Cannabidiol (CBD) and terpene formulations that enhance restorative sleep in humans

Abstract

Disclosed herein are formulations of cannabidiol (CBD) and terpenes that increase restorative sleep and reduce anxiety and depression in humans.

Description

[Technical field]

[0001] The present invention relates generally to novel formulations of CBD and terpenes and their uses for the treatment of diseases, and more specifically to formulations and their uses for the treatment of sleep-related disorders.

[0002] Insomnia is a disorder in which people have inadequate or poor quality sleep due to a number of factors, such as difficulty falling asleep, frequent waking during the night with difficulty falling asleep again, waking too early in the morning, or waking unrefreshed.

[0003] A Consumer Reports survey of 1,267 adults indicates that nearly 80% of Americans have trouble sleeping at least once a week. Insomnia is the most common sleep disorder and is an established risk factor for anxiety, depression, and other disorders. Insomnia is clinically defined as the perception or symptoms of inadequate or poor quality sleep due to many factors, such as difficulty falling asleep, frequent awakenings during the night with difficulty falling asleep again, waking too early in the morning, or waking unrefreshed. Insomnia results in significant impairment and / or impairment in daytime functioning for those who suffer from it. The prevalence of clinically diagnosed insomnia has increased in recent years to about 19% of the adult population in the United States, representing about 46 million people. Some studies suggest that the proportion of undiagnosed insomnia in the United States may be as high as 25% (about 80 million people). 1 .

[0004] CBD is the active ingredient in EPIDIOLEX®, a drug approved by the FDA in 2018 for the treatment of epileptic seizures associated with two rare and severe forms of epilepsy, Lennox-Gastaut syndrome and Dravet syndrome. In 2018, the U.S. Congress also passed the Hemp Farming Act of 2018 (the Farm Bill), which removed hemp (defined as cannabis with less than 0.3% THC) from Schedule I controlled substances, making it a regular agricultural commodity. This bill led to widespread refining, sale, and interstate commerce of CBD, a molecule derived from hemp ($4.7 billion in U.S. sales in 2021). As a result, in-store and online retailers have flooded the market with CBD products, many of which have unproven therapeutic claims (e.g., to treat insomnia). Unfortunately, U.S. consumers are currently using CBD to treat a variety of ailments in the absence of rigorous clinical trials. In fact, about 14% of the U.S. adult population (about 29 million adults) admit to using CBD (Gallup Survey, U.S. News & World Report). Despite this, there is a critical lack of rigorous clinical research supporting the use of CBD for many of the ailments that Americans ostensibly use it to treat. The FDA's greatest concern is the sale of unapproved CBD products that make therapeutic claims to prevent, diagnose, mitigate, treat, or cure serious diseases, but that do not have new drug approval.

[0005] In a recent survey by Consumer Reports, about 40% of adults who reported having tried CBD said they used a CBD product to help them sleep, and most of them said they believed it worked. Yet to date, no rigorous, well-controlled, and adequately powered studies have been reported in the scientific literature to determine whether CBD affects sleep physiology.

[0006] The present invention seeks to solve these and other problems. Summary of the Invention

[0007] Provided herein are methods and compositions for increasing restorative sleep in humans.

[0008] CBD formulations are composed of CBD and multiple terpenes, including linalool, myrcene, phytol, limonene, α-terpinene, α-terpineol, α-pinene, and β-caryophyllene, for treating insomnia and other sleep disorders, including pain, anxiety, and depression.

[0009] The present methods, systems, and apparatus are set forth in part in the description which follows, and in part will be obvious from the description, or may be learned by practice of the present methods, apparatus, and systems. The advantages of the present methods, apparatus, and systems will be realized and attained by means of the elements and combinations particularly pointed out in the appended claims. It is to be understood that both the foregoing general description and the following detailed description are exemplary and explanatory only and are not restrictive of the methods, apparatus, and systems as claimed.

[0010] Thus, it is not the object of the present invention to include within the present invention all known products, processes for making a product, or methods for using a product, such that the applicants reserve the rights to all known products, processes, or methods and hereby disclose a disclaimer thereof. Furthermore, it is noted that the present invention does not intend to include within its scope all products, or methods for making a product, or methods for using a product that do not meet the description and enablement requirements of the USPTO (35 U.S.C. § 112, first paragraph) or the EPO (Article 83 EPC). In the practice of the present invention, it may be advantageous to follow Article 53(c) EPC and Rules 28(b) and (c) of the EPC. All rights to expressly disclaim all embodiments that are the subject of any granted patents of the applicants in this application class or any other class, or in any third party previously filed application, are expressly reserved. Nothing herein is to be construed as a commitment.

[0011] In the accompanying drawings, like elements are identified by like reference numerals in certain preferred embodiments of the present invention. [Brief description of the drawings]

