprises monitoring the subject for improvement of cannabinoid overdose symptoms. In some instances, parenteral administration is used to treat subjects showing neurologic, cardiovascular, gastrointestinal, ocular, respiratory, or other cannabinoid toxicity symptom. In some instances, neurologic symptoms comprise one or more of ataxia, agitation, confusion, tremor, dizziness / vertigo, seizure, hallucinations / delusions, slurred speech, or headache. In some instances, cardiovascular symptoms comprise one or more of tachycardia, hypotension, bradycardia, hypertension. In some instances, gastrointestinal symptoms comprise one or more of vomiting, nausea, and abdominal pain. In some instances, ocular symptoms comprise one or more of mydriasis, red eye / conjunctivitis, nystagmus, and miosis. In some instances, respiratory symptoms comprise one or more of respiratory depression and hyperventilation / tachypnea. In some instances, additional symptoms comprise one or more of pallor, fever / hyperthermia, acidosis, muscle weakness, hypothermia, urinary retention, and electrolyte abnormality.

[0118] Administration (e.g., parenteral) with a compound described herein (e.g., Compound 1) to treat cannabinoid intoxication may occur immediately after exposure to cannabis, extract thereof, or synthetic cannabinoid (e.g., first time;), or at a later time (e.g., second time). In some instances, administration (e.g., ingestion of edibles, inhalation, etc.) of cannabis or other cannabinoid occurs at the same time as administration of a cannabinoid intoxication treatment (e.g., Compound 1). In some instances, administration (e.g., ingestion of edibles, inhalation, etc.) of cannabis or other cannabinoid occurs prior to treatment. In some instances, administration (e.g., ingestion of edibles, inhalation, etc.) of cannabis or other cannabinoid occurs 0.1, 0.2, 0.5, 0.7.1, 1.5, 2, 3, 4, 5, 6, 8, 10, 12, 14, 16, or about 20 hours prior to treatment (e.g., administration of Compound 1). In some instances, administration (e.g., ingestion of edibles, inhalation, etc.) of cannabis or other cannabinoid occurs at least 0.1, 0.2, 0.5, 0.7, 1, 1.5, 2, 3, 4, 5, 6, 8, 10, 12, 14, 16, or no more than 20 hours prior to treatment (e.g., administration of Compound 1). In some instances, administration(e.g., ingestion of edibles, inhalation, etc.) of cannabis or other cannabinoid occurs at least 0.1, 0.2, 0.5, 0.7, 1, 1.5, 2, 3, 4, 5, 6, 8, 10, 12, 14, 16, or at least 20 hours prior to treatment (e.g., administration of Compound 1). In some instances, administration (e.g., ingestion of edibles, inhalation, etc.) of cannabis or other cannabinoid occurs at least 0.1-20.0.1-16, 0.1-12, 0.1-10, 0.1- 8, 0.1-6, 0.1-6, 0.1-4, 0.1-1, 0.5-12, 0.5-8, 0.5-6, 0.5-4, 1-8, 1-6, 1-4, 1-2, 2-4, 2-6, 2-8, 4-12, 4-6, 4- 8, 4-12, 6-12, 6-14, or 6-20 hours prior to treatment (e.g., administration of Compound 1).

[0119] In some embodiments, the method further comprising treatment for drug overdose prior to treatment with (R)-N-(tert-butyl)-3-((4-chlorophenyl)(2- (trifluoromethyl)phenyl)methoxy)azetidine-1-carboxamide. In some embodiments, the prior treatment comprises one or more of administration of an opiate antagonist, activated charcoal, or emetic.

[0120] In another aspect, the present disclosure provides a method of using (R)-N-(tert-butyl)-3- ((4-chlorophenyl)(2-(trifluoromethyl)phenyl)methoxy)azetidine-1-carboxamide, or the pharmaceutical composition as described herein, comprising administering a therapeutically effective amount of (R)-N-(tert-butyl)-3-((4-chlorophenyl)(2- (trifluoromethyl)phenyl)methoxy)azetidine-1-carboxamide prior to exposure to a cannabinoid. In some embodiments, the cannabinoid is tetrahydrocannabinol (THC).

[0121] In another aspect, the present disclosure provides a method of treating a subject suspected of a drug overdose, comprising administering a therapeutically effective amount of (R)-N-(tert- butyl)-3-((4-chlorophenyl)(2-(trifluoromethyl)phenyl)methoxy)azetidine-1-carboxamide to the subject and monitoring said subject for reduced symptoms associated with overdose. In some embodiments, the monitoring comprises monitoring heart rate or respiration.

[0122] In another aspect, the present disclosure provides a method of treating cannabis use disorder (CUD) in a subject in need thereof, comprising administering a therapeutically effective amount of (R)-N-(tert-butyl)-3-((4-chlorophenyl)(2-(trifluoromethyl)phenyl)methoxy)azetidine-1- carboxamide, or the pharmaceutical composition as described herein. In some embodiments, the subject is addicted to a compound from the Cannabis genus. In some embodiments, the subject is addicted to a synthetic cannabinoid. In some embodiments, the synthetic cannabinoid is capable of binding to the CB1 receptor.

[0123] In various embodiments of the methods as described herein, (R)-N-(tert-butyl)-3-((4- chlorophenyl)(2-(trifluoromethyl)phenyl)methoxy)azetidine-1-carboxamide is Form I. In another embodiment, (R)-N-(tert-butyl)-3-((4-chlorophenyl)(2-(trifluoromethyl)phenyl)methoxy)azetidine- 1-carboxamide is Form II.

[0124] In various embodiments of the methods described herein, the method further comprising a diagnostic test prior to treatment with (R)-N-(tert-butyl)-3-((4-chlorophenyl)(2- (trifluoromethyl)phenyl)methoxy)azetidine-1-carboxamide. In some embodiments, the diagnostic test is a blood test. In some embodiments, the subject has a cannabinoid plasma concentration of at least 25 μg / L. In some embodiments, the diagnostic test is a blood test. In some embodiments, the subject has a cannabinoid plasma concentration of at least 50 μg / L. In some embodiments, the subject has a cannabinoid plasma concentration of about 25 μg / L to 350 μg / L. In some embodiments, the subject has a cannabinoid plasma concentration of about 50 μg / L to 350 μg / L. In some embodiments, the subject has a cannabinoid plasma concentration of about 75 μg / L to 350 μg / L. In some embodiments, the subject has a cannabinoid plasma concentration of about 100 μg / L to 350 μg / L. In some embodiments, the subject has a cannabinoid plasma concentration of about 150 μg / L to 350 μg / L. In some embodiments, the subject has a cannabinoid plasma concentration of about 200 μg / L to 350 μg / L.

[0125] In various embodiments of the methods described here, the amount of (R)-N-(tert-butyl)-3- ((4-chlorophenyl)(2-(trifluoromethyl)phenyl)methoxy)azetidine-1-carboxamide is between about 0.1 mg to about 200 mg. In another embodiment, the amount of (R)-N-(tert-butyl)-3-((4- chlorophenyl)(2-(trifluoromethyl)phenyl)methoxy)azetidine-1-carboxamide is between about 1 mg to about 200 mg. In another embodiment, the amount of (R)-N-(tert-butyl)-3-((4-chlorophenyl)(2- (trifluoromethyl)phenyl)methoxy)azetidine-1-carboxamide is between about 0.5 mg to about 200 mg. In another embodiment, the amount of (R)-N-(tert-butyl)-3-((4-chlorophenyl)(2- (trifluoromethyl)phenyl)methoxy)azetidine-1-carboxamide is between about 2 mg to about 200 mg. In another embodiment, the amount of (R)-N-(tert-butyl)-3-((4-chlorophenyl)(2- (trifluoromethyl)phenyl)methoxy)azetidine-1-carboxamide is between about 5 mg to about 200 mg. In another embodiment, the amount of (R)-N-(tert-butyl)-3-((4-chlorophenyl)(2- (trifluoromethyl)phenyl)methoxy)azetidine-1-carboxamide is between about 10 mg to about 200 mg. In another embodiment, the amount of (R)-N-(tert-butyl)-3-((4-chlorophenyl)(2- (trifluoromethyl)phenyl)methoxy)azetidine-1-carboxamide is between about 15 mg to about 200 mg. In another embodiment, the amount of (R)-N-(tert-butyl)-3-((4-chlorophenyl)(2- (trifluoromethyl)phenyl)methoxy)azetidine-1-carboxamide is between about 20 mg to about 200 mg. In another embodiment, the amount of (R)-N-(tert-butyl)-3-((4-chlorophenyl)(2- (trifluoromethyl)phenyl)methoxy)azetidine-1-carboxamide is between about 25 mg to about 200 mg. In another embodiment, the amount of (R)-N-(tert-butyl)-3-((4-chlorophenyl)(2- (trifluoromethyl)phenyl)methoxy)azetidine-1-carboxamide is between about 30 mg to about 200 mg. In another embodiment, the amount of (R)-N-(tert-butyl)-3-((4-chlorophenyl)(2-(trifluoromethyl)phenyl)methoxy)azetidine-1-carboxamide is between about 35 mg to about 200 mg. In another embodiment, the amount of (R)-N-(tert-butyl)-3-((4-chlorophenyl)(2- (trifluoromethyl)phenyl)methoxy)azetidine-1-carboxamide is between about 40 mg to about 200 mg. In another embodiment, the amount of (R)-N-(tert-butyl)-3-((4-chlorophenyl)(2- (trifluoromethyl)phenyl)methoxy)azetidine-1-carboxamide is between about 45 mg to about 200 mg. In another embodiment, the amount of (R)-N-(tert-butyl)-3-((4-chlorophenyl)(2- (trifluoromethyl)phenyl)methoxy)azetidine-1-carboxamide is between about 50 mg to about 200 mg. In another embodiment, the amount of (R)-N-(tert-butyl)-3-((4-chlorophenyl)(2- (trifluoromethyl)phenyl)methoxy)azetidine-1-carboxamide is between about 75 mg to about 200 mg. In another embodiment, the amount of (R)-N-(tert-butyl)-3-((4-chlorophenyl)(2- (trifluoromethyl)phenyl)methoxy)azetidine-1-carboxamide is between about 100 mg to about 200 mg. In another embodiment, the amount of (R)-N-(tert-butyl)-3-((4-chlorophenyl)(2- (trifluoromethyl)phenyl)methoxy)azetidine-1-carboxamide is between about 125 mg to about 200 mg. In another embodiment, the amount of (R)-N-(tert-butyl)-3-((4-chlorophenyl)(2- (trifluoromethyl)phenyl)methoxy)azetidine-1-carboxamide is between about 150 mg to about 200 mg. In another embodiment, the amount of (R)-N-(tert-butyl)-3-((4-chlorophenyl)(2- (trifluoromethyl)phenyl)methoxy)azetidine-1-carboxamide is between about 175 mg to about 200 mg. In another embodiment, the amount of (R)-N-(tert-butyl)-3-((4-chlorophenyl)(2- (trifluoromethyl)phenyl)methoxy)azetidine-1-carboxamide is 25-500, 25-400, 25-300, 25-250, 25- 200, 25-150, 25-100, or 25-75 mg. In another embodiment, the amount of (R)-N-(tert-butyl)-3-((4- chlorophenyl)(2-(trifluoromethyl)phenyl)methoxy)azetidine-1-carboxamide is 50-500, 50-400, 50- 300, 50-250, 50-200, 50-150, 50-100, or 50-75 mg. In another embodiment, the amount of (R)-N- (tert-butyl)-3-((4-chlorophenyl)(2-(trifluoromethyl)phenyl)methoxy)azetidine-1-carboxamide is 75- 500, 75-400, 75-300, 75-250, 75-200, 75-150, 75-100, or 75-125 mg. In another embodiment, the amount of (R)-N-(tert-butyl)-3-((4-chlorophenyl)(2-(trifluoromethyl)phenyl)methoxy)azetidine-1- carboxamide is 100-500, 100-400, 100-300, 100-250, 100-200, 100-150, 100-125 mg. In another embodiment, the amount of (R)-N-(tert-butyl)-3-((4-chlorophenyl)(2- (trifluoromethyl)phenyl)methoxy)azetidine-1-carboxamide is 1-200 mg, 10-50 mg, 10-30 mg, or 20-30 mg. In another embodiment, the amount of (R)-N-(tert-butyl)-3-((4-chlorophenyl)(2- (trifluoromethyl)phenyl)methoxy)azetidine-1-carboxamide is 5-300 mg, 5-100 mg, or 10-30 mg. In another embodiment, the amount of (R)-N-(tert-butyl)-3-((4-chlorophenyl)(2- (trifluoromethyl)phenyl)methoxy)azetidine-1-carboxamide is 1-50, 1-30, 1-25, 1-20, 1-15, 1-20, 1- 5, or 1-3 mg. In another embodiment, the amount of (R)-N-(tert-butyl)-3-((4-chlorophenyl)(2- (trifluoromethyl)phenyl)methoxy)azetidine-1-carboxamide is about 1 mg, about 5 mg, about 10mg, about 15 mg, about 20 mg, about 30 mg or about 50 mg. In some instances, administration is parenteral. Further provided herein are methods wherein the amount of compound administered parenterally to the subject is about 1 mg, about 5 mg, about 10 mg, about 15 mg, about 20 mg, about 30 mg or about 50 mg.

[0126] In various embodiments, the method is capable of ameliorating one or more symptoms of the acute drug overdose reaction in no more than 30 minutes. In another embodiment, the method is capable of ameliorating one or more symptoms of the acute drug overdose reaction in no more than 1 hour. In various embodiments, the method is capable of ameliorating one or more symptoms of the acute drug overdose reaction in no more than 10 minutes. In another embodiment, the method is capable of ameliorating one or more symptoms of the acute drug overdose reaction in no more than 15 minutes. In various embodiments, the method is capable of ameliorating one or more symptoms of the acute drug overdose reaction in no more than 45 minutes. In another embodiment, the method is capable of ameliorating one or more symptoms of the acute drug overdose reaction in no more than 20 minutes. In another embodiment, the method is capable of ameliorating one or more symptoms of the acute drug overdose reaction in no more than 5 minutes. In another embodiment, the method is capable of ameliorating one or more symptoms of the acute drug overdose reaction in no more than 3 minutes. In another embodiment, the method is capable of ameliorating one or more symptoms of the acute drug overdose reaction in no more than 1 minute. In another embodiment, the method is capable of ameliorating one or more symptoms of the acute drug overdose reaction in no more than 1 minute. In another embodiment, the method is capable of ameliorating one or more symptoms of the acute drug overdose reaction in no more than 30 seconds. In another embodiment, the method is capable of ameliorating one or more symptoms of the acute drug overdose reaction in no more than 10 seconds. In various embodiments, the method is capable of ameliorating one or more symptoms of the acute drug overdose reaction in 5-60, 5-45, 5-30, 5-25, 5-20, 5-15, 5-10, 10- 60, 10-120, 10-30, 20-60, 20-120, 50-120, 60-120, or 90-120 minutes. In various embodiments, the method is capable of ameliorating one or more symptoms of the acute drug overdose reaction in 5- 60, 5-45, 5-30, 5-25, 5-20, 5-15, 5-10, 10-60, 10-120, 10-30, 20-60, 20-120, 50-120, 60-120, or 90- 120 minutes by parenteral injection. In various embodiments, the method is capable of ameliorating one or more symptoms of the acute drug overdose reaction in 5-60, 5-45, 5-30, 5-25, 5-20, 5-15, 5- 10, 10-60, 10-120, 10-30, 20-60, 20-120, 50-120, 60-120, or 90-120 seconds by parenteral injection.

[0127] Compounds described herein (e.g., Compound 1) in some instances have desirable PK profiles for treating cannabinoid overdose. In some instances, concentrations (e.g., Cmax, AUC, etc.) of Compound 1 are measured in plasma.

[0128] In various embodiments of the methods described herein, the amount of (R)-N-(tert-butyl)- 3-((4-chlorophenyl)(2-(trifluoromethyl)phenyl)methoxy)azetidine-1-carboxamide in the bloodstream of the subject reaches at least about 50 ng / mL, at least about 100 ng / mL or at least about 200 ng / mL within one hour after parenteral administration. In another embodiment, the amount of (R)-N-(tert-butyl)-3-((4-chlorophenyl)(2-(trifluoromethyl)phenyl)methoxy)azetidine-1- carboxamide in the bloodstream of the subject reaches at least 200 ng / mL within 50 minutes after parenteral administration. In another embodiment, the amount of (R)-N-(tert-butyl)-3-((4- chlorophenyl)(2-(trifluoromethyl)phenyl)methoxy)azetidine-1-carboxamide in the bloodstream of the subject reaches at least 200 ng / mL within 40 minutes after parenteral administration. In another embodiment, the amount of (R)-N-(tert-butyl)-3-((4-chlorophenyl)(2- (trifluoromethyl)phenyl)methoxy)azetidine-1-carboxamide in the bloodstream of the subject reaches at least 200 ng / mL within 30 minutes after parenteral administration. In another embodiment, the amount of (R)-N-(tert-butyl)-3-((4-chlorophenyl)(2- (trifluoromethyl)phenyl)methoxy)azetidine-1-carboxamide in the bloodstream of the subject reaches at least 200 ng / mL within 20 minutes after parenteral administration. In another embodiment, the amount of (R)-N-(tert-butyl)-3-((4-chlorophenyl)(2- (trifluoromethyl)phenyl)methoxy)azetidine-1-carboxamide in the bloodstream of the subject reaches at least 200 ng / mL within 10 minutes after parenteral administration. In another embodiment, the amount of (R)-N-(tert-butyl)-3-((4-chlorophenyl)(2- (trifluoromethyl)phenyl)methoxy)azetidine-1-carboxamide in the bloodstream of the subject reaches at least 200 ng / mL within 5 minutes after parenteral administration. In another embodiment, the amount of (R)-N-(tert-butyl)-3-((4-chlorophenyl)(2- (trifluoromethyl)phenyl)methoxy)azetidine-1-carboxamide in the bloodstream of the subject reaches at least 200 ng / mL within 3 minutes after parenteral administration. In another embodiment, the amount of (R)-N-(tert-butyl)-3-((4-chlorophenyl)(2- (trifluoromethyl)phenyl)methoxy)azetidine-1-carboxamide in the bloodstream of the subject reaches at least 200 ng / mL within 1 minute after parenteral administration. In another embodiment, the amount of (R)-N-(tert-butyl)-3-((4-chlorophenyl)(2-(trifluoromethyl)phenyl)methoxy)azetidine- 1-carboxamide in the bloodstream of the subject reaches at least 200 ng / mL within 30 seconds after parenteral administration. In another embodiment, the amount of ®-N-(tert-butyl)-3-((4- chlorophenyl)(2-(trifluoromethyl)phenyl)methoxy)azetidine-1-carboxamide in the bloodstream of the subject reaches at least 200 ng / mL within 15 seconds after parenteral administration. In another embodiment, the amount of (R)-N-(tert-butyl)-3-((4-chlorophenyl)(2-(trifluoromethyl)phenyl)methoxy)azetidine-1-carboxamide in the bloodstream of the subject reaches at least 200 ng / mL within 10 seconds after parenteral administration.

[0129] In various embodiments of the methods described herein, the amount of (R)-N-(tert-butyl)- 3-((4-chlorophenyl)(2-(trifluoromethyl)phenyl)methoxy)azetidine-1-carboxamide in the bloodstream of the subject reaches at least 200 ng / mL within one hour after parenteral administration. In another embodiment, the amount of (R)-N-(tert-butyl)-3-((4-chlorophenyl)(2- (trifluoromethyl)phenyl)methoxy)azetidine-1-carboxamide in the bloodstream of the subject reaches at least 150 ng / mL within 50 minutes after parenteral administration. In another embodiment, the amount of (R)-N-(tert-butyl)-3-((4-chlorophenyl)(2- (trifluoromethyl)phenyl)methoxy)azetidine-1-carboxamide in the bloodstream of the subject reaches at least 150 ng / mL within 40 minutes after parenteral administration. In another embodiment, the amount of (R)-N-(tert-butyl)-3-((4-chlorophenyl)(2- (trifluoromethyl)phenyl)methoxy)azetidine-1-carboxamide in the bloodstream of the subject reaches at least 150 ng / mL within 30 minutes after parenteral administration. In another embodiment, the amount of (R)-N-(tert-butyl)-3-((4-chlorophenyl)(2- (trifluoromethyl)phenyl)methoxy)azetidine-1-carboxamide in the bloodstream of the subject reaches at least 150 ng / mL within 20 minutes after parenteral administration. In another embodiment, the amount of (R)-N-(tert-butyl)-3-((4-chlorophenyl)(2- (trifluoromethyl)phenyl)methoxy)azetidine-1-carboxamide in the bloodstream of the subject reaches at least 150 ng / mL within 10 minutes after parenteral administration. In another embodiment, the amount of (R)-N-(tert-butyl)-3-((4-chlorophenyl)(2- (trifluoromethyl)phenyl)methoxy)azetidine-1-carboxamide in the bloodstream of the subject reaches at least 150 ng / mL within 5 minutes after parenteral administration. In another embodiment, the amount of (R)-N-(tert-butyl)-3-((4-chlorophenyl)(2- (trifluoromethyl)phenyl)methoxy)azetidine-1-carboxamide in the bloodstream of the subject reaches at least 150 ng / mL within 5 minutes after parenteral administration. In another embodiment, the amount of (R)-N-(tert-butyl)-3-((4-chlorophenyl)(2- (trifluoromethyl)phenyl)methoxy)azetidine-1-carboxamide in the bloodstream of the subject reaches at least 150 ng / mL within 3 minutes after parenteral administration. In another embodiment, the amount of (R)-N-(tert-butyl)-3-((4-chlorophenyl)(2- (trifluoromethyl)phenyl)methoxy)azetidine-1-carboxamide in the bloodstream of the subject reaches at least 150 ng / mL within 1 minute after parenteral administration. In another embodiment, the amount of (R)-N-(tert-butyl)-3-((4-chlorophenyl)(2-(trifluoromethyl)phenyl)methoxy)azetidine- 1-carboxamide in the bloodstream of the subject reaches at least 150 ng / mL within 30 seconds afterparenteral administration. In another embodiment, the amount of (R)-N-(tert-butyl)-3-((4- chlorophenyl)(2-(trifluoromethyl)phenyl)methoxy)azetidine-1-carboxamide in the bloodstream of the subject reaches at least 150 ng / mL within 15 seconds after parenteral administration. In another embodiment, the amount of (R)-N-(tert-butyl)-3-((4-chlorophenyl)(2- (trifluoromethyl)phenyl)methoxy)azetidine-1-carboxamide in the bloodstream of the subject reaches at least 150 ng / mL within 10 seconds after parenteral administration.