[0012] [Figure 1] FIG. 1 is a pie chart showing GABAA receptors and binding sites. [Diagram 2] 2A-2D are graphs showing that CBD formulations increase the percentage of time spent in (FIG. 2A) REM sleep and (FIG. 2B) restorative sleep in study participant DR11, as well as (FIG. 2C) REM sleep and (FIG. 2D) restorative sleep in DR11 [**p<0.01 (t-test). n=7 days per treatment group. Values ​​are mean±SEM]. [Diagram 3]3A-3B are graphs showing that CBD formulations increase the percentage of time spent in (FIG. 3A) REM sleep and (FIG. 3B) recovery sleep in study participant DR11, whereas CBD alone is less effective. [*p<0.05 (One-way ANOVA). n=7 days per treatment group. Values ​​are mean±SEM] [Figure 4] FIG. 4A is a graph showing that the CBD formulation tended to increase the percentage of REM sleep [p=0.06; (t-test). n=23 participants per treatment group. Values ​​are means±SEM], and FIG. 4B is a graph showing that the CBD formulation tended to increase the percentage of restorative sleep in pooled data from Le Reve 1.0 [p=0.32 (t-test). n=23 participants per treatment group. Values ​​are means±SEM]. [Diagram 5] 5A-5B are graphs showing that CBD formulations increase the percentage of (FIG. 5A) REM sleep and (FIG. 5B) recovery sleep in pooled responders [**p=0.001; ****p<0.0001 (t-test). n=11 responders per treatment group. Values ​​are mean±SEM] [Figure 6] 6A-6B are graphs showing that CBD formulations increase the percentage of (6A) REM sleep in participants with moderate insomnia and (6B) restorative sleep in pooled responders with insomnia [**p<0.01 (t-test). n=7-9 responders per treatment group. Values ​​are means ± SEM]. [Figure 7]FIG. 7 is a graph showing that study participants perceived that the CBD formulation helped them sleep better [p=0.13; (t-test). n=23 responders per treatment group. Values ​​are mean±SEM]. At the end of each treatment period, study participants used the PGI questionnaire to determine whether the treatment affected their sleep compared to the baseline period before treatment began. Scoring matrix: 1=treatment helped; 2-treatment had no effect; 3-treatment made it worse. With this data, lower scores indicate potential benefit in supporting sleep. The results showed that the CBD formulation appears to improve the perception of good sleep compared to the placebo control. [Figure 8] Figures 8A-8C are graphs showing CBD formulations reducing anxiety. At the end of each treatment period, study participants completed a clinically validated survey entitled the Hamilton Anxiety Rating Scale29. Each item on this scale is scored on a scale of 0 (absent) to 4 (severe), with total scores ranging from 0 to 53, with <14 indicating mild severity, 15-21 indicating mild to moderate severity, and 22-27 indicating moderate to severe severity. Based on this study, the CBD formulation reduced anxiety in participants DR13 (Figure 8A), DR16 (Figure 8B), and DR21 (Figure 8C) compared to a placebo control or CBD alone. [Figure 9] FIG. 9A is a graph showing that the CBD formulation reduces anxiety in "responders." At the end of each treatment period, study participants filled out a survey entitled the Hamilton Anxiety Rating Scale 29. Each item on this scale is scored on a scale of 0 (absent) to 4 (severe), with total scores ranging from 0 to 53, with <14 indicating mild severity, 15 to 21 indicating mild to moderate severity, and 22 to 27 indicating moderate to severe severity. Based on this study, the CBD formulation appeared to reduce anxiety compared to the placebo control or CBD alone [*p<0.05 (one-way ANOVA). n=10 "responders" per treatment group. Values ​​are mean±SEM]. FIG. 9B is a graph showing that the mean anxiety scores of responders were higher than non-responders after taking the placebo control. [Figure 10] 10A-10B are graphs showing that CBD formulations increase the percentage of (10A) REM sleep and (10B) restorative sleep in an independent cohort of participants with moderate to severe insomnia. [*p<0.05; (t-test). n=13 participants per treatment group. Values ​​are mean±SEM]. [Figure 11] 11A-11B are graphs showing that CBD formulations increase the percentage of (11A) REM sleep and (11B) recovery sleep in the combined data sets from Clinical Trials 1 and 2 [*p<0.05; (t-test). n=36 participants per treatment group. Values ​​are means ± SEM]. FIG. 11C is a graph showing that CBD formulations show a trend to increase the percentage of deep sleep in the combined data from Le Reve 1.0 and 2.0 [p=0.17 (t-test). n=36 participants per treatment group. Values ​​are means ± SEM]. [Figure 12] FIG. 12 is a schematic flow chart of a clinical trial of the embodiment. [Figure 13] 13A-13F are graphs showing that CBD-terpene formulations increase the percentage of time spent in SWS+REM sleep (restorative sleep) in DR24 (FIG. 13A), DR45 (FIG. 13B), DR51 (FIG. 13C), DR111 (FIG. 13D), DR112 (FIG. 13E), and DR128 (FIG. 13F) [*p<0.05 (t-test); **p<0.01 (t-test); ***p<0.001; ****p<0.0001 (t-test). n=15-28 days per treatment group. Values ​​are mean±SEM]. [Figure 14] 14A-14F are graphs showing that CBD-terpene formulations increase the percentage of time spent in (FIG. 14A) REM, (FIG. 14B) SWS, (FIG. 14C) SWS+REM (restorative sleep) of study participant DR51, and (FIG. 14D) REM, and (FIG. 14E) SWS, and (FIG. 14F) SWS+REM (restorative sleep) [**p<0.01; ***p<0.001 (t-test). n=19-25 participants per treatment group. Values ​​are mean±SEM]. [Figure 15] 15A-15F are graphs showing that CBD-terpene formulations increase the percentage of time spent in study participant DR128 (FIG. 15A) REM, (FIG. 15B) SWS, (FIG. 15C) SWS+REM (restorative sleep), and (FIG. 15D) REM and (FIG. 15E) SWS, and (FIG. 15F) SWS+REM (restorative sleep). *p<0.05 (t-test); ***p<0.001; ****p<0.0001 (t-test). n=15-28 days per treatment group. Values ​​are mean±SEM.] [Figure 16] 16A-16F are graphs showing that CBD-terpene formulations reduce light sleep compared to placebo in study participant DR24 (FIG. 16A), study participant DR45 (FIG. 16B), study participant DR51 (FIG. 16C), study participant DR111 (FIG. 16D), study participant DR112 (FIG. 16E), and study participant DR128 (FIG. 16F). *p<0.05 (t-test); ***p<0.001; ****p<0.0001 (t-test). n=15-28 days per treatment group. Values ​​are mean±SEM. [Figure 17] 17A-17F are graphs showing that CBD-terpene formulations increase total sleep time (TST) compared to placebo in study participant DR24 (FIG. 17A), study participant DR45 (FIG. 17B), study participant DR51 (FIG. 17C), study participant DR111 (FIG. 17D), study participant DR112 (FIG. 17E), and study participant DR128 (FIG. 17F) [(t-test). n=15-28 days per treatment group. Values ​​are mean±SEM]. "ns" is not significant. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0013] The foregoing and other features and advantages of the present invention will be apparent from the following detailed description of exemplary embodiments, when read in conjunction with the accompanying drawings, which are merely examples of the invention rather than limiting, the scope of the invention being defined by the appended claims and their equivalents.

[0014] The embodiments of the present invention will now be described with reference to the drawings, in which like numerals reflect like elements throughout. The terminology used in the description presented herein is not intended to be interpreted in any restrictive or limiting manner, as this terminology is utilized solely in conjunction with the detailed description of certain specific embodiments of the present invention. Furthermore, the embodiments of the present invention may include several novel features, none of which merely contribute to its desirable attributes or are essential to the practice of the invention described herein.

[0015] Use of the terms "a," "an," and "the" and similar referents in the context of describing the present invention should be construed to encompass both the singular and the plural, unless otherwise stated herein or clearly contradicted by context. Furthermore, it will be understood that the terms "comprises," "comprising," "comprising," "includes," and / or "including," as used herein, specify the presence of stated features, integers, steps, operations, elements, and / or components, but do not preclude the presence or addition of one or more other features, integers, steps, operations, elements, components, and / or groups thereof.

[0016] The description of ranges of values ​​herein, unless otherwise stated herein, is intended to be treated merely as a shorthand method of referring individually to each separate value within the range, and each separate value is incorporated herein as if it were individually stated herein. The term "about", when used with a numerical value, should be interpreted to indicate a deviation and inclusion of up to 10% from the numerical value stated. The use of any examples or exemplary language provided herein (e.g., "eg" or "such as") is intended merely to better illustrate the invention, and does not impose limitations on the scope of the invention unless otherwise claimed. No language in this specification should be construed as indicating any non-claimed element as essential to the practice of the invention.

[0017] References to "one embodiment," "an embodiment," "example embodiment," "various embodiments," and the like may indicate that the described embodiments of the invention may include a particular feature, structure, or characteristic, but not all embodiments necessarily include the particular feature, structure, or characteristic. Additionally, repeated use of the phrases "in one embodiment" or "in an exemplary embodiment" does not necessarily refer to the same embodiment, although they may be.

[0018] As used herein, the term "method" refers to methods, means, techniques, and procedures for accomplishing a given task, including, but not limited to, methods, means, techniques, and procedures known to practitioners in the fields of chemistry, pharmacology, biology, biochemistry, and medicine, or readily developed from known methods, means, techniques, and procedures by practitioners in the fields of chemistry, pharmacology, biology, biochemistry, and medicine. Unless otherwise expressly stated, it is never intended that any method or embodiment described herein be interpreted as requiring that its steps be performed in a particular order. Thus, no order is intended to be inferred in any respect unless a method claim specifically recites in the claim or description that the steps are limited to a particular order. This applies to all possible unstated bases of interpretation, including simple meaning derived from the arrangement of steps or operational flow, grammatical construction or punctuation, or logical questions regarding the number or type of embodiments described herein.

[0019] definition

[0020] "Sleep disorder" means any condition in which a subject has difficulty falling asleep or staying asleep, e.g., insomnia, conditions associated with difficulty falling asleep due to anxiety, stress, and depression; difficulty falling asleep resulting in poor concentration and focus; difficulty falling asleep due to age-related forgetfulness, dementia, or other cognitive impairment; difficulty falling asleep due to substance abuse, psychiatric disorders, breathing disorders, or due to other sleep disorders such as periodic limb movements; difficulty falling asleep or staying asleep due to other sleep-related problems such as poor sleep hygiene, which may include the use of alcoholic or caffeinated beverages. poor sleep hygiene includes irregular bedtimes, or inadequate temperature, ventilation, sound, or light in the sleep environment; narcolepsy, and rapid eye movement (REM) sleep behavior disorder; disorders associated with neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, and multiple sclerosis; disruptive REM sleep disorders associated with drug withdrawal, particularly alcohol withdrawal or sedative-hypnotic withdrawal; and circadian rhythm disruptions associated with sleep apnea, shift work sleep disorder, and jet lag.

[0021] The term "anxiety" as used herein refers to a mental disorder in which anxiety and avoidance behavior predominates. Examples of such disorders include phobias (including agoraphobia), panic disorder, obsessive-compulsive disorder, post-traumatic stress disorder, acute stress disorder, generalized anxiety disorder, and substance-induced anxiety disorder.

[0022] "Depression" includes pathological or clinical depression and is usually diagnosed when sadness or elation is excessively intense and continues beyond the impact of the anticipated event. Symptoms often recur episodically or follow a low-grade intermittent chronic course, impairing the patient's functioning. Bipolar mood disorder is generally characterized by episodes of depression, usually lasting 6-9 months, followed by periods of elation during the course of the illness. Unipolar mood disorder is characterized by episodes of syndromal depression, usually lasting 6-9 months.

[0023] "REM sleep" is characterized by rapid eye movement, loss of muscle tone, dream content, fluctuations in autonomic functions (irregular breathing, pulse, body temperature, and blood pressure), a brain metabolic rate similar to that of wakefulness, and desynchronized neuronal activity. There is no noradrenergic or serotonergic activity during REM. Although REM sleep does not serve the same purpose (neuronal activity similar to that of wakefulness), it may serve yet another role: full restoration of the sensitivity of monoamine receptors (especially those of norepinephrine, serotonin, and histamine). This is achieved by the cessation of release of monoamine neurotransmitters during REM sleep (resulting in sleep paralysis and reduced environmental awareness). Other theories related to this hypothesis claim that REM sleep is important for memory (especially memory consolidation) and intellectual function. Research has shown that REM sleep is increased during intensive learning experiences, and that loss of REM sleep results in reduced creative problem-solving abilities. Experiments have shown that perceptual skills, such as those learned through repeated practice, improve overnight and are disrupted when REM sleep is selectively interrupted.Other experimental data suggest that the brain activity that occurs during REM sleep plays an important role in brain development.

[0024] Furthermore, REM sleep has been linked to the proper functioning of growth and development of nervous system activity. The fact that REM sleep is resistant to age-related changes may suggest a role in maintaining nervous system function. Furthermore, although the purpose of dreaming (a key distinguishing feature of REM) is less well understood than REM, many theories about it reinforce the cognitive-health importance of REM sleep. These theories include the proposal that dreaming (and thus REM) is associated with long-term consolidation of semantic memories, learning, and the recovery of traumatic experiences.

[0025] "Restorative sleep" is a generalized connotation of the important role sleep plays in reactivation. Mechanisms underlying the restorative process include neutralization of neurotoxins that accumulate during wakefulness, response to the increase in sleep-inducing substances produced during the wakefulness process, synthesis of neurochemicals, and redistribution of brain chemicals. Increased tissue synthesis, cell division, and growth hormone release are observed during slow-wave sleep (SWS). Athletes have a higher percentage of SWS than others. Oxygen consumption is decreased during SWS, suggesting a reduction in catabolism. SWS is increased after starvation in an apparent compensatory effect. Hyperthyroidism increases SWS and hypothyroidism decreases SWS, and SWS is high during the peak years of physical development in children and decreases in old age. Finally, studies have shown that SWS has an intensity component. This intensity dimension of SWS allows mammals to compensate for lost sleep without significantly increasing sleep time. During NREM sleep, and in particular SWS, it appears that it plays a central role in physical restoration: the low metabolic rate and low body temperature of NREM apparently provide an environment conducive to neural repair.

[0026] The term "synergistic" as used herein refers to the phenomenon where the cumulative pharmacological effect of two or more components used in combination is greater than the sum of their respective effects when they are tested individually. The term "potentiate" as used herein refers to the phenomenon where the effectiveness of an active component is significantly greater when combined with a second component, where the second component itself does not demonstrate any efficacy in the same pharmacological test. In some cases of potentiation, the second component may not only not have a measured pharmacological effect, but may even cause an opposite effect when assayed alone. An example of such a case is as follows: component A is an anxiolytic; component B is an anxiolytic; when A and B are combined, the combination produces an effect greater than the anxiolytic effect seen with A alone. In the context of the present invention, potentiation is considered as a special case of synergy. Thus, the term "synergistic" (or synergistic, etc.), when used to define the properties of the compositions of the present invention, also includes within its meaning the potentiating effect described immediately above in this specification.