[0130] In some instances, (R)-N-(tert-butyl)-3-((4-chlorophenyl)(2- (trifluoromethyl)phenyl)methoxy)azetidine-1-carboxamide is dosed to provide a Tmax of no more than 5, 4, 3, 2.5, 2.25, 2, 1.75, 1.5, 1.25, 1, 0.75, 0.5, or 0.25 hours. In some instances, (R)-N-(tert- butyl)-3-((4-chlorophenyl)(2-(trifluoromethyl)phenyl)methoxy)azetidine-1-carboxamide is dosed to provide a Tmax of 0.1-5, 0.1-4, 0.1-3, 0.1-2, 0.1-1.5, 0.1-1, 0.25-3, 0.25-2, 0.25-1.5, 0.25-1, 0.5-3, 0.5-2.5, 0.5-2, 0.5-1.5, 0.5-1.25, 0.5-1, 0.5-0.75, or 0.1-0.75 hr. In some instances, (R)-N-(tert- butyl)-3-((4-chlorophenyl)(2-(trifluoromethyl)phenyl)methoxy)azetidine-1-carboxamide dosed at 100-200 mg provides a Tmax of 0.1-5, 0.1-4, 0.1-3, 0.1-2, 0.1-1.5, 0.1-1, 0.25-3, 0.25-2, 0.25-1.5, 0.25-1, 0.5-3, 0.5-2.5, 0.5-2, 0.5-1.5, 0.5-1.25, 0.5-1, 0.5-0.75, or 0.1-0.75 hr. In some instances, (R)-N-(tert-butyl)-3-((4-chlorophenyl)(2-(trifluoromethyl)phenyl)methoxy)azetidine-1- carboxamide dosed at 25-250 mg provides a Tmax of 0.1-5, 0.1-4, 0.1-3, 0.1-2, 0.1-1.5, 0.1-1, 0.25- 3, 0.25-2, 0.25-1.5, 0.25-1, 0.5-3, 0.5-2.5, 0.5-2, 0.5-1.5, 0.5-1.25, 0.5-1, 0.5-0.75, or 0.1-0.75 hr. In some instances, (R)-N-(tert-butyl)-3-((4-chlorophenyl)(2- (trifluoromethyl)phenyl)methoxy)azetidine-1-carboxamide dosed at no more than 200 mg provides a Tmax of 0.1-5, 0.1-4, 0.1-3, 0.1-2, 0.1-1.5, 0.1-1, 0.25-3, 0.25-2, 0.25-1.5, 0.25-1, 0.5-3, 0.5-2.5, 0.5-2, 0.5-1.5, 0.5-1.25, 0.5-1, 0.5-0.75, or 0.1-0.75 hr. In some instances, (R)-N-(tert-butyl)-3-((4- chlorophenyl)(2-(trifluoromethyl)phenyl)methoxy)azetidine-1-carboxamide dosed at no more than 150 mg provides a Tmax of 0.1-5, 0.1-4, 0.1-3, 0.1-2, 0.1-1.5, 0.1-1, 0.25-3, 0.25-2, 0.25-1.5, 0.25- 1, 0.5-3, 0.5-2.5, 0.5-2, 0.5-1.5, 0.5-1.25, 0.5-1, 0.5-0.75, or 0.1-0.75 hr. In some instances, (R)-N- (tert-butyl)-3-((4-chlorophenyl)(2-(trifluoromethyl)phenyl)methoxy)azetidine-1-carboxamide dosed at no more than 100 mg provides a Tmax of 0.1-5, 0.1-4, 0.1-3, 0.1-2, 0.1-1.5, 0.1-1, 0.25-3, 0.25-2, 0.25-1.5, 0.25-1, 0.5-3, 0.5-2.5, 0.5-2, 0.5-1.5, 0.5-1.25, 0.5-1, 0.5-0.75, or 0.1-0.75 hr. In some instances, (R)-N-(tert-butyl)-3-((4-chlorophenyl)(2- (trifluoromethyl)phenyl)methoxy)azetidine-1-carboxamide dosed at no more than 75 mg provides a Tmax of 0.1-5, 0.1-4, 0.1-3, 0.1-2, 0.1-1.5, 0.1-1, 0.25-3, 0.25-2, 0.25-1.5, 0.25-1, 0.5-3, 0.5-2.5, 0.5-2, 0.5-1.5, 0.5-1.25, 0.5-1, 0.5-0.75, or 0.1-0.75 hr. In some instances, (R)-N-(tert-butyl)-3-((4- chlorophenyl)(2-(trifluoromethyl)phenyl)methoxy)azetidine-1-carboxamide dosed at no more than 50 mg provides a Tmax of 0.1-5, 0.1-4, 0.1-3, 0.1-2, 0.1-1.5, 0.1-1, 0.25-3, 0.25-2, 0.25-1.5, 0.25-1,0.5-3, 0.5-2.5, 0.5-2, 0.5-1.5, 0.5-1.25, 0.5-1, 0.5-0.75, or 0.1-0.75 hr. In some instances, (R)-N- (tert-butyl)-3-((4-chlorophenyl)(2-(trifluoromethyl)phenyl)methoxy)azetidine-1-carboxamide dosed at no more than 30 mg provides a Tmax of 0.1-5, 0.1-4, 0.1-3, 0.1-2, 0.1-1.5, 0.1-1, 0.25-3, 0.25-2, 0.25-1.5, 0.25-1, 0.5-3, 0.5-2.5, 0.5-2, 0.5-1.5, 0.5-1.25, 0.5-1, 0.5-0.75, or 0.1-0.75 hr. In some instances, (R)-N-(tert-butyl)-3-((4-chlorophenyl)(2- (trifluoromethyl)phenyl)methoxy)azetidine-1-carboxamide dosed at no more than 20 mg provides a Tmax of 0.1-5, 0.1-4, 0.1-3, 0.1-2, 0.1-1.5, 0.1-1, 0.25-3, 0.25-2, 0.25-1.5, 0.25-1, 0.5-3, 0.5-2.5, 0.5-2, 0.5-1.5, 0.5-1.25, 0.5-1, 0.5-0.75, or 0.1-0.75 hr. In some instances, (R)-N-(tert-butyl)-3-((4- chlorophenyl)(2-(trifluoromethyl)phenyl)methoxy)azetidine-1-carboxamide dosed at 10-50 mg provides a Tmax of 0.1-5, 0.1-4, 0.1-3, 0.1-2, 0.1-1.5, 0.1-1, 0.25-3, 0.25-2, 0.25-1.5, 0.25-1, 0.5-3, 0.5-2.5, 0.5-2, 0.5-1.5, 0.5-1.25, 0.5-1, 0.5-0.75, or 0.1-0.75 hr. In some instances, (R)-N-(tert- butyl)-3-((4-chlorophenyl)(2-(trifluoromethyl)phenyl)methoxy)azetidine-1-carboxamide dosed at 20-75 mg provides a Tmax of 0.1-5, 0.1-4, 0.1-3, 0.1-2, 0.1-1.5, 0.1-1, 0.25-3, 0.25-2, 0.25-1.5, 0.25-1, 0.5-3, 0.5-2.5, 0.5-2, 0.5-1.5, 0.5-1.25, 0.5-1, 0.5-0.75, or 0.1-0.75 hr. In some instances, (R)-N-(tert-butyl)-3-((4-chlorophenyl)(2-(trifluoromethyl)phenyl)methoxy)azetidine-1- carboxamide dosed at 15-50 mg provides a Tmax of 0.1-5, 0.1-4, 0.1-3, 0.1-2, 0.1-1.5, 0.1-1, 0.25- 3, 0.25-2, 0.25-1.5, 0.25-1, 0.5-3, 0.5-2.5, 0.5-2, 0.5-1.5, 0.5-1.25, 0.5-1, 0.5-0.75, or 0.1-0.75 hr. In some instances, (R)-N-(tert-butyl)-3-((4-chlorophenyl)(2- (trifluoromethyl)phenyl)methoxy)azetidine-1-carboxamide dosed at 10-100 mg provides a Tmax of 0.1-5, 0.1-4, 0.1-3, 0.1-2, 0.1-1.5, 0.1-1, 0.25-3, 0.25-2, 0.25-1.5, 0.25-1, 0.5-3, 0.5-2.5, 0.5-2, 0.5- 1.5, 0.5-1.25, 0.5-1, 0.5-0.75, or 0.1-0.75 hr. In some instances, the dosage is configured for parenteral administration.

[0131] In some instances, (R)-N-(tert-butyl)-3-((4-chlorophenyl)(2- (trifluoromethyl)phenyl)methoxy)azetidine-1-carboxamide dosed at no more than 200 mg provides a Cmax of about 100-500 ng / mL, about 50-1000 ng / mL, about 50-400 ng / mL, about 50-300 ng / mL, about 50-200 ng / mL, about 50-500 ng / mL, about 75-750 ng / mL, about 100-500 ng / mL, about 100-400 ng / mL, or about 100-300 ng / mL. In some instances, (R)-N-(tert-butyl)-3-((4- chlorophenyl)(2-(trifluoromethyl)phenyl)methoxy)azetidine-1-carboxamide dosed at no more than 100 mg provides a Cmax of about 100-500 ng / mL, about 50-1000 ng / mL, about 50-400 ng / mL, about 50-300 ng / mL, about 50-200 ng / mL, about 50-500 ng / mL, about 75-750 ng / mL, about 100- 500 ng, about 100-400 ng / mL, or about 100-300 ng / mL. In some instances, (R)-N-(tert-butyl)-3- ((4-chlorophenyl)(2-(trifluoromethyl)phenyl)methoxy)azetidine-1-carboxamide dosed at no more than 75 mg provides a Cmax of about 100-500 ng / mL, about 50-1000 ng / mL, about 50-400 ng / mL, about 50-300 ng / mL, about 50-200 ng / mL, about 50-500 ng / mL, about 75-750 ng / mL, about 100-500I / mL, about 100-400 ng / mL, or about 100-300 ng / mL. In some instances, (R)-N-(tert-butyl)-3- ((4-chlorophenyl)(2-(trifluoromethyl)phenyl)methoxy)azetidine-1-carboxamide dosed at no more than 50 mg provides a Cmax of about 100-500 ng / mL, about 50-1000 ng / mL, about 50-400 ng / mL, about 50-300 ng / mL, about 50-200 ng / mL, about 50-500 ng / mL, about 75-750 ng / mL, about 100- 500 ng / mL, about 100-400 ng / mL, or about 100-300 ng / mL. In some instances, (R)-N-(tert-butyl)- 3-((4-chlorophenyl)(2-(trifluoromethyl)phenyl)methoxy)azetidine-1-carboxamide dosed at no more than 30 mg provides a Cmax of about 100-500 ng / mL, about 50-1000 ng / mL, about 50-400 ng / mL, about 50-300 ng / mL, about 50-200 ng / mL, about 50-500 ng / mL, about 75-750 ng / mL, about 100- 500 ng / mL, about 100-400 ng / mL, or about 100-300 ng / mL. In some instances, (R)-N-(tert-butyl)- 3-((4-chlorophenyl)(2-(trifluoromethyl)phenyl)methoxy)azetidine-1-carboxamide dosed at no more than 20 mg provides a Cmax of about 100-500 ng / mL, about 50-1000 ng / mL, about 50-400 ng / mL, about 50-300 ng / mL, about 50-200 ng / mL, about 50-500 ng / mL, about 75-750 ng / mL, about 100- 500 ng / mL, about 100-400 ng / mL, or about 100-300 ng / mL. In some instances, (R)-N-(tert-butyl)- 3-((4-chlorophenyl)(2-(trifluoromethyl)phenyl)methoxy)azetidine-1-carboxamide dosed at no more than 15 mg provides a Cmax of about 100-500 ng / mL, about 50-1000 ng / mL, about 50-400 ng / mL, about 50-300 ng / mL, about 50-200 ng / mL, about 50-500 ng / mL, about 75-750 ng / mL, about 100- 500 ng / mL, about 100-400 ng / mL, or about 100-300 ng / mL. In some instances, (R)-N-(tert-butyl)- 3-((4-chlorophenyl)(2-(trifluoromethyl)phenyl)methoxy)azetidine-1-carboxamide dosed at no more than 10 mg provides a Cmax of about 100-500 ng / mL, about 50-1000 ng / mL, about 50-400 ng / mL, about 50-300 ng / mL, about 50-200 ng / mL, about 50-500 ng / mL, about 75-750 ng / mL, about 100- 500 ng / mL, about 100-400 ng / mL, or about 100-300 ng / mL. In some instances, (R)-N-(tert-butyl)- 3-((4-chlorophenyl)(2-(trifluoromethyl)phenyl)methoxy)azetidine-1-carboxamide dosed at no more than 5 mg provides a Cmax of about 100-500 ng / mL, about 50-1000 ng / mL, about 50-400 ng / mL, about 50-300 ng / mL, about 50-200 ng / mL, about 50-500 ng / mL, about 75-750 ng / mL, about 100- 500 ng / mL, about 100-400 ng / mL, or about 100-300 ng / mL. In some instances, (R)-N-(tert-butyl)- 3-((4-chlorophenyl)(2-(trifluoromethyl)phenyl)methoxy)azetidine-1-carboxamide dosed at no more than 1 mg provides a Cmax of about 100-500 ng / mL, about 50-1000 ng / mL, about 50-400 ng / mL, about 50-300 ng / mL, about 50-200 ng / mL, about 50-500 ng / mL, about 75-750 ng / mL, about 100- 500 ng / mL, about 100-400 ng / mL, or about 100-300 ng / mL. In some instances, (R)-N-(tert-butyl)- 3-((4-chlorophenyl)(2-(trifluoromethyl)phenyl)methoxy)azetidine-1-carboxamide dosed at 15-50 mg provides a Cmax of about 100-500 ng / mL, about 50-1000 ng / mL, about 50-400 ng / mL, about 50-300 ng / mL, about 50-200 ng / mL, about 50-500 ng / mL, about 75-750 ng / mL, about 100-500 ng / mL, about 100-400 ng / mL, or about 100-300 ng / mL. In some instances, (R)-N-(tert-butyl)-3- ((4-chlorophenyl)(2-(trifluoromethyl)phenyl)methoxy)azetidine-1-carboxamide dosed at 20-50 mgprovides a Cmax of about 100-500 ng / mL, about 50-1000 ng / mL, about 50-400 ng / mL, about 50- 300 ng / mL, about 50-200 ng / mL, about 50-500 ng / mL, about 75-750 ng / mL, about 100-500 ng / mL, about 100-400 ng / mL, or about 100-300 ng / mL. In some instances, (R)-N-(tert-butyl)-3- ((4-chlorophenyl)(2-(trifluoromethyl)phenyl)methoxy)azetidine-1-carboxamide dosed at 10-75 mg provides a Cmax of about 100-500 ng / mL, about 50-1000 ng / mL, about 50-400 ng / mL, about 50- 300 ng / mL, about 50-200 ng / mL, about 50-500 ng / mL, about 75-750 ng / mL, about 100-500 ng / mL, about 100-400 ng / mL, or about 100-300 ng / mL. In some instances, the dosage is parenteral.