[0027] The term "CBD" formulation, as used herein, refers to a pharma- ceutically acceptable composition, which is within the bounds of sound medical judgment and is suitable for contact with mammalian, particularly human, tissues without undue toxicity, irritation, allergic response, and other problematic complications, commensurate with a reasonable risk-benefit ratio. CBD formulations include configurational isomers (e.g., cis and trans isomers) and all optical isomers (enantiomers), isomers, and diastereomers), racemates, diastereoisomers, and mixtures of these isomers, as well as solvates, hydrates, isomorphs, polymorphs, tautomers, esters, salt forms, and prodrugs. The term "prodrug" refers to a compound that is a drug precursor and releases the drug in vivo through some chemical or physiological process after administration (e.g., a prodrug is converted to the desired dosage form when a physiological pH is reached or through enzymatic action). Exemplary prodrugs release the corresponding free acid upon cleavage, as well as a hydrolyzable ester-forming residue of a compound of the invention.

[0028] In this disclosure, an "effective amount" or "effective dose" of a CBD, a terpene, a combination of a terpene and CBD, or a composition refers to the amount of CBD or terpene that reaches the bloodstream and / or body tissues of a subject after administration to the subject.

[0029] CBD

[0030] In the context of the present invention, the terms "cannabidiol compound", "cannabidiol", or "CBD" (which may be used interchangeably unless the context dictates otherwise) refer to any natural, semi-synthetic, or synthetic cannabinoid compound.

[0031] CBD is the compound “Δ 2 These compounds include (1)Δ 5-Cannabidiol (2-(6-isopropenyl-3-methyl-5-cyclohexen-1-yl)-5-pentyl-1,3-benzenediol); (2) Δ 4 -Cannabidiol (2-(6-isopropenyl-3-methyl-4-cyclohexen-1-yl)-5-pentyl-1,3-benzenediol); (3) Δ 3 -Cannabidiol (2-(6-isopropenyl-3-methyl-3-cyclohexen-1-yl)-5-pentyl-1,3-benzenediol); (4) Δ 3,7 -Cannabidiol (2-(6-isopropenyl-3-methylenecyclohex-1-yl)-5-pentyl-1,3-benzenediol), (5)Δ 2 -Cannabidiol (2-(6-isopropenyl-3-methyl-2-cyclohexen-1-yl)-5-pentyl-1,3-benzenediol); (6) Δ 1 -Cannabidiol (2-(6-isopropenyl-3-methyl-1-cyclohexen-1-yl)-5-pentyl-1,3-benzenediol); and (7) Δ 6 -Cannabidiol (2-(6-isopropenyl-3-methyl-6-cyclohexen-1-yl)-5-pentyl-1,3-benzenediol).

[0032] CBD may include cannabidiolic acid (CBDA), tetrahydrocannabinol (THC), tetrahydrocannabinolic acid (THCA), cannabigerol (CBG), cannabichromene (CBC), cannabinol (CBN), cannabielsoin (CBE), iso-tetrahydrocannabinol (iso-THC), cannabicyclol (CBL), cannabicitran (CBT), cannahivarin (CBV), tetrahydrocannabivarin (THCV), cannabidivarin (CBDV), cannabichromevarin (CBCV), cannabigerovarin (CBGV), and cannabigerol monomethyl ether (CBGM), salts thereof, derivatives thereof, and mixtures of cannabinoids. Each possibility represents a separate embodiment of the present invention.

[0033] In one embodiment, the CBD formulation has the following general formula (I): [ka] (In the formula, R1 is alkyl; R2 is a linear or branched alkyl group having 5 to 12 carbon atoms; an -OR3 group, where R3 is a linear or branched alkyl group having 5 to 9 carbon atoms or a linear or branched alkyl group substituted at the terminal carbon atom by a phenyl group; or (CH2) n -O-alkyl groups, where n is an integer from 1 to 7 and the alkyl group has 1 to 5 carbons. Includes.

[0034] In one embodiment, R1 is CH3 and R2 is a straight chain alkyl having 5 carbon atoms (i.e., -CH 11 ).

[0035] In another embodiment, the CBD compound is cannabidiol. CBD has the molecular formula C 21 H 30 O2, which is represented by the following formula (II): [ka]

[0036] The cannabidiol of formula (II) may be natural cannabidiol that can be obtained by extraction from a preparation (e.g., processed plant material) of any member of the Cannabis genus plant or cannabis. In one embodiment, natural cannabidiol may be extracted from Cannabis sativa or one of its preparations, such as marijuana, hashish, etc. In one embodiment, natural cannabidiol may be extracted from Cannabis sativa using methods such as those described in U.S. Pat. No. 6,403,123 and Gaoni and Mechoulam [J Chem Soc 93:217-224 (1971)], both of which are incorporated herein by reference.

[0037] The cannabidiol may also be synthetic cannabidiol or a derivative thereof, which may be made using methods such as, but not limited to, those described in U.S. Patent Publication No. 2003 / 16672, which is incorporated herein by reference.

[0038] In some embodiments, the composition comprises a CBD derivative. The term "CBD derivative" as used herein means a CBD derivative that has an anti-inflammatory or sedative effect, or that has an ameliorating effect on an inflammatory disease, disorder, or condition; or a CBD derivative that binds to the CB(1) and / or CB(2) cannabinoid receptors.

[0039] In some embodiments, the CBD derivative is selected from (-)-7-hydroxy-CBD, known from International Patent Publication No. 2015 / 198077 to reduce triglyceride levels and treat fatty liver; (-)-CBD-7-acid, known from Haj 2015 to have anti-inflammatory effects; and the dimethylheptvl (DMH) homologue of CBD, known to have anti-inflammatory effects (Ben-Shabat 2006; Juknat 2016), and the corresponding compounds of the enantiomeric (+)-CBD series.

[0040] In some embodiments, the CBD derivative is characterized by a structure in which at least one of the hydroxyl substituents is converted to its stable form. In some embodiments, the CBD derivative is a cannabinol that contains a quinone ring. In one embodiment, the CBD derivative is an endocannabinoid derivative. In another embodiment, the pentyl group on the phenyl group of CBD is replaced with any linear or branched alkyl group selected from (C1-C18) alkyl, which may be optionally substituted.

[0041] In some embodiments, the CBD is prepared from a cannabis extract. In some embodiments, the term "CBD or a derivative thereof" refers to 80%-99% pure CBD. In some embodiments, the term "CBD or a derivative thereof" refers to 90%-99% pure CBD. In some embodiments, the term "CBD or a derivative thereof" refers to 93%-99% pure CBD. In some embodiments, the term "CBD or a derivative thereof" refers to 95%-99% pure CBD. In some embodiments, the term "CBD or a derivative thereof" refers to 95%-97% pure CBD. In some embodiments, the term "CBD or a derivative thereof" refers to 97% pure CBD. All percentages herein above are by weight.

[0042] In some embodiments, the CBD or derivatives thereof are substantially and / or essentially devoid of tetrahydrocannabinol (THC). In some embodiments, the compositions of the invention described herein are substantially and / or essentially devoid of THC. In one embodiment, substantially and / or essentially devoid of THC means less than 9% THC by weight. In one embodiment, substantially and / or essentially devoid of THC is less than 7% THC by weight. In one embodiment, substantially and / or essentially devoid of THC is less than 5% THC by weight. In one embodiment, substantially and / or essentially devoid of THC is less than 3% THC by weight. In one embodiment, substantially and / or essentially devoid of THC is less than 1% THC by weight. In one embodiment, substantially and / or essentially devoid of THC is less than 0.5% THC by weight. In one embodiment, substantially and / or essentially devoid of THC is less than 0.3% THC by weight. In one embodiment, substantially and / or essentially devoid of THC is less than 0.1% THC by weight.

[0043] In some embodiments, the CBD is synthetically prepared.

[0044] Terpenes

[0045] Terpenes have the formula (C5H8) n These unsaturated hydrocarbons, which include more than 30,000 compounds, are mainly produced by plants, especially conifers. Terpenes are further classified according to the number of carbon atoms, such as monoterpenes (C10), sesquiterpenes (C15), and diterpenes (C20). Terpenes useful in the present invention include terpenes having 10 carbon atoms (C10) to 25 carbon atoms (C25). Preferred terpenes useful in the present invention are terpenes having 10 carbon atoms or 15 carbon atoms. Preferred terpene mixtures are mixtures having a predominant amount, i.e., greater than 50% by weight, of C10 terpenes and C15 terpenes. More preferred mixtures are mixtures having a predominant amount, i.e., greater than 50% by weight, of C10 terpenes.

[0046] The CBD formulation comprises at least eight terpenes, wherein the eight terpenes comprise linalool, myrcene, phytol, limonene, α-terpinene, α-terpineol, α-pinene, and β-caryophyllene, wherein the weight ratio of linalool:myrcene is about 1.0:1.0, the weight ratio of myrcene:phytol is about 1.0:1.0, the weight ratio of phytol:limonene is about 1.0:1.0, the weight ratio of limonene:α-terpinene is about 1.0:1.0, the weight ratio of α-terpinene:α-terpineol is about 1.0:1.0, the weight ratio of α-terpineol:α-pinene is about 1.0:1.0, and the weight ratio of α-pinene:β-caryophyllene is about 1.0:1.0. In other embodiments, the weight ratio of linalool:myrcene is in the range of 1.0:2.0 to 2.0:1.0, the weight ratio of myrcene:phytol is in the range of 1.0:2.0 to 2.0:1.0, the weight ratio of phytol:limonene is in the range of 1.0:2.0 to 2.0:1.0, the weight ratio of limonene:α-terpinene is in the range of 1.0:2.0 to 2.0:1.0, the weight ratio of α-terpinene:α-terpineol is in the range of 1.0:2.0 to 2.0:1.0, the weight ratio of α-terpineol:α-pinene is in the range of 1.0:2.0 to 2.0:1.0, and the weight ratio of α-pinene:β-caryophyllene is in the range of 1.0:2.0 to 2.0:1.0. In further embodiments of the foregoing, the weight ratio of linalool:myrcene is in the range of 1:0.9-0.9-1, the weight ratio of myrcene:phytol is in the range of 1:0.9-0.9-1, the weight ratio of phytol:limonene is in the range of 1:0.9-0.9-1, the weight ratio of limonene:α-terpinene is in the range of 1:0.9-0.9-1, the weight ratio of α-terpinene:α-terpineol is in the range of 1:0.9-0.9-1, the weight ratio of α-terpineol:α-pinene is in the range of 1:0.9-0.9-1 and the weight ratio of α-pinene:β-caryophyllene is in the range of 1:0.9-0.9-1.In further embodiments of the above, the weight ratio of linalool:myrcene is in the range of 1:0.8-0.8-1, the weight ratio of myrcene:phytol is in the range of 1:0.8-0.8-1, the weight ratio of phytol:limonene is in the range of 1:0.8-0.8-1, the weight ratio of limonene:α-terpinene is in the range of 1:0.8-0.8-1, the weight ratio of α-terpinene:α-terpineol is in the range of 1:0.8-0.8-1, the weight ratio of α-terpineol:α-pinene is in the range of 1:0.8-0.8-1 and the weight ratio of α-pinene:β-caryophyllene is in the range of 1:0.8-0.8-1. In certain embodiments, the weight ratio of linalool:myrcene is in the range of 1.2:1.0 to 1.0:1.2, the weight ratio of myrcene:phytol is in the range of 1.2:1.0 to 1.0:1.2, the weight ratio of phytol:limonene is in the range of 1.2:1.0 to 1.0:1.2, the weight ratio of limonene:α-terpinene is in the range of 1.2:1.0 to 1.0:1.2, the weight ratio of α-terpinene:α-terpineol is in the range of 1.2:1.0 to 1.0:1.2, the weight ratio of α-terpineol:α-pinene is in the range of 1.2:1.0 to 1.0:1.2, and the weight ratio of α-pinene:β-caryophyllene is in the range of 1.2:1.0 to 1.0:1.2. In certain embodiments, the weight ratio of linalool:myrcene is in the range of 1.1:1.0 to 1.0:1.1, the weight ratio of myrcene:phytol is in the range of 1.1:1.0 to 1:0:1.1, the weight ratio of phytol:limonene is in the range of 1.1:1.0 to 1.0:1.1, the weight ratio of limonene:α-terpinene is in the range of 1.1:1.0 to 1.0:1.1, the weight ratio of α-terpinene:α-terpineol is in the range of 1.1:1.0 to 1.0:1.1, the weight ratio of α-terpineol:α-pinene is in the range of 1.1:1.0 to 1.0:1.1, and the weight ratio of α-pinene:β-caryophyllene is in the range of 1.1:1.0 to 1.0:1.1.

[0047] In one embodiment, the eight terpenes include linalool, myrcene, phytol, limonene, α-terpinene, α-terpineol, α-pinene and β-caryophyllene, and are administered in a dose-response or dose-dependent manner to identify the exact concentration of each terpene that induces maximum response.The dose-response method describes the magnitude of the subject's response as a function of exposure (or dose) to terpene after a specific exposure time.The dose-response relationship can be described by a dose-response curve.

[0048] Linalool is a monoterpenoid that is an octa-1,6-diene substituted by methyl groups at the 3- and 7-positions and by a hydroxy group at the 3-position. It has been isolated from plants such as Ocimum canum. Linalool refers to the two enantiomers of a naturally occurring terpene alcohol found in many flower and spice plants. Linalool has multiple commercial uses, most of which are based on its pleasant odor. Linalool, a colorless oil, is classified as an acyclic monoterpenoid.