[0132] In some instances, (R)-N-(tert-butyl)-3-((4-chlorophenyl)(2- (trifluoromethyl)phenyl)methoxy)azetidine-1-carboxamide provides a dosage normalized plasma AUClastof about 25-600 h*ng / mL / mg, about 25-500 h*ng / mL / mg, about 25-450 h*ng / mL / mg, about 50-500 h*ng / mL / mg, about 50-450 h*ng / mL / mg, about 50-400 h*ng / mL / mg, about 50-300 h*ng / mL / mg, about 50-250 h*ng / mg, about 40-300 h*ng / mL / mg, or about 50-200 h*ng / mL / mg. In some instances, (R)-N-(tert-butyl)-3-((4-chlorophenyl)(2- (trifluoromethyl)phenyl)methoxy)azetidine-1-carboxamide dosed at no more than 200 mg provides a AUClast of about 1000-3500 h*ng / mL, about 1000-3000 ng / mL, about 1250-3000 ng / mL, about 1500-2800 ng / mL, about 1000-2500 ng / mL, or about 1200-3000 ng / mL. In some instances, (R)-N- (tert-butyl)-3-((4-chlorophenyl)(2-(trifluoromethyl)phenyl)methoxy)azetidine-1-carboxamide dosed at no more than 150 mg provides a AUClast of about 1000-3500 h*ng / mL, about 1000-3000 ng / mL, about 1250-3000 ng / mL, about 1500-2800 ng / mL, about 1000-2500 ng / mL, or about 1200- 3000 ng / mL. In some instances, (R)-N-(tert-butyl)-3-((4-chlorophenyl)(2- (trifluoromethyl)phenyl)methoxy)azetidine-1-carboxamide dosed at no more than 100 mg provides a AUClast of about 1000-3500 h*ng / mL, about 1000-3000 ng / mL, about 1250-3000 ng / mL, about 1500-2800 ng / mL, about 1000-2500 ng / mL, or about 1200-3000 ng / mL. In some instances, (R)-N- (tert-butyl)-3-((4-chlorophenyl)(2-(trifluoromethyl)phenyl)methoxy)azetidine-1-carboxamide dosed at no more than 75 mg provides a AUClast of about 1000-3500 h*ng / mL, about 1000-3000 ng / mL, about 1250-3000 ng / mL, about 1500-2800 ng / mL, about 1000-2500 ng / mL, or about 1200- 3000 ng / mL. In some instances, (R)-N-(tert-butyl)-3-((4-chlorophenyl)(2- (trifluoromethyl)phenyl)methoxy)azetidine-1-carboxamide dosed at no more than 50 mg provides a AUClast of about 1000-3500 h*ng / mL, about 1000-3000 ng / mL, about 1250-3000 ng / mL, about 1500-2800 ng / mL, about 1000-2500 ng / mL, or about 1200-3000 ng / mL. In some instances, (R)-N- (tert-butyl)-3-((4-chlorophenyl)(2-(trifluoromethyl)phenyl)methoxy)azetidine-1-carboxamide dosed at no more than 40 mg provides a AUClast of about 1000-3500 h*ng / mL, about 1000-3000 ng / mL, about 1250-3000 ng / mL, about 1500-2800 ng / mL, about 1000-2500 ng / mL, or about 1200- 3000 ng / mL. In some instances, (R)-N-(tert-butyl)-3-((4-chlorophenyl)(2-(trifluoromethyl)phenyl)methoxy)azetidine-1-carboxamide dosed at no more than 30 mg provides a AUClast of about 1000-3500 h*ng / mL, about 1000-3000 ng / mL, about 1250-3000 ng / mL, about 1500-2800 ng / mL, about 1000-2500 ng / mL, or about 1200-3000 ng / mL. In some instances, (R)-N- (tert-butyl)-3-((4-chlorophenyl)(2-(trifluoromethyl)phenyl)methoxy)azetidine-1-carboxamide dosed at no more than 20 mg provides a AUClast of about 1000-3500 h*ng / mL, about 1000-3000 ng / mL, about 1250-3000 ng / mL, about 1500-2800 ng / mL, about 1000-2500 ng / mL, or about 1200- 3000 ng / mL. In some instances, (R)-N-(tert-butyl)-3-((4-chlorophenyl)(2- (trifluoromethyl)phenyl)methoxy)azetidine-1-carboxamide dosed at no more than 15 mg provides a AUClast of about 1000-3500 h*ng / mL, about 1000-3000 ng / mL, about 1250-3000 ng / mL, about 1500-2800 ng / mL, about 1000-2500 ng / mL, or about 1200-3000 ng / mL. In some instances, (R)-N- (tert-butyl)-3-((4-chlorophenyl)(2-(trifluoromethyl)phenyl)methoxy)azetidine-1-carboxamide dosed at no more than 10 mg provides a AUClast of about 500-3500 h*ng / mL, about 500-3000 ng / mL, about 1250-3000 ng / mL, about 1500-2800 ng / mL, about 1000-2500 ng / mL, or about 1200- 3000 ng / mL. In some instances, (R)-N-(tert-butyl)-3-((4-chlorophenyl)(2- (trifluoromethyl)phenyl)methoxy)azetidine-1-carboxamide dosed at no more than 5 mg provides a AUClast of about 100-3500 h*ng / mL, about 200-3000 ng / mL, about 1250-3000 ng / mL, about 500- 2800 ng / mL, about 300-2500 ng / mL, or about 400-3000 ng / mL. In some instances, (R)-N-(tert- butyl)-3-((4-chlorophenyl)(2-(trifluoromethyl)phenyl)methoxy)azetidine-1-carboxamide dosed at no more than 1 mg provides a AUClast of about 100-3500 h*ng / mL, about 100-3000 ng / mL, about 125-3000 ng / mL, about 150-2800 ng / mL, about 200-2500 ng / mL, or about 500-3000 ng / mL. In some instances, the dosage is parenteral.

[0133] In some instances, (R)-N-(tert-butyl)-3-((4-chlorophenyl)(2- (trifluoromethyl)phenyl)methoxy)azetidine-1-carboxamide provides a dosage normalized plasma AUC5hof about 5-60 h*ng / mL / mg, about 5-50 h*ng / mL / mg, about 5-45 h*ng / mL / mg, about 5-45 h*ng / mL / mg, about 7-60 h*ng / mL / mg, about 7-50 h*ng / mL / mg, about 7-45 h*ng / mL / mg, about 7- 40 h*ng / mL / mg, about 10-60 h*ng / mL / mg, about 10-50 h / mL / mg, about 10-50 h*ng / mL / mg, or about 10-40 h*ng / mL / mg. In some instances, (R)-N-(tert-butyl)-3-((4-chlorophenyl)(2- (trifluoromethyl)phenyl)methoxy)azetidine-1-carboxamide dosed at no more than 200 mg provides a AUC5h of about 200-2000 h*ng / mL, about 200-1500 h*ng / mL, about 200-1200 h*ng / mL, about 300-2500 h*ng / mL, about 300-2000 h*ng / mL, about 300-1750 h*ng / mL, about 300-1500 h*ng / mL, about 400-3000 h*ng / mL, about 400-2000 h*ng / mL, about 400-1500 h*ng / mL, about 400-1200 h*ng / mL, or about 400-1000 h*ng / mL. In some instances, (R)-N-(tert-butyl)-3-((4- chlorophenyl)(2-(trifluoromethyl)phenyl)methoxy)azetidine-1-carboxamide dosed at no more than 150 mg provides a AUC5hof about 200-2000 h*ng / mL, about 200-1500 h*ng / mL, about 200-1200h*ng / mL, about 300-2500 h*ng / mL, about 300-2000 h*ng / mL, about 300-1750 h*ng / mL, about 300-1500 h*ng / mL, about 400-3000 h*ng / mL, about 400-2000 h*ng / mL, about 400-1500 h*ng / mL, about 400-1200 h*ng / mL, or about 400-1000 h*ng / mL. In some instances, (R)-N-(tert- butyl)-3-((4-chlorophenyl)(2-(trifluoromethyl)phenyl)methoxy)azetidine-1-carboxamide dosed at no more than 100 mg provides a AUC5h of about 200-2000 h*ng / mL, about 200-1500 h*ng / mL, about 200-1200 h*ng / mL, about 300-2500 h*ng / mL, about 300-2000 h*ng / mL, about 300-1750 h*ng / mL, about 300-1500 h*ng / mL, about 400-3000 h*ng / mL, about 400-2000 h*ng / mL, about 400-1500 h*ng / mL, about 400-1200 h*ng / mL, or about 400-1000 h*ng / mL. In some instances, (R)-N-(tert-butyl)-3-((4-chlorophenyl)(2-(trifluoromethyl)phenyl)methoxy)azetidine-1- carboxamide dosed at no more than 75 mg provides a AUC5hof about 200-2000 h*ng / mL, about 200-1500 h*ng / mL, about 200-1200 h*ng / mL, about 300-2500 h*ng / mL, about 300-2000 h*ng / mL, about 300-1750 h*ng / mL, about 300-1500 h*ng / mL, about 400-3000 h*ng / mL, about 400-2000 h*ng / mL, about 400-1500 h*ng / mL, about 400-1200 h*ng / mL, or about 400-1000 h*ng / mL. In some instances, (R)-N-(tert-butyl)-3-((4-chlorophenyl)(2- (trifluoromethyl)phenyl)methoxy)azetidine-1-carboxamide dosed at no more than 50 mg provides a AUC5h of about 200-2000 h*ng / mL, about 200-1500 h*ng / mL, about 200-1200 h*ng / mL, about 300-2500 h*ng / mL, about 300-2000 h*ng / mL, about 300-1750 h*ng / mL, about 300-1500 h*ng / mL, about 400-3000 h*ng / mL, about 400-2000 h*ng / mL, about 400-1500 h*ng / mL, about 400-1200 h*ng / mL, or about 400-1000 h*ng / mL. In some instances, (R)-N-(tert-butyl)-3-((4- chlorophenyl)(2-(trifluoromethyl)phenyl)methoxy)azetidine-1-carboxamide dosed at no more than 40 mg provides a AUC5hof about 200-2000 h*ng / mL, about 200-1500 h*ng / mL, about 200-1200 h*ng / mL, about 300-2500 h*ng / mL, about 300-2000 h*ng / mL, about 300-1750 h*ng / mL, about 300-1500 h*ng / mL, about 400-3000 h*ng / mL, about 400-2000 h*ng / mL, about 400-1500 h*ng / mL, about 400-1200 h*ng / mL, or about 400-1000 h*ng / mL. In some instances, (R)-N-(tert- butyl)-3-((4-chlorophenyl)(2-(trifluoromethyl)phenyl)methoxy)azetidine-1-carboxamide dosed at no more than 30 mg provides a AUC5h of about 200-2000 h*ng / mL, about 200-1500 h*ng / mL, about 200-1200 h*ng / mL, about 300-2500 h*ng / mL, about 300-2000 h*ng / mL, about 300-1750 h*ng / mL, about 300-1500 h*ng / mL, about 400-3000 h*ng / mL, about 400-2000 h*ng / mL, about 400-1500 h*ng / mL, about 400-1200 h*ng / mL, or about 400-1000 h*ng / mL. In some instances, (R)-N-(tert-butyl)-3-((4-chlorophenyl)(2-(trifluoromethyl)phenyl)methoxy)azetidine-1- carboxamide dosed at no more than 25 mg provides a AUC5hof about 200-2000 h*ng / mL, about 200-1500 h*ng / mL, about 200-1200 h*ng / mL, about 300-2500 h*ng / mL, about 300-2000 h*ng / mL, about 300-1750 h*ng / mL, about 300-1500 h*ng / mL, about 400-3000 h*ng / mL, about 400-2000 h*ng / mL, about 400-1500 h*ng / mL, about 400-1200 h*ng / mL, or about 400-1000h*ng / mL. In some instances, (R)-N-(tert-butyl)-3-((4-chlorophenyl)(2- (trifluoromethyl)phenyl)methoxy)azetidine-1-carboxamide dosed at no more than 20 mg provides a AUC5h of about 200-2000 h*ng / mL, about 200-1500 h*ng / mL, about 200-1200 h*ng / mL, about 300-2500 h*ng / mL, about 300-2000 h*ng / mL, about 300-1750 h*ng / mL, about 300-1500 h*ng / mL, about 400-3000 h*ng / mL, about 400-2000 h*ng / mL, about 400-1500 h*ng / mL, about 400-1200 h*ng / mL, or about 400-1000 h*ng / mL. In some instances, (R)-N-(tert-butyl)-3-((4- chlorophenyl)(2-(trifluoromethyl)phenyl)methoxy)azetidine-1-carboxamide dosed at no more than 15 mg provides a AUC5h of about 200-2000 h*ng / mL, about 200-1500 h*ng / mL, about 200-1200 h*ng / mL, about 300-2500 h*ng / mL, about 300-2000 h*ng / mL, about 300-1750 h*ng / mL, about 300-1500 h*ng / mL, about 400-3000 h*ng / mL, about 400-2000 h*ng / mL, about 400-1500 h*ng / mL, about 400-1200 h*ng / mL, or about 400-1000 h*ng / mL. In some instances, (R)-N-(tert- butyl)-3-((4-chlorophenyl)(2-(trifluoromethyl)phenyl)methoxy)azetidine-1-carboxamide dosed at no more than 10 mg provides a AUC5h of about 200-2000 h*ng / mL, about 200-1500 h*ng / mL, about 200-1200 h*ng / mL, about 300-2500 h*ng / mL, about 300-2000 h*ng / mL, about 300-1750 h*ng / mL, about 300-1500 h*ng / mL, about 400-3000 h*ng / mL, about 400-2000 h*ng / mL, about 400-1500 h*ng / mL, about 400-1200 h*ng / mL, or about 400-1000 h*ng / mL. In some instances, (R)-N-(tert-butyl)-3-((4-chlorophenyl)(2-(trifluoromethyl)phenyl)methoxy)azetidine-1- carboxamide dosed at no more than 5 mg provides a AUC5h of about 200-2000 h*ng / mL, about 200-1500 h*ng / mL, about 200-1200 h*ng / mL, about 300-2500 h*ng / mL, about 300-2000 h*ng / mL, about 300-1750 h*ng / mL, about 300-1500 h*ng / mL, about 400-3000 h*ng / mL, about 400-2000 h*ng / mL, about 400-1500 h*ng / mL, about 400-1200 h*ng / mL, or about 400-1000 h*ng / mL. In some instances, (R)-N-(tert-butyl)-3-((4-chlorophenyl)(2- (trifluoromethyl)phenyl)methoxy)azetidine-1-carboxamide dosed at no more than 1 mg provides a AUC5hof about 200-2000 h*ng / mL, about 200-1500 h*ng / mL, about 200-1200 h*ng / mL, about 300-2500 h*ng / mL, about 300-2000 h*ng / mL, about 300-1750 h*ng / mL, about 300-1500 h*ng / mL, about 400-3000 h*ng / mL, about 400-2000 h*ng / mL, about 400-1500 h*ng / mL, about 400-1200 h*ng / mL, or about 400-1000 h*ng / mL. In some instances, the dosage is parenteral.

[0134] In various embodiments, the method reduces the subject’s ability to experience euphoria after inhaling or consuming Cannabis or a synthetic cannabinoid.