[0049] Myrcene or β-myrcene is a natural hydrocarbon of an alkene (7-methyl-3-methylene-1,6-octadiene). Myrcene is more accurately classified as a monoterpene. Monoterpenes are dimers of isoprenoid precursors, and myrcene is the main component of the essential oil of Adenandra villosa in South Africa, and myrcene is also found in bay laurel, hemp, and hops. In one embodiment, α-myrcene is the structural isomer 2-methyl-6-methylene-1,7-octadiene. Myrcene has analgesic, antioxidant, antidepressant, anti-inflammatory, and muscle relaxant properties. Myrcene affects the permeability of cell membranes, allowing more CBD and / or terpenese to reach nerve cells.

[0050] Phytol (florasol, phytosol) is an acyclic diterpene alcohol (2E,7R,11R)-3,7,11,15-tetramethylhexadec-2-en-1-ol or hexadec-2-en-1-ol substituted with methyl groups at positions 3, 7, 11, and 15. The diterpene is composed of four isoprene units and has the molecular formula C 20 H 32 Examples of diterpenes and diterpenoids are cafestol, kahweol, cembrene; and taxadiene (the precursor of taxol).

[0051] Limonene is a colorless liquid aliphatic hydrocarbon classified as a cyclic monoterpene, 1-methyl-4-prop-1-en-2-ylcyclohexene. The D-isomer, commonly occurring in nature as an orange scent, is a flavoring in food production. d-Limonene ((+)-limonene) is the (R)-enantiomer; racemic limonene is known as dipentene. Limonene may be an antidepressant and may synergistically promote the absorption of other terpenes by rapidly penetrating cell membranes. This result may increase systolic pressure.

[0052] Alpha-terpinene (α-terpinene) is one of three isomeric monoterpenes that differ in the location of their two double bonds (the others are β-terpinene and γ-terpinene). In α-terpinene, the double bonds are at the 1- and 3-positions of the p-menthane skeleton and are known as 1-methyl-4-propan-2-ylcyclohexa-1,3-diene. It has a role as a component of volatile oils and plant metabolites. It is a monoterpene and a cyclohexadiene. α-Terpinene has been isolated from cardamom and marjoram oils, as well as other natural sources.

[0053] Alpha-terpineol (α-terpineol) is a terpineol that is a propan-2-ol substituted at the 2-position with 4-methylcyclohex-3-en-1-yl. α-Terpineol is known as 2-(4-methylcyclohex-3-en-1-yl)propan-2-ol and has a role as a plant metabolite. Terpineol is any of four isomeric monoterpenoids. Terpenoids are terpenes modified by the addition of a functional group, in this case an alcohol. Terpineol has been isolated from a variety of sources, such as cardamom, cajuput oil, pine oil, and petitgrain oil. There are four isomers: α-terpineol, β-terpineol, γ-terpineol, and terpinen-4-ol. β-terpineol and γ-terpineol differ only in the position of the double bond. Terpineol is usually a mixture of these isomers with α-terpineol as the major component.

[0054] Alpha-pinene (α-pinene) is a compound of the terpene class and is one of two isomers of pinene, known as 2,6,6-trimethylbicyclo[3.1.1]hept-2-ene. It is an alkene, containing a reactive four-membered ring, or bicyclo[3.1.1]hept-2-ene, substituted with methyl groups at the 2-, 6-, and 6-positions, respectively. It is found in the oils of many types of conifers, especially pine. It is also found in the essential oils of rosemary and Satureja myrtifolia. Both enantiomers are known in nature; (1S,5S)- or (-)-α-pinene is more common in European pines, and the (1R,5R)- or (+)-α-isomer is more common in North America. This racemic mixture is present in some oils, such as eucalyptus oil and orange peel oil.

[0055] Beta-caryophyllene (β-caryophyllene) is a naturally occurring bicyclic sesquiterpene that is a component of many essential oils, especially clove oil, oil from the stems and flowers of Syzygium aromaticum, Cannabis sativa, rosemary, and hops. β-Caryophyllene is usually found as a mixture that includes isocaryophyllene (the cis double bond isomer) and the ring-opened isomer α-humulene (formerly known as α-caryophyllene). Caryophyllene is notable for having a cyclobutane ring and a trans double bond in the nine-membered ring.

[0056] Description of the embodiments

[0057] Generally, CBD formulations are composed of high purity (>99.9%) hemp-derived cannabidiol (CBD) and terpenes as a sleep aid for people with insomnia and other sleep disorders. In one embodiment, the CBD formulation does not contain detectable Δ9-tetrahydrocannabinol (Δ9-THC). The CBD formulation contains multiple terpenes that act synergistically with the use of CBD and CBD formulations for the treatment of diseases. In one embodiment, the CBD formulation contains about 150 mg of CBD and about 0.5 mg each of the terpenes linalool, myrcene, phytol, limonene, α-terpinene, α-terpineol, α-pinene, and β-caryophyllene, which are used for the treatment of insomnia. In one embodiment, an effective amount for treating insomnia and other sleep disorders is about 300 mg of CBD and about 1.0 mg each of the terpenes linalool, myrcene, phytol, limonene, α-terpinene, α-terpineol, α-pinene, and β-caryophyllene. In other embodiments, the effective amount for each individual with insomnia or other sleep disorders may vary as described below.

[0058] In one embodiment, the CBD formulation comprises about 150mg of CBD and about 0.5mg each of the terpenes linalool, myrcene, phytol, limonene, α-terpinene, α-terpineol, α-pinene, and β-caryophyllene, which are used synergistically with CBD to treat anxiety. In one embodiment, the effective dose for treating anxiety is about 300mg of CBD and about 1.0mg each of the terpenes linalool, myrcene, phytol, limonene, α-terpinene, α-terpineol, α-pinene, and β-caryophyllene. In other embodiments, the effective dose for each individual with anxiety may vary as described below.

[0059] In one embodiment, the CBD formulation comprises about 150mg CBD and about 0.5mg each of the terpenes linalool, myrcene, phytol, limonene, α-terpinene, α-terpineol, α-pinene, and β-caryophyllene, which are used synergistically with CBD to treat depression. In one embodiment, the effective dose for treating depression is about 300mg CBD and about 1.0mg each of the terpenes linalool, myrcene, phytol, limonene, α-terpinene, α-terpineol, α-pinene, and β-caryophyllene. In other embodiments, the effective dose for each individual with depression may vary as described below.

[0060] In some embodiments, the CBD formulations provided herein contain between about 50 mg and about 4000 mg of CBD per effective dose, or alternatively, 50 mg, 100 mg, 150 mg, 200 mg, 250 mg, 300 mg, 350 mg, 400 mg, 450 mg, 500 mg, 550 mg, 600 mg, 650 mg, 700 mg, 750 mg, 800 mg, 850 mg, 900 mg, 9 ...100 mg, 150 mg, 150 mg, 150 mg, g, 1000mg, 1050mg, 1200mg, 1250mg, 1300mg, 1350mg, 1400mg, 1450mg, 1500mg, 1550mg, 1600mg, 1650mg, 1700mg, 1750mg, 1800mg, 1850mg, 1900mg, 2250mg, 2500mg, 2750mg, 3000mg, 3500mg, or 4000mg of CBD.

[0061] In some embodiments, the CBD formulations provided herein may contain about 0.1 mg to 5.0 mg of linalool per effective dose. For example, the compositions provided herein may contain about 0.1 mg to 3.0 mg, 0.5 mg to 3.0 mg, 1 mg to 3.0 mg, 0.1 mg to 2.5 mg, 0.5 mg to 2.5 mg, 1 mg to 2.5 mg, 0.1 mg to 2.0 mg, 0.5 mg to 2.0 mg, 1 mg to 2.0 mg, 0.1 mg to 1.5 mg, 0.5 mg to 1.5 mg, 1 mg to 1.5 mg / ml, 0.1 mg The dosage may contain from 10 mg to about 100 mg of linalool per effective dose.

[0062] In some embodiments, the CBD formulations provided herein may contain between about 0.1 mg and 5.0 mg of myrcene per effective dose. For example, the compositions provided herein may contain between about 0.1 mg and 3.0 mg, between 0.5 mg and 3.0 mg, between 1 mg and 3.0 mg, between 0.1 mg and 2.5 mg, between 0.5 mg and 2.5 mg, between 1 mg and 2.5 mg, between 0.1 mg and 2.0 mg, between 0.5 mg and 2.0 mg, between 1 mg and 2.0 mg, between 0.1 mg and 1.5 mg, between 0.5 mg and 1.5 mg, between 1 mg and 1.5 mg / ml, between 0.1 mg The dosage may contain from about 10 mg to about 100 mg of myrcene per effective dose.

[0063] In some embodiments, the CBD formulations provided herein may contain between about 0.1 mg and 5.0 mg of phytol per effective dose. For example, the formulations provided herein may contain between about 0.1 mg and 3.0 mg, between 0.5 mg and 3.0 mg, between 1 mg and 3.0 mg, between 0.1 mg and 2.5 mg, between 0.5 mg and 2.5 mg, between 1 mg and 2.5 mg, between 0.1 mg and 2.0 mg, between 0.5 mg and 2.0 mg, between 1 mg and 2.0 mg, between 0.1 mg and 1.5 mg, between 0.5 mg and 1.5 mg, between 1 mg and 1.5 mg / ml, between 0.1 mg The dosages may contain from about 10 mg to about 100 mg of phytol per effective dose.

[0064] In some embodiments, the CBD formulations provided herein may contain between about 0.1 mg and 5.0 mg of limonene per effective dose. For example, the formulations provided herein may contain between about 0.1 mg and 3.0 mg, between 0.5 mg and 3.0 mg, between 1 mg and 3.0 mg, between 0.1 mg and 2.5 mg, between 0.5 mg and 2.5 mg, between 1 mg and 2.5 mg, between 0.1 mg and 2.0 mg, between 0.5 mg and 2.0 mg, between 1 mg and 2.0 mg, between 0.1 mg and 1.5 mg, between 0.5 mg and 1.5 mg, between 1 mg and 1.5 mg / ml, between 0.1 mg The dosages may contain from 10 mg to about 100 mg of limonene per effective dose.

[0065] In some embodiments, the CBD formulations provided herein may contain about 0.1 mg to 5.0 mg of alpha-terpinene per effective dose. For example, the compositions provided herein may contain about 0.1 mg to 3.0 mg, 0.5 mg to 3.0 mg, 1 mg to 3.0 mg, 0.1 mg to 2.5 mg, 0.5 mg to 2.5 mg, 1 mg to 2.5 mg, 0.1 mg to 2.0 mg, 0.5 mg to 2.0 mg, 1 mg to 2.0 mg, 0.1 mg to 1.5 mg, 0.5 mg to 1.5 mg, 1 mg to 1.5 mg / ml, 0.1 mg to The dosages may contain 1.0 mg, 0.5 mg to 1.0 mg, 1 mg to 10 mg, 0.1 mg to 5.0 mg, 0.5 mg to 5.0 mg, 1 mg to 5.0 mg, 0.1 mg to 2 mg, 0.5 mg to 2 mg, 1 mg to 2 mg, 2 mg to 4.0 mg, 2 mg to 3.0 mg, 2 mg to 2.5 mg, 2 mg to 5.0 mg, 2 mg to 4.5 mg, 2 mg to 2.5 mg, or 2 mg to 5 mg of alpha-terpinene. Alternatively, the dosages may contain 10 mg to about 100 mg of alpha-terpinene per effective dose.

[0066] In some embodiments, the CBD formulations provided herein may contain between about 0.1 mg and 5.0 mg of alpha-terpineol per effective dose. For example, the compositions provided herein may contain between about 0.1 mg and 3.0 mg, 0.5 mg and 3.0 mg, 1 mg and 3.0 mg, 0.1 mg and 2.5 mg, 0.5 mg and 2.5 mg, 1 mg and 2.5 mg, 0.1 mg and 2.0 mg, 0.5 mg and 2.0 mg, 1 mg and 2.0 mg, 0.1 mg and 1.5 mg, 0.5 mg and 1.5 mg, 1 mg and 1.5 mg / ml, 0.1 mg and 1 ... The dosages may contain from 10 mg to about 100 mg of alpha-terpineol per effective dose.

[0067] In some embodiments, the CBD formulations provided herein may contain between about 0.1 mg and 5.0 mg of α-pinene per effective dose. For example, the compositions provided herein may contain between 0.1 mg and 3.0 mg, 0.5 mg and 3.0 mg, 1 mg and 3.0 mg, 0.1 mg and 2.5 mg, 0.5 mg and 2.5 mg, 1 mg and 2.5 mg, 0.1 mg and 2.0 mg, 0.5 mg and 2.0 mg, 1 mg and 2.0 mg, 0.1 mg and 1.5 mg, 0.5 mg and 1.5 mg, 1 mg and 1.5 mg / ml, 0.1 mg The dosages may contain from 10 mg to about 100 mg of α-pinene per effective dose.

[0068] In some embodiments, the CBD formulations provided herein may contain between about 0.1 mg and 5.0 mg of β-caryophyllene per effective dose. For example, the compositions provided herein may contain between 0.1 mg and 3.0 mg, between 0.5 mg and 3.0 mg, between 1 mg and 3.0 mg, between 0.1 mg and 2.5 mg, between 0.5 mg and 2.5 mg, between 1 mg and 2.5 mg, between 0.1 mg and 2.0 mg, between 0.5 mg and 2.0 mg, between 1 mg and 2.0 mg, between 0.1 mg and 1.5 mg, between 0.5 mg and 1.5 mg, between 1 mg and 1.5 mg / ml, between 0. ... The dosages may contain from 10 mg to about 100 mg of beta-caryophyllene per effective dose.

[0069] CBD and terpenes affect sleep physiology

[0070] CBD formulations will be tested on sleep physiology in well-controlled, adequately powered, and rigorous studies in humans.