[0135] Compositions and formulations described herein may be administered as single or multiple doses. In some embodiments, described herein are methods of using the (R)-N-(tert-butyl)-3-((4- chlorophenyl)(2-(trifluoromethyl)phenyl)methoxy)azetidine-1-carboxamide as a single dose, one- time treatment for overdose THC or SC, or both. The overdose can also be from consumption of cannabis, synthetic cannabinoid, or any compound that is an agonist of the CB1 receptor. In someinstances, methods described herein include treatment to children who inadvertently consume cannabis or cannabinoid edibles. In related aspects, any suspected overdose patient that presents a mentally disoriented or psychotic or cannot articulate the nature of their condition or the substances that have been ingested or administered can be treated with (R)-N-(tert-butyl)-3-((4- chlorophenyl)(2-(trifluoromethyl)phenyl)methoxy)azetidine-1-carboxamide.

[0136] The methods described herein include pre-exposure prophylaxis treatments. The long-term effects of CB1 antagonism, which in some instances includes anhedonia, potentially makes them unsuitable for chronic use. However, in the same way that a subject who is addicted to alcohol might consume disulfiram before entering a situation when tempted to consume alcohol, one can take a CB1 antagonist, such as (R)-N-(tert-butyl)-3-((4-chlorophenyl)(2- (trifluoromethyl)phenyl)methoxy)azetidine-1-carboxamide, before encountering a situation where they may likely be exposed to or tempted to ingest THC or SCs or both. Similarly, in some instances, (R)-N-(tert-butyl)-3-((4-chlorophenyl)(2-(trifluoromethyl)phenyl)methoxy)azetidine-1- carboxamide is used to prevent effects from secondhand smoke from marijuana. The method of using (R)-N-(tert-butyl)-3-((4-chlorophenyl)(2-(trifluoromethyl)phenyl)methoxy)azetidine-1- carboxamide in some instances includes use by a subject who wishes to gain acceptance to a situation or group by smoking marijuana or SCs, but also wants to remain mentally alert, such as during an undercover police or law enforcement investigation. Methods of Preparing Parenteral Formulations of Compound 1

[0137] Provided herein are methods of manufacturing pharmaceutical compositions for parenteral administration. In some embodiments, a method comprises one or more steps of: preparing an organic phase; mixing the organic phase with an aqueous phase to generate a mixture; shearing the mixture; extruding the mixture; concentrating the mixture; removing the solvent and sterile- filtering the mixture. In some embodiments, methods comprise preparing parenteral formulations of liposomes. In some embodiments, methods comprise preparing parenteral formulations of liposomes having a concentration of at least 1, 2, 3, or at least 4 mg / mL of Compound 1.

[0138] In some embodiments, preparing the organic phase comprises generating liposomes. In some embodiments, preparing the organic phase comprises: mixing the compound with a first excipient in a first solvent to generate a first solution; mixing a second excipient in a second solvent to generate a second solution; and combining the first solution and the second solution. In some embodiments, the first solution is mixed at about room temperature. In some embodiments, the first solution is mixed at 15-25 degrees C. In some embodiments, the second solution is mixed at 30-80, 30-60, 40-50, 40-60, 50-60 or 50-80 degrees C. In some embodiments, combining the first solution and the second solution occurs at about room temperature. In some embodiments, the first solutionor the second solution independently comprises an alcohol, ether, ketone, aldehyde, amide, amine, alkane, or haloalkane solvent or mixture thereof. In some embodiments, the first solution or the second solution independently comprises methanol, ethanol, or chloroform or mixture thereof.

[0139] The aqueous phase may comprise a buffer as described herein. In some embodiments, the buffer comprises one or more of a salt, a solvent, and a stabilizer. In some embodiments, the buffer comprises a pH of 6-8, 6-7, 7-8, or 7-9. In some embodiments, the buffer is isotonic and isohydric. In some embodiments, the buffer comprises a sugar. In some embodiments, the buffer is isotonic. In some embodiments, the buffer comprises glucose, sucrose, lactose, trehalose, maltose, or other sugar.. In some embodiments, the buffer comprises a phosphate buffer. In some embodiments, the buffer comprises sodium phosphate dibasic, potassium phosphate monobasic, or a combination thereof.

[0140] Shearing (or homogenization) may be used to form the liposomes by mixing the organic phase containing the liposome components with an excess of an aqueous phase and simultaneously decrease and control the size of the liposome particles. Shearing (or homogenization) may be used to decrease the size of the liposome particles. In some embodiments, shearing comprises mixing at 2000-7000, 2000-6000, 2000-5000, 2000-400, 3000-4000, 3000-5000, 3000-6000, 4000-5000, 4000-6000, or 5000-6000 RPM. In some embodiments, sheering comprises use of a square mixing screen. In some embodiments, the organic phase is added to the aqueous phase during shearing. In some instances, the organic phase is added over at least 3, 4, 5, 6, 7, 8, 9, or at least 10 minutes. In some instances, the phases are sheared for at least 2, 4, 5, 6, 8, 10, 12, 15, or at least 20 minutes. In some instance, the mixing and shearing results in an average particle size of 100-500, 100-400, 100-300, 100-250, 100-200, 150-500, 150-400, 150-300, 150-250, 150-200, 175-300, 175-250, 175-200, 200-500, 200-400, 200-300, or 300-500 nm. In some instance, shearing results in an average particle size of no more than 500, 400, 300, 275, 250, 225, 200, 190, 180, 175, 170, 160, 150, or no more than 140 nm. In some instance, shearing results in particles having a PDI of no more than 0.05, 0.1, 0.14, 0.15, 0.16, 0.17, 0.18, 0.19, 0.2, 0.25, 0.3, 0.35, 0.4 or no more than 0.5.

[0141] Extrusion may be used to further modulate particle sizes in a mixture. In some embodiments, extrusion comprises 1, 2, 3, 4, or more than 4 passes through a filter. In some embodiments, the filter comprises a 500, 450, 400, 350, 300, 250, 200, 150, 100 nm or smaller filter. Extrusion in some embodiments is conducted at a temperature of 5-10, 5-25, 5-50, 5-80, 10- 80, 25-80, 30-80, 30-60, 40-50, 40-60, 50-60 or 50-80 degrees C. Extrusion in some embodiments is conducted at a pressure of at least 5, 10, 25, 50, 60, 70, 80, 90, 100, 120, or at least 150 bar. Multiple extruder heads may also be utilized. In some instance, extrusion results in an average particle size of no more than 500, 400, 300, 275, 250, 225, 200, 190, 180, 175, 170, 160, 150, or nomore than 140 nm. In some instance, extrusion results in particles having a PDI of no more than 0.05, 0.1, 0.14, 0.15, 0.16, 0.17, 0.18, 0.19, 0.2, 0.25, 0.3, 0.35, 0.4 or no more than 0.5. In some instance, extrusion results in a decrease of at least 20, 15, 10, 5, or at least 3 percent in average particle size relative to pre-extrusion. In some instances, a first filter is used for a first pass extrusion, and a second filter is used for a second pass extrusion. In some instances, each subsequent extrusion uses a smaller filter size.

[0142] Mixtures may be manipulated to concentrate particles and / or to or reduce the level of residual solvents. In some embodiments, concentrating comprises filtration. In some embodiments, concentrating comprises tangential flow filtration. In some embodiments, concentrating comprises dialysis.

[0143] In some embodiments, the method comprises sterilizing a formulation. In some embodiments, mixtures are filtered through a 800, 700, 600, 500, 450, 400, 300, 250, 200, 150, 100 nm or smaller filter for sterilization. In some instances, more than one sterile filtration is used. In some embodiments, mixtures are first filtered through an about 220 nm filter. In some embodiments, mixtures are first filtered through an about 220 nm filter, followed by about a 450 nm filter. In some embodiments, mixtures are first filtered through no more than a 220 nm filter. In some embodiments, mixtures are first filtered through no more than a 220 nm filter, followed by no more than a 450 nm filter. In some instances, a first filter is used for a first pass sterilization, and a second filter is used for a second pass sterilization. In some instances, each subsequent sterilization uses a smaller filter size. In some embodiments, the method comprises freezing after sterilization. In some embodiments, the method comprises lyophilizing after sterilization.

[0144] Methods for preparing formulations described herein may comprise in-line mixing. In some embodiments, methods comprise continuous controlled in-line T mixing. In some embodiments, aqueous and organic phases (e.g., as part of liposome formulation) are mixed using in-line mixing. In some embodiments, aqueous and organic phases are mixed using continuous controlled in-line T mixing. In some embodiments, after in-line mixing the product is subjected to tangential flow filtration. In some embodiments, after in-line mixing the product is subjected to tangential flow filtration followed by sterile filtration. Additional Definitions

[0145] As used herein, “active agent” is used to indicate a chemical entity which has biological activity. In certain embodiments, an “active agent” is a compound having pharmaceutical utility. For example, an active agent may be an anti-cancer therapeutic.

[0146] As used herein, “modulation” refers to a change in activity as a direct or indirect response to the presence of a chemical entity as described herein, relative to the activity of in the absence ofthe chemical entity. The change may be an increase in activity or a decrease in activity, and may be due to the direct interaction of the compound with the target or due to the interaction of the compound with one or more other factors that in turn affect the target's activity. For example, the presence of the chemical entity may, for example, increase or decrease the target activity by directly binding to the target, by causing (directly or indirectly) another factor to increase or decrease the target activity, or by (directly or indirectly) increasing or decreasing the amount of target present in the cell or organism.

[0147] As used herein, “therapeutically effective amount” of a chemical entity described herein refers to an amount effective, when administered to a human or non-human subject, to provide a therapeutic benefit such as amelioration of symptoms, slowing of disease progression, or prevention of disease.

[0148] “Treating” or “treatment” encompasses administration of Compound 1, or a pharmaceutically acceptable salt thereof, to a mammalian subject, particularly a human subject, in need of such an administration and includes (i) arresting the development of clinical symptoms of the disease, such as cancer, (ii) bringing about a regression in the clinical symptoms of the disease, such as cancer, and / or (iii) prophylactic treatment for preventing the onset of the disease, such as cancer.

[0149] As used herein, a “pharmaceutically acceptable” component is one that is suitable for use with humans and / or animals without undue adverse side effects (such as toxicity, irritation, and allergic response) commensurate with a reasonable benefit / risk ratio.

[0150] “Pharmaceutically acceptable salts” include, but are not limited to salts with inorganic acids, such as hydrochlorate, carbonate, phosphate, hydrogenphosphate, diphosphate, hydrobromate, sulfate, sulfinate, nitrate, and like salts; as well as salts with an organic acid, such as malate, malonate, maleate, fumarate, tartrate, succinate, citrate, acetate, lactate, gluconate, methanesulfonate, Tris (hydroxymethyl-aminomethane), p-toluenesulfonate, propionate, 2- hydroxyethylsulfonate, benzoate, salicylate, stearate, oxalate, pamoate, and alkanoate such as acetate, HOOC-(CH2)n-COOH where n is 0-4, and like salts. Other salts include sulfate, methanesulfonate, bromide, trifluoroacetate, picrate, sorbate, benzilate, salicylate, nitrate, phthalate or morpholine. Pharmaceutically acceptable cations include, but are not limited to sodium, potassium, calcium, aluminum, lithium, and ammonium.

[0151] In addition, if the compounds described herein are obtained as an acid addition salt, the free base can be obtained by basifying a solution of the acid salt. Conversely, if the product is a free base, an addition salt, particularly a pharmaceutically acceptable addition salt, may be produced by dissolving the free base in a suitable organic solvent and treating the solution with an acid, inaccordance with conventional procedures for preparing acid addition salts from base compounds. Those skilled in the art will recognize various synthetic methodologies that may be used to prepare non-toxic pharmaceutically acceptable addition salts.

[0152] As used herein, “subject” refers to a mammal that has been or will be the object of treatment, observation, or experiment. The methods described herein can be useful in both human therapy and veterinary applications. In some embodiments, the subject is a human.

[0153] “Prodrugs” described herein include any compound that becomes Compound 1 when administered to a subject, e.g., upon metabolic processing of the prodrug. Similarly, “pharmaceutically acceptable salts” includes “prodrugs” of pharmaceutically acceptable salts. Examples of prodrugs include derivatives of functional groups, such as a carboxylic acid group, in Compound 1. Exemplary prodrugs of a carboxylic acid group include, but are not limited to, carboxylic acid esters such as alkyl esters, hydroxyalkyl esters, arylalkyl esters, and aryloxyalkyl esters. Other exemplary prodrugs include lower alkyl esters such as ethyl ester, acyloxyalkyl esters such as pivaloyloxymethyl (POM), glycosides, and ascorbic acid derivatives. Other exemplary prodrugs include amides of carboxylic acids. A discussion of prodrugs is provided in T. Higuchi and V. Stella, Pro-drugs as Novel Delivery Systems, Vol.14 of the A.C.S. Symposium Series, in Edward B. Roche, ed., Bioreversible Carriers in Drug Design, American Pharmaceutical Association and Pergamon Press, 1987, and in Design of Prodrugs, ed. H. Bundgaard, Elsevier, 1985.

[0154] A “solvate” is formed by the interaction of a solvent and a compound. The term “compound” is intended to include solvates of compounds. Similarly, “pharmaceutically acceptable salts” includes solvates of pharmaceutically acceptable salts. Suitable solvates are pharmaceutically acceptable solvates, such as hydrates, including monohydrates and hemi-hydrates. Also included are solvates formed with the one or more crystallization solvents.