[0071] CBD formulations contain highly purified (>98% pure) forms of the terpenes linalool, myrcene, phytol, limonene, α-terpinene, α-terpineol, α-pinene, and β-caryophyllene (food grade (GRAS), natural, organic, non-GMO, dairy-free, gluten-free, vegan). Preclinical studies in animals have shown that these terpenes have sedative properties. 5-9 However, their potential effects on human sleep physiology have not been established. Importantly, these terpenes are designated as GRAS (Generally Regarded as Safe) by the FDA for human oral consumption and have been used as food additives for decades.

[0072] Many published studies have shown that some of these terpenes (myrcene, α-pinene, phytol, terpinolene, and α-terpineol) induce sedation through a similar mechanism of action in which they modulate the gamma-aminobutyric acid (GABA) neurotransmitter system (Figure 1). A The receptors are ionotropic receptors and ligand-gated ion channels. Its endogenous ligand is gamma-aminobutyric acid (GABA), the major inhibitory neurotransmitter in the central nervous system that exerts its effects via a reduction in neuronal activity.

[0073] GABAergic Terpene GABA A Mechanism of sedative activity of

[0074] Two receptors for GABA - GABA A Receptors (Ion Channels) and GABA B There are receptors (G protein-coupled receptors) that act on GABA receptors. The class of clinically prescribed sedatives called benzodiazepines are A They act through receptors. Benzodiazepines are in widespread clinical use to treat anxiety and insomnia. 10 In fact, the benzodiazepines alprazolam (Xanax), clonazepam (Klonopin), diazepam (Valium), and lorazepam (Ativan) are among the most commonly prescribed drugs in the United States. Zolpidem (Ambien) is a commonly prescribed insomnia drug that acts as a sedative and hypnotic. It also binds GABA in the same position as the benzodiazepines. A They work by increasing the effects of GABA in the central nervous system by binding to receptors. Other commonly prescribed insomnia medications, including triazolam (Halcion) and zaleplon (Sonata), also bind to GABA in the same position as benzodiazepines. A They work by binding to receptors. All of these sleep medications increase the activation of receptors by GABA, resulting in inhibition of neuronal activity, sedation, and hypnosis.

[0075] The above terpenes are GABA A These terpenes exert their effects through the same benzodiazepine binding site on the receptor. The pharmacological profile of these terpenes is similar to that of the benzodiazepines. Flumazenil is a benzodiazepine binding site antagonist and blocks the effects of these terpenes on sedation in rodents in vitro and in vivo. 8,11,12 Myrcene and α-pinene inhibited GABA in cell experiments. A Increased receptor activity 13 The effects of α-pinene on neurons are completely blocked by flumazenil 13 In rodents, flumazenil was inhibited by the administration of lemongrass oil (high in myrcene). 14 , α-pinene 11 , and phytol 12 α-Terpineol also inhibited the sedative effects of GABA in cells. A It can increase the activity of 15 Its pharmacological actions in rodents have not been characterized, but are similar to other GABAergic terpenes. Phytol may have additional GABA-related mechanisms through inhibition of SSADH, the enzyme that breaks down GABA. 16 Therefore, this is GABA A In addition to increasing receptor activation, it may be possible to increase GABA levels in the brain.

[0076] The terpene limonene also induces sedation in animals. For example, studies in rodents have found that limonene reduces locomotor activity, induces sleep, and impairs motor coordination. 8 Another study showed that after one week of limonene administration, GABA levels in the brain increased, and that its effects were related to GABA A It was shown that this could be blocked by the antagonist flumazenil. 17 .

[0077] The terpene linalool also increases sleep in rodents18 Linalool does not bind to the GABA site or A It does not bind to the benzodiazepine site of the receptor. Nevertheless, a 2014 study showed that it inhibits GABA receptors in cells. A It was shown that the activity of 13 .

[0078] The sedative properties of the terpene β-caryophyllene are distinct from GABAergic terpenes 19、20 In rodents, β-caryophyllene had no effect on locomotor activity or motor coordination; however, it mildly promoted sleep. 19、20 The mechanism by which β-caryophyllene induces sedation is unclear but appears to be independent of the GABAergic neurotransmitter system.

[0079] In summary, preclinical data demonstrate that all of the terpenes in CBD formulations (linalool, myrcene, phytol, limonene, α-terpinene, α-terpineol, α-pinene, and β-caryophyllene) induce sedation in animals, and that most of these terpenes act by mediating GABAergic stimulation at the same site where most prescription insomnia medications also act. A They have been shown to induce sedation by activating the benzodiazepine site on the receptor, but most importantly, the effects of these terpenes on sedation and insomnia in humans have not been established.

[0080] CBD reduces anxiety.

[0081] Several clinical trials have shown that CBD can reduce acute anxiety. 21 Participants with social anxiety disorder and controls were blindly assigned to receive CBD or a placebo control, and then performed a simulated public speaking test. CBD led to a significant reduction in anxiety, cognitive impairment, and discomfort during the anticipated speech, and significantly reduced hyper-alertness. 22It is well established that THC has anxiogenic (anxiety-promoting) properties in clinical trials, and these effects can be blocked by CBD. 23、24 .

[0082] The only drawback to using CBD preparations is the potential safety concerns regarding its potential to cause liver damage. However, these concerns are all due to its use in combination with a small number of rarely used prescription drugs that are contraindicated with CBD preparations. In view of the liver damage issue, the side effects of CBD preparations should be easily minimized by placing a warning label on the package.

[0083] In one embodiment, optimizing the concentrations of certain terpenes found in a CBD formulation may result in a sleep aid with superior efficacy to the CBD formulation. Thus, alternative terpene concentrations are provided herein.

[0084] In one embodiment, the subject or consumer decides the exact dosage that works for them. The consumer is guided by a novel smartphone-based application by a sleep coach or a physician.

[0085] The main advantage of CBD formulations is that they are novel sleep aids that increase REM and restorative sleep with an excellent safety profile. The effect of CBD formulations on enhancing restorative sleep cannot be overstated. Most prescription insomnia medications of the benzodiazepine family function as sedatives / hypnotics and have not been shown to have any effect on restorative sleep. They simply cause loss of consciousness and have a number of serious adverse reactions that limit their usefulness. Furthermore, based on the clinical data collected below, CBD formulations are also useful for treating anxiety and / or depression. CBD formulations may also have utility for other indications, including but not limited to, the treatment of pain, autism, and other sleep-related disorders.

[0086] Dosage form

[0087] In one embodiment, the CBD formulation is in the form of a capsule that can be taken orally by a consumer. The CBD formulation is free of any contaminants, including foreign substances, pesticides, pathogenic microorganisms, mold, residual solvents, heavy metals, and THC. A Certificate of Analysis (COA) has been provided verifying analytical testing for the CBD formulation.

[0088] The methods described herein may include administering an effective amount