[0155] Pharmaceutically acceptable forms of the compounds recited herein include pharmaceutically acceptable salts, chelates, non-covalent complexes, prodrugs, and mixtures thereof.

[0156] A “chelate” is formed by the coordination of a compound to a metal ion at two (or more) points. The term “compound” is intended to include chelates of compounds. Similarly, “pharmaceutically acceptable salts” includes chelates of pharmaceutically acceptable salts.

[0157] A “non-covalent complex” is formed by the interaction of a compound and another molecule wherein a covalent bond is not formed between the compound and the molecule. For example, complexation can occur through van der Waals interactions, hydrogen bonding, and electrostatic interactions (also called ionic bonding). Such non-covalent complexes are included inthe term “compound”. Similarly, pharmaceutically acceptable salts include “non-covalent complexes” of pharmaceutically acceptable salts.

[0158] When ranges are used herein for physical properties, such as molecular weight, or chemical properties, such as chemical formulae, all combinations and sub combinations of ranges and specific embodiments therein are intended to be included.

[0159] The term “about” when referring to a number or a numerical range means that the number or numerical range referred to is an approximation within experimental variability (or within statistical experimental error), and thus the number or numerical range may vary from, for example, between 1% and 15% of the stated number or numerical range. In some instances of numerical ranges, “about” means ± 10%.

[0160] As used herein, ”level” means the levels of Glasgow coma metric or coma scale. Numbered Embodiments

[0161] Embodiment 1. A pharmaceutical composition configured for parenteral administration comprising a compound having the structure: and at least one excipient. Embodiment 2. The pharmaceutical composition of embodiment 1 wherein the parenteral formulation is selected from a nanosuspension, oil and water emulsion, liposome, or micelle. Embodiment 3. The pharmaceutical composition of embodiment 2, wherein the parenteral formulation comprises an oil and water emulsion. Embodiment 4. The pharmaceutical composition of embodiment 3, wherein the at least one excipient comprises an oil. Embodiment 5. The pharmaceutical composition of embodiment 3, wherein the excipient comprises soybean oil (SBO), Miglycol 812, olive oil, coconut oil, or a mixture thereof. Embodiment 6. The pharmaceutical composition of embodiment 4, wherein the pharmaceutical composition comprises soybean oil and at least one of coconut oil, olive oil, or Miglyol 812. Embodiment 7. The pharmaceutical composition of embodiment 4, wherein the pharmaceutical composition comprises a 5:1 to 1:5 mixture of soybean oil to any one of coconut oil, olive oil, or Miglyol 812. Embodiment 8. The pharmaceutical composition of embodiment 3, wherein the compound is present at 5-20 mg / mL. Embodiment 9. The pharmaceutical composition of embodiment 2, wherein the parenteral formulation comprises micelles. Embodiment 10. The pharmaceutical composition of embodiment 9, wherein the parenteral formulation comprises a phospholipid. Embodiment 11. Thepharmaceutical composition of embodiment 9, wherein the excipient comprises Miglyol 812, Lipoid E80, saline, or a combination thereof. Embodiment 12. The pharmaceutical composition of embodiment 9, wherein the pharmaceutical composition comprises 0.5-3% Lipoid E80. Embodiment 13. The pharmaceutical composition of embodiment 9, wherein the compound is present at 5-20 mg / mL. Embodiment 14. The pharmaceutical composition of embodiment 2, wherein the parenteral formulation comprises a liposome. Embodiment 15. The pharmaceutical composition of embodiment 14, wherein the at least one excipient comprises a phospholipid. Embodiment 16. The pharmaceutical composition of embodiment 15, wherein the pharmaceutical composition comprises 10-50 mg / mL phospholipid. Embodiment 17. The pharmaceutical composition of embodiment 14, wherein the at least one excipient comprises Lipoid S100 or dimyristoylphosphatidylglycerol (DMPG). Embodiment 18. The pharmaceutical composition of embodiment 14, wherein the compound is present a 0.5-10 mg / mL. Embodiment 19. The pharmaceutical composition of embodiment 2, wherein the parenteral formulation comprises a nanosuspension. Embodiment 20. The pharmaceutical composition of embodiment 19, wherein the at least one excipient comprises poloxamer 188, polyvinyl ketone (PVK) K17, PVK K30, or Sodium Deoxycholate. Embodiment 21. The pharmaceutical composition of 19, wherein the pharmaceutical composition comprises 0.1-5% poloxamer 188. Embodiment 22. The pharmaceutical composition of embodiment 19, wherein the pharmaceutical composition comprises 0.05-05% sodium deoxycholate. Embodiment 23. The pharmaceutical composition of embodiment 19, wherein the pharmaceutical composition comprises 0.2-2% PVP K17 or PVP K30. Embodiment 24. The pharmaceutical composition of embodiment 19, wherein the compound is present at 50-200 mg / mL. Embodiment 25. A method of treating a known or suspected acute cannabinoid intoxication in a subject in need thereof, the method comprising: administering to the subject a therapeutically-effective amount of a parenteral formulation of a compound having the structure, wherein treating improves one or more metrics associated with acute cannabinoid intoxication. Embodiment 26. The method of embodiment 1, wherein the metric is measured by a healthcare provider or emergency responder. Embodiment 27. The method of embodiment 1, wherein the metric is self-reported by the subject. Embodiment 28. The method of any one of embodiments 25-27, wherein the amount of compound administered to the subject is1-200 mg, 1-10 mg, 1-25 mg, 5-20 mg, 10-50 mg, 10-30 mg, or 20-30 mg. Embodiment 29. The method of any one of embodiments 25-27, wherein the method further comprises administering 5- 300 mg, 5-100 mg, or 10-30 mg of delta-9-tetrahydrocannabinol (THC) to the subject. Embodiment 30. The method of any one of embodiments 25-27, wherein the acute cannabinoid intoxication results from ingestion of an edible form of cannabis. Embodiment 31. The method of any one of embodiments 25-30, wherein the parenteral route of administration comprises intravenous (IV), intramuscular (IM), or subcutaneous (SC). Embodiment 32. The method of any one of embodiments 25-30, wherein the pharmaceutical composition is delivered in a liquid volume of 0.1-5 mL. Embodiment 33. The method of any one of embodiments 25-30, wherein the subject exhibits symptoms of cannabinoid hyperemesis syndrome. Embodiment 34. The method of any one of embodiments 25-30, wherein the subject is experiencing nausea and / or vomiting. EXAMPLES

[0162] The following examples serve to further describe the manner of using the present disclosure. These examples are presented for illustrative purpose and should not serve to limit the true scope of the present disclosure.

[0163] In carrying out the procedures of the methods described herein, it is of course to be understood that references to particular buffers, media, reagents, cells, culture conditions, and the like are not intended to be limiting, but are to be read so as to include all related materials that one of ordinary skill in the art would recognize as being of interest or value in the particular context in which that discussion is presented. For example, it is often possible to substitute on buffer system or culture medium for another and still achieve similar, if not identical, results. Those of skill in the art will have sufficient knowledge of such systems and methodologies so as to able, without undue experimentation, to make such substitutions as will optimally serve their purposes in using the methods and procedures disclosed herein. Example 1 –Oil and Water Emulsion Formulations of Compound 1

[0164] Screen of Oil in Water Emulsions

[0165] Solubility of ANEB-001 was determined for several oils. The time it took ANEB-001 [10 mg / mL] to dissolve in a selection of oils at various temperatures is recorded in Table 2. The compound appeared to dissolve quickest in Miglyol 812, and a mixture of soybean oil and Miglyol 812.Table 2Key: “D” = dissolved; “ND” = not dissolved.

[0166] A solubility challenge experiment showed that ANEB-001 was soluble in Miglyol at 20 mg / mL and even >100 mg / mL. Miglyol is an oil excipient which can be used in parenteral emulsions. Example 2 – Evaluation of Parenteral Formulations of Compound 1

[0167] ANEB-001 was evaluated in oil-in-water emulsions formed by a mixture of Miglyol and phospholipids. ANEB-001 was dissolved in Miglyol to form 6 mg / mL or 60 mg / mL solutions. The phospholipid Lipoid E80 (1.2% w / v) was added and heated at 50C for 3 hours to solubilize ingredients. The solutions were diluted 1:10 with saline [0.9% w / v] to provide an oil in water emulsion of ANEB-001 [10 mg / ml ]. The stability of the 10% ANEB-001 emulsion was evaluated at either 50C or 2-8 C. The solutions were stable at the two temperatures and the two concentrations for at least 14 days. See FIGS.1-8.

[0168] Oil-in water emulsions with 10 or 20% oil phase and particle size of approximately 250 nm were prepared enabling the IV, IM, or SC administration of a large range of ANEB-001 concentrations / doses. In addition, no crystallization of the drug substance was observed after dilution of this emulsion in saline for 16 h at ambient temperature. The emulsions were prepared by vigorously mixing the oil and water phases. Example 3 – Evaluation of Liposomal Formulations of Compound 1

[0169] A screening of various drug to lipid ratios and short-term stability testing were performed. For example, ANEB-001, Lipoid S100 and DMPG-Na were loaded in 100 mL flask. The mixture was dissolved in MeOH: Chloroform: Water (65:55:4). Once dissolved, the mixture was dried with a rotary evaporator and vacuum overnight. The solid was re-constituted in PBS pH 6.8 [10 ml] and extruded twice through a 200 nm filter and once through a 100 nm filter.

[0170] A formulation with 2 mg ANEB-001 / mL and 30 mg lipid / mL and 1 : 15 drug to lipid mass ratio, enabling the IV, IM or SC administration of ANEB-001, appeared to have acceptable chemical and physical stability properties. Example 4 – Evaluation of Nanoparticle Suspension Formulations of Compound 1

[0171] ANEB-001 was evaluated in nanoparticles including a mixture of excipients, such as polyvinylpyrrolidone [PVP], nonionic triblock copolymers composed of a central hydrophobic chain of polyoxypropylene flanked by two hydrophilic chains of polyoxyethylene [poloxamer], PBS and sodium deoxycholate. See Table 3. ANEB-001 concentrations ranged from 40 to 100 mg / mL.

[0172] A liquid nanosuspension with crystalline ANEB-001 was achieved with high drug loading (~100 mg / mL ANEB-001). Formulation E [10% ANEB-001 with 1% PVP K17 and 0.15% Na Deoxy] was selected for nanomilling and stability analysis. The particle size distribution analysis {PSD} after a week at either 5C or 25C is shown in FIGS.9-10. At 5C, a bimodal PSD curve was observed with peaks at 1.4 and 4 um. At 25C, a bimodal PSD curve was observed with peaks at 1.5 and 9 um.

[0173] Formulation F [10% ANEB-001 with 1% PVP K17 and 0.20% Na Deoxy] at either 40 mg / mL or 100 mg / mL loads was also selected for nanomilling and stability analysis. The particle size distribution analysis {PSD} after a week at either 5C or 25C is shown in FIGS.11-14. At 5C, a PSD curve was observed with peak at 4 um. At 25C, a PSD curve was observed with a peak at um. At 5C and 100 mg / mL, a monomodal PSD curve was observed with the tail on right side with particles as big as 5.5 μm. At 5C and 40 mg / mL, a monomodal PSD curve was observed with the tail on right side with particles as big as 7 μm. At 25C and 100 mg / mL, a monomodal PSD curve was observed with the tail on right side with particles as large as 3 μm.OM. At 25C and 40 mg / mL, a monomodal PSD curve was observed with the tail on right side with particles as large as 5 μm.OM. Table 3Example 5 – PK evaluation of Parenteral Formulations of Compound 1

[0174] Prototypes of three formulations (o / w emulsion, liposomes, and nanosuspension) were evaluated for PK and tolerability assessment in dogs. See Table 4. The emulsion was administered intramuscularly or intravenously at a concentration of 0.20 mL / kg [2.00 mg / kg]. The emulsion was mixed prior to being administered. The liposome was administered intravenously at a concentration of 1.35mL / kg [2.00 mg / kg (3% liposome)], 1.20 mL / kg [1.67mg / kg (3% liposome)] for intravenous infusion, 1.00 mL / kg [3.33 mg / kg (5% liposome) or 1.50 mg / kg (3% liposome)] for subcutaneous administration or intramuscularly at 0.25 mL / kg [0.50 mg / kg (3% liposome)]. The nanosuspension was administered subcutaneously at a concentration of 0.20 mL / kg. Each formulation was administered as a single dose to 6 male beagle dogs by intravenous, intramuscular, and subcutaneous dosing, with a 2 week washout between doses. Plasma samples were taken at the following schedule: Pre dose then 2, 5, 10, 15 and 30 minutes then 1, 2, 4, 6, 8, 12, and 24 hours post dose. For intravenous infusion, plasma samples were taken Pre dose then 5 (during infusion), 15 (end of infusion) and then 17, 20, 30 minutes then 1, 2, 4, 6, 8, 12, and 24 hours post dose. Table 4

[0175] The amount of compound was analyzed by quantitative bioanalysis by LC-MS / MS of dog (male Beagle) plasma samples. A TSQ Quantiva with Thermo Vanquish LC System Water + 0.1% formic acid as solvent system A and acetonitrile + 0.1% formic acid was Solvent B. A flow rate of 0.8 ml / min in a Phenomenex Luna Omega column [1.6µm, C18100Å, 50 x 2.1mm] heated at 60 °C. A gradient of 80%A / 20%B to 0.1% A / 99.9%B was used. See FIGS.15-20. Based on the results of the PK studies in dogs, the intravenous liposome formulation appears to have the greatest potential to provide high exposure to Compound 1 and a rapid onset of action, suitable for a human IV product for ACI. A Cmax after IM administration of about 115 ng / mL was observed. A Tmax of12 minutes was observed for IM dosing (FIG.17) The relative bioavailability for IM administration was about 66%. IV bolus was similar to IV infusion. See FIG.20.

[0176] The nanosuspension formulation demonstrated reasonable exposure levels and delayed drug release characteristics after IM or SC dosing.

[0177] The oil-In water emulsion shows a large variability of PK profile probably after IV dosing, potentially attributable to the wide size distribution of the particles in this formulation. Pharmacokinetic measurements are shown in Tables 5-8. Table 5. Liposomal PK Data IV (2 mg / kg)Table 6. Liposomal PK Data IM (0.5 mg / kg)Table 7. Liposomal PK Data IV Infusion (2.0 mg / kg)Table 8. Liposomal PK Data SC (1.5 mg / kg)Example 6 – Liposomal formulations of Compound 1

[0178] A phospholipid mixture and Compound 1 were dissolved in the respective organic solvents and then dried in rotary evaporator followed by overnight storage under high vacuum (freeze-drier), to ensure complete drying. The initial target was for the final solution to have a concentration of 1mg / mL of Compound 1 loaded into 3% w / v multi-lamellar vesicles in saline. In some instances, Compound 1 and one or more components were pre-dissolved in one solvent or solvent mixture, and then later mixed with additional components. The liposomal mixture was then re-constituted in 0.9% sodium chloride (NaCl) in water for injection (WFI) and was analyzed under normal and polarized light microscopy after T=1, 4 and 24 hours to check for any signs of precipitation. A control was prepared by dissolving Compound 1 in ethanol at a concentration of 20 mg / mL and diluting that with 20mL of the 0.9% w / v NaCl in WFI. Table 9. LiposomesExample 7 – Preparation of a Liposomal Formulation of Compound 1

[0179] Compound 1 was formulated in a liposomal dosage form comprising 2 to 3 mg Compound 1 / ml and 1:15 drug to lipid weight ratio and 97:3 soybean phosphatidylcholine (sold as Lipoid S100, Lipoid Gmbh) / DMPG sodium weight ratio as lipid components and an isotonic sucrose buffer. The buffer comprises phosphate buffer, pH 7.4: (279.4 mM Sucrose, 8.26 mM Phosphate (7 mM sodium phosphate dibasic and 1.26 mM potassium phosphate monobasic)).

[0180] Step 1: Preparation of organic phase. Compound 1 was mixed with soybean phosphatidylcholine in ethanol at room temperature until clear; DMPG-Na was mixed in water with added ethanol at 50°C until clear; the two ethanol phases were mixed at room temperature.

[0181] Step 2. The organic phase is mixed until addition to aqueous phase sucrose / phosphate buffer. Addition occurs within 30 minutes to prevent precipitation of the DMPG, to a target concentration of 2mg / mL Compound 1).

[0182] Step 3. High shear mixing for 10 minutes at 3000-5000rpm with a square mixing screen is conducted.

[0183] Step 4. Mixture is extruded for 1-2 passes through 200nm PCTE filter, with a target average particle size to below 200nm with narrow PDI.

[0184] Step 5. Tangential Flow Filtration is used to reduce ethanol content to below 5000ppm (target NMT 1500ppm, see Table 11), and Compound 1 to a target concentration of 2-3mg / mL.

[0185] Step 6. Filling. Mixture is sterile filtered through 0.2 micron PES filter under nitrogen into clear glass vials (pharma grade).

[0186] Step 7. Vials are frozen at -20℃. Vials may also be lyophilized for storage.

[0187] After three freeze / thaw cycles, formulations were evaluated by light microscopy under polarized light to check for the presence of crystals (Table 10). No degradation of samples was observed by HPLC after about 1-2 weeks from manufacture. Conditions for crystallization were obtained using (1) pre-extrusion samples of 2 mg / mL compound 1 in buffer sodium phosphate / sucrose only (2 month old sample); or (2) pre-extrusion samples of 3 mg / mL compound 1 in buffer sodium chloride / sodium+potassium phosphate / sucrose, pH 7.4 (both 0.1L scale). With other process conditions no crystallization or precipitation of Compound 1 was observed.Table 10: Homogenization Evaluation, 3mg / mL (4L scale)Key: * Buffer 8.3mM phosphate components and 280 mM sucrose; + Buffer 8.3mM phosphate components and 190 mM sucrose Particle Size: A: 150-175; B: 176-200; C: >200 PDI: A: 0.1-0.15; B: 0.16-0.2; C: >0.2 n.d. = not determined Table 11: TFF (Repligen system) and removal of Residual EthanolKey: A: <1000; B: 1001-5000; C: 5001-10,000; D: >10,000Example 8 – Liposomal formulations

[0188] Following the general formulations and methods of 7, process steps were evaluated for the development of liposomal formulations of Compound 1, and results are shown in Table 12. Data for batch 23 demonstrated particle sizes of 150-175nm after freeze-thaw that was supportive of the liposomal formulation’s stability after at least one freeze-thaw cycle. Data for batch 45 demonstrated the concentration of Compound 1 can be controlled by the process to up to 3mg / ml; the drug to lipid ratio is maintained through the processing and the liposomes are negatively charged as shown in the zeta potential results). Table 12: Liposomal formulation processesKey: n.t. = not tested Particle Size: A: 150-175; B: 176-200; C: >200 PDI: A: 0.1-0.15; B: 0.16-0.2; C: >0.2 Ethanol: A: <1000; B: 1001-5000; C: 5001-10,000; D: >10,000 Impurities: A: <0.6; B:0.6-0.75; C: >0.75 Example 9 – Mixed micelle formulations of Compound 1

[0189] The drug loading on different mixed micelle combinations comprising of a bile salt and phospholipids were assessed. Final solutions were prepared to have a concentration of 1mg / mL of Compound 1 loaded into 3-10% w / v mixed micelles. The bile salts that were used were sodium glycocholate and sodium deoxycholate, and the phospholipids used were Lipoid S100 (Soybean Phosphatidylcholine) and DMPC (1,2-dimyristoyl-sn-glycero-3-phosphocholine) (provided by Lipoid). Two different molar ratios of bile salt to phospholipid were tested, 1:1 and 2:1. The protocol followed was to first prepare a concentrated solution of mixed micelles at 30% w / v in 0.9% w / v NaCl in milli-Q water and load the micelles with 10mg / ml Compound 1. The final dilution of the Compound 1 was performed to achieve an expected mixed micelle concentration of 3-10% w / v.

[0190] Mixed Micelles with Lipoid S100. First, the bile salt was added to 5ml of saline (0.9% NaCl in milli-Q water) and the solution was vortexed until the bile salt dissolved. Then, the phospholipid was added, and the mixture was left shaking over 48 hours at 25°C until the solutions were clear, indicating equilibrium was reached. The sodium glycocholate: Lipoid S100 mixture at a 1:1 molar ratio remained hazy but became clear upon addition of Compound 1 and shaking at 37°C. The micellar size of the solution was then analyzed via DLS using the Zetasizer Ultra to ensure the formation of mixed micelles via the particle size number data generated, and the results are tabulated in Table 13 below. Table 13. DLS analysis of mixed micelle blank solutions with LipoidS100

[0191] Then, the mixed micelle solutions were loaded with Compound 1 (10mg / mL) and were left shaking for a total of 24 hours at 37°C and an extra 24 hours at 50°C. Compound 1 did not solubilize fully; as the drug did not solubilize fully, the experiments were then centrifuged at 10,000 rpm for 10 minutes and the supernatant was collected and analyzed via HPLC to obtain an assay value and microscopy to check for any signs of precipitation. The assay values obtained via the HPLC are presented in Table 14 below. Table 14. HPLC assay of mixed micellar solutions supernatant upon centrifugation at 10,000rpm for 10 minutes.

[0192] The supernatants were then diluted with 0.9%w / v NaCl down to 1mg / mL based on the assay value obtained by the HPLC. Microscopy images were obtained from the supernatants and the diluted samples for all mixed micelle combinations. The diluted samples were tested under DLS and microscopy, where precipitation was found to have occurred. Therefore, under these conditions Compound 1 formed a supersaturated solution in the mixed micelles and crystallized out.

[0193] Mixed Micelles with DMPC. First, the bile salt was added to 5ml of saline (0.9% NaCl in miliQ water) and the solution was vortexed until the bile salt dissolved. Then, the phospholipid was added, and the mixture was left shaking over 48 hours at 37°C, until the solutions were clear, indicating equilibrium was reached. The particle size of the equilibrated mixed micellar solutions were then analyzed via DLS using the Zetasizer Ultra, and the results are tabulated in Table 15.Table 15. DLS analysis of Mixed Micelles with DMPC before adding Compound 1

[0194] Then, the mixed micelle solutions were loaded with Compound 1 (10mg / mL) and were left shaking for a total of 48 hours at 50°C. As Compound 1 did not solubilize fully in any mixed micellar solution with DMPC, the solutions were then centrifuged at 10,000 rpm for 10 minutes and the supernatant was collected and assayed via HPLC and the results are presented in Table 16. HPLC assay of the supernatant of the mixed micelles with DMPC upon centrifugation was also conducted to measure concentrations of Compound 1. The maximum concentration achieved was 4.5 mg / mL by the sodium glycocholate: DMPC in a 1:1 molar ratio. Table 16

[0195] The supernatants were then diluted with 0.9%w / v NaCl down to 1mg / mL based on the assay value obtained in the HPLC as shown in Table 16 above. The diluted samples were also tested via microscopy, where precipitation was evident.

[0196] Mixed Micelles-Lower drug loading. A lower drug loading of Compound 1 in mixed micelles was also evaluated. Sodium deoxycholate: DMPC blank mixed micelles were loaded with Compound 1 at a concentration of 3 mg / mL (~90% of saturation solubility as presented in Table 16. The reason this concentration was chosen was to remain within the 3-10% w / v range of final mixed micelles concentration upon dilution with saline solutions with a final concentration of Compound 1 being 1 mg / mL. The solution was left shaking at 50°C for ~48 hours, after whichthere was still undissolved drug present. The solution was then centrifuged at 10,000 rpm for 10 minutes and the supernatant was assayed via HPLC. The resulting concentration for sample sodium deoxycholate DMPC in a 2:1 molar ratio was 1.2 (mg / mL) concentration of Compound 1 in supernatant with a recovery of 40.5%. Example 10 – Manufacture of Parenteral Formulation using in-line mixing

[0197] The general methods of Example 7 were followed with modification: continuous controlled in-line T mixing was used to mix aqueous and organic phases. The product was also subjected to tangential flow filtration followed by sterile filtration. Example 11 – Treatment of a Pediatric Patient with a Parenteral Formulation

[0198] A six-year old child suspected of consuming cannabinoid-containing edibles is admitted to the emergency room. The child is administered a parenteral formulation of any one of Examples 1- 10 by I.V. and monitored for amelioration of symptoms (if present) or change in condition. Example 12 – Treatment of a Patient with a Respiratory Depression

[0199] A patient suspected of smoking synthetic cannabinoids is admitted to the emergency room. The patient is suffering from respiratory depression, and is administered a parenteral formulation of any one of Examples 1-10 by I.V. and monitored for amelioration of symptoms.

[0200] While some embodiments have been shown and described, various modifications and substitutions may be made thereto without departing from the spirit and scope of the present disclosure. For example, for claim construction purposes, it is not intended that the claims set forth hereinafter be construed in any way narrower than the literal language thereof, and it is thus not intended that exemplary embodiments from the specification be read into the claims. Accordingly, it is to be understood that the present disclosure has been described by way of illustration and not limitations on the scope of the claims.

Claims

CLAIMS WHAT IS CLAIMED IS:

1. A pharmaceutical composition configured for parenteral administration comprising a compound having the structure:and at least one excipient, wherein the parenteral formulation comprises a nanosuspension, oil and water emulsion, liposome, or micelle.

2. The pharmaceutical composition of claim 1, wherein the parenteral formulation comprises a liposome.

3. The pharmaceutical composition of claim 2, wherein the at least one excipient comprises a lipid.

4. The pharmaceutical composition of claim 3, wherein the at least one excipient comprises a phospholipid.

5. The pharmaceutical composition of claim 4, wherein the at least one excipient comprises a phosphatidylcholine.

6. The pharmaceutical composition of claim 4, wherein the at least one excipient comprises a diacylglycerol phospholipid.

7. The pharmaceutical composition of claim 2, wherein the at least one excipient comprises 1,2-distearoyl-sn-glycero-3-phospho-rac-glycerol (DSPG), cholesterol, hydrogenated soybean phosphatidylcholine (HSPC), 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine (POPC), phosphatidylcholine, dimyristoylphosphatidylglycerol (DMPG), or a salt thereof.

8. The pharmaceutical composition of claim 2, wherein the formulation comprises at least two excipients selected from the group consisting of 1,2-distearoyl-sn-glycero-3-phospho-rac-glycerol (DSPG), cholesterol, hydrogenated soybean phosphatidylcholine (HSPC), 1-palmitoyl-2-oleoyl-sn- glycero-3-phosphocholine (POPC), phosphatidylcholine, dimyristoylphosphatidylglycerol (DMPG) and any salts thereof.

9. The pharmaceutical composition of claims 7 or 8, wherein the phosphatidylcholine is obtained from hen egg yolk, soybeans, Non-GMO Soybeans, sunflowers, or is synthetically produced.

10. The pharmaceutical composition of claims 7 or 8, wherein the phosphatidylcholine has a purity of at least 80%.

11. The pharmaceutical composition of claims 7 or 8, wherein the phosphatidylcholine has a purity of at least 94%.

12. The pharmaceutical composition of claim 8, wherein the phosphatidylcholine is sold under the trade name LIPOID E 80 or LIPOID S 100 by Lipoid GmbH.

13. The pharmaceutical composition of claim 8, wherein the first excipient comprises Lipoid S 100 and the second excipient comprises DMPG, wherein the weight ratio of the first excipient to the second excipient is about 97:

3.

14. The pharmaceutical composition of any one of claims 2-12, wherein the ratio of compound to lipid is about 1:5 to about 1:25 (w / w).

15. The pharmaceutical composition of any one of claims 8-13, wherein the ratio of the first excipient to the second excipient is about 90:10 to about 99:

1.

16. The pharmaceutical composition of claim 15, wherein the first excipient comprises HSPC, DMPC, phosphatidylcholine, DOPG, POPC, or a salt thereof.

17. The pharmaceutical composition of claim 15, wherein the first excipient comprises HSPC, DMPC, soybean phosphatidylcholine, DOPG, POPC, or a salt thereof.

18. The pharmaceutical composition of claim 15 or 16, wherein the second excipient comprises DSPG, DMPG, DMPC, or a salt thereof.

19. The pharmaceutical composition of any one of claims 2-18, wherein the pharmaceutical composition comprises about 10-50 mg / mL phospholipid.

20. The pharmaceutical composition of claim 2-19, wherein the compound is present at 0.5-10 mg / mL.

21. The pharmaceutical composition of claim 2-19, wherein the compound is present at about 2mg / mL or about 3 mg / mL.

22. The pharmaceutical composition of any one of claims 1-21, wherein the pharmaceutical composition comprises a buffer.

23. The pharmaceutical composition of claim 22, wherein the buffer comprises at least one phosphate.

24. The pharmaceutical composition of claim 23, wherein the at least one phosphate comprises sodium phosphate dibasic, potassium phosphate monobasic, or a combination thereof.

25. The pharmaceutical composition of claim 22, wherein the buffer comprises an excipient.

26. The pharmaceutical composition of claim 22, wherein the buffer comprises a stabilizer.

27. The pharmaceutical composition of claim 22, wherein the stabilizer comprises a sugar.

28. The pharmaceutical composition of claim 27, wherein the sugar comprises sucrose, glucose, lactose, trehalose, or maltose.

29. The pharmaceutical composition of claim 22, wherein the buffer has a pH of about 7-8.

30. The pharmaceutical composition of claim 22, wherein the buffer is isotonic.

31. The pharmaceutical composition of any one of claims 1-30, wherein the pharmaceutical composition comprises an average particle size of no more than 200 nm.

32. The pharmaceutical composition of any one of claims 1-30, wherein the pharmaceutical composition comprises an average particle size of about 100-300 nm.

33. The pharmaceutical composition of any one of claims 1-32, wherein the pharmaceutical composition comprises a polydispersity index (PDI) of no more than 0.

2.

34. The pharmaceutical composition of any one of claims 1-32, wherein the pharmaceutical composition comprises a polydispersity index (PDI) of about 0.1 to 0.

3.

35. The pharmaceutical composition of any one of claims 1-21, wherein the pharmaceutical composition is a solid.

36. The pharmaceutical composition of any one of claims 1-21, wherein the pharmaceutical composition is frozen.

37. The pharmaceutical composition of any one of claims 1-21, wherein the pharmaceutical composition is lyophilized.

38. The pharmaceutical composition of any one of claims 1-21, wherein the pharmaceutical composition is a liquid or solution.

39. The pharmaceutical composition of any one of claims 1-21, wherein the pharmaceutical composition is substantially free of crystals.

40. The pharmaceutical composition of any one of claims 1-21, wherein the pharmaceutical composition is substantially free of crystals as measured under light microscopy.

41. The pharmaceutical composition of any one of claims 1-21, wherein the pharmaceutical composition is substantially free of crystals after at least one week, one month, two months, six months, or at least a year.

42. The pharmaceutical composition of any one of claims 1-21, wherein the pharmaceutical composition is stable at room temperature for at least one week, one month, two months, six months, or at least a year.

43. The pharmaceutical composition of any one of claims 1-21, wherein the pharmaceutical composition is stable at no more than 0 degrees C for at least one week, one month, two months, six months, or at least a year.

44. The pharmaceutical composition of any one of claims 1-21, wherein the pharmaceutical composition is stable at no more than -20 degrees C for at least one week, one month, two months, six months, or at least a year.

45. The pharmaceutical composition of any one of claims 1-21, wherein the pharmaceutical composition is essentially unchanged at room temperature for at least one week, one month, two months, six months, or at least a year as measured by HPLC.

46. The pharmaceutical composition of any one of claims 1-21, wherein the pharmaceutical composition comprises no more than 5000 ppm residual solvent.

47. The pharmaceutical composition of any one of claims 1-21, wherein the pharmaceutical composition comprises no more than 5000 ppm residual ethanol.

48. The pharmaceutical composition of any one of claims 1-21, wherein the pharmaceutical composition comprises no more than 1500 ppm residual ethanol.

49. The pharmaceutical composition of claim 1, wherein the parenteral formulation comprises a nanosuspension.

50. The pharmaceutical composition of claim 49, wherein the at least one excipient comprises poloxamer 188, polyvinyl ketone (PVK) K17, PVK K30, or sodium deoxycholate.

51. The pharmaceutical composition of claim 49, wherein the pharmaceutical composition comprises 0.1-5% poloxamer 188.

52. The pharmaceutical composition of claim 49, wherein the pharmaceutical composition comprises 0.05-05% sodium deoxycholate.

53. The pharmaceutical composition of claim 49, wherein the pharmaceutical composition comprises about 0.2-2% PVP K17 or PVP K30.

54. The pharmaceutical composition of claim 49, wherein the compound is present at about 50- 200 mg / mL.

55. The pharmaceutical composition of claim 1, wherein the parenteral formulation comprises an oil and water emulsion.

56. The pharmaceutical composition of claim 55, wherein the at least one excipient comprises an oil.

57. The pharmaceutical composition of claim 55, wherein the excipient comprises soybean oil (SBO), Miglycol 812, olive oil, coconut oil, or a mixture thereof.

58. The pharmaceutical composition of claim 56, wherein the pharmaceutical composition comprises soybean oil and at least one of coconut oil, olive oil, or Miglyol 812.

59. The pharmaceutical composition of claim 56, wherein the pharmaceutical composition comprises about a 5:1 to about 1:5 mixture of soybean oil to any one of coconut oil, olive oil, or Miglyol 812 60. The pharmaceutical composition of claim 55, wherein the compound is present at about 5- 20 mg / mL.

61. The pharmaceutical composition of claim 1, wherein the parenteral formulation comprises micelles.

62. The pharmaceutical composition of claim 61, wherein the parenteral formulation comprises a phospholipid.

63. The pharmaceutical composition of claim 61, wherein the excipient comprises Miglyol 812, Lipoid E80, saline, or a combination thereof.

64. The pharmaceutical composition of claim 61, wherein the pharmaceutical composition comprises about 0.5-3% Lipoid E80.

65. The pharmaceutical composition of claim 61, wherein the compound is present at about 1- 20 mg / mL.

66. The pharmaceutical composition of claim 61, wherein the compound is present at about 1-5 mg / mL.

67. A method of treating known or suspected cannabinoid toxicity in a subject in need thereof, the method comprising: administering to the subject a therapeutically-effective amount of a parenteral formulation of a compound having the structure, wherein the parenteral formulation comprises a nanosuspension, oil and water emulsion, liposome, or micelle, and wherein treating improves one or more metrics associated with cannabinoid-induced toxicity.

68. The method of claim 1, wherein the metric is measured by a healthcare provider or emergency responder.

69. The method of claim 1, wherein the metric is self-reported by the subject.

70. The method of any one of claims 67-69, wherein the amount of compound administered to the subject is 1-200 mg, 1-10 mg, 1-25 mg, 5-20 mg, 10-50 mg, 10-30 mg, or 20-30 mg.

71. The method of any one of claims 67-69, wherein the amount of compound administered to the subject is about 1 mg, about 5 mg, about 10 mg, about 15 mg, about 20 mg, about 30 mg or about 50 mg.

72. The method of any one of claims 67-69, wherein the method further comprises administering 5-300 mg, 5-100 mg, or 10-30 mg of delta-9-tetrahydrocannabinol (THC) to the subject.

73. The method of any one of claims 67-69, wherein the cannabinoid-induced toxicity results from ingestion of an edible form of cannabis.

74. The method of any one of claims 67-69, wherein the cannabinoid-induced toxicity results from ingestion of a synthetic cannabinoid.

75. The method of any one of claims 72-74, wherein the synthetic cannabinoid, edible form of cannabis, or THC is self-administered.

76. The method of any one of claims 67-73, wherein the parenteral route of administration comprises intravenous (IV), intramuscular (IM), or subcutaneous (SC).

77. The method of claim 76, wherein the parenteral route of administration comprises intravenous (IV).

78. The method of claim 77, wherein intravenous (IV) comprises IV bolus, IV drip, or IV push.

79. The method of any one of claims 67-73, wherein the pharmaceutical composition is delivered in a liquid volume of about 0.1-5 mL.

80. The method of any one of claims 67-73, wherein the pharmaceutical composition is delivered in a liquid volume of about 25-1000 mL.

81. The method of any one of claims 67-73, wherein the concentration the compound reaches a plasma concentration of at least 10, 25, 50, 100, 150, or at least 200 ng / mL within 10 minutes.

82. The method of any one of claims 67-73, wherein the concentration the compound reaches a plasma concentration of at least 10, 25, 50, 100, 150, or at least 200 ng / mL within 5 minutes.

83. The method of any one of claims 67-73, wherein the concentration the compound reaches a plasma concentration of at least 10, 25, 50, 100, 150, or at least 200 ng / mL within 2 minutes.

84. The method of any one of claims 67-73, wherein the concentration the compound reaches a plasma concentration of at least 10, 25, 50, 100, 150, or at least 200 ng / mL within 60 seconds.

85. The method of any one of claims 67-73, wherein the subject exhibits symptoms of cannabinoid hyperemesis syndrome.

86. The method of any one of claims 67-73, wherein the subject is experiencing one or more of nausea, vomiting, coughing, and choking.

87. The method of any one of claims 67-73, wherein the subject is experiencing respiratory depression.

88. The method of any one of claims 67-73, wherein the subject is experiencing anaphylactic shock.

89. The method of any one of claims 67-73, wherein the subject is experiencing trauma or swelling to the face, mouth, throat, esophagus, or digestive tract.

90. The method of any one of claims 67-73, wherein the subject is unwilling or unable to ingest an oral medicament.

91. The method of any one of claims 67-73, wherein one or more symptoms of overdose are ameliorated in no more than 5 minutes.

92. The method of any one of claims 67-73, wherein one or more symptoms of overdose are ameliorated in no more than 1 minute.

93. The method of any one of claims 67-73, wherein the subject is a pediatric patient.

94. The method of any one of claims 67-73, wherein the subject is selected from an adolescent, child, infant, or neonate.

95. The method of claim 93, wherein the patient is no more than 28 days, 2 years, 12 years, or 21 years old.

96. The method of claim 93, wherein the patient is 1-28 days old, 29 days to less than 2 years old, 2 years to less than 12 years old, or 12 years to less than 21 years old.

97. The method of any one of claims 67-96, wherein the method further comprises monitoring the subject for improvement of cannabinoid overdose symptoms.

98. A method of manufacturing a pharmaceutical composition of any one of claims 1-66.

99. A method of manufacturing a pharmaceutical composition of any one of claims 2-48.

100. The method of claim 99, wherein the method comprises: (a) preparing an organic phase; (b) mixing the organic phase with an aqueous phase to generate a mixture; (c) shearing the mixture; (d) extruding the mixture; (e) concentrating the mixture; and (f) sterile-filtering the mixture.

101. The method of claim 100, wherein preparing the organic phase comprises: (a) mixing the compound with a first excipient in a first solvent to generate a first solution; (b) mixing a second excipient in a second solvent to generate a second solution; and (c) combining the first solution and the second solution.

102. The method of claim 101, wherein the first solution is mixed at about room temperature.

103. The method of claim 101, wherein the second solution is mixed at about 40-60 degrees C.

104. The method of claim 101, wherein combining occurs at about room temperature.

105. The method of claim 101, wherein the aqueous phase comprises a buffer.

106. The method of claim 101, wherein shearing occurs at about 3000-5000 RPM with a square mixing screen.

107. The method of claim 101, wherein extruding comprises 1-2 passes through a 200 nm filter.

108. The method of claim 101, wherein concentrating comprises tangential flow filtration.

109. The method of claim 101, wherein the method further comprises freezing or lyophilizing after step (f).

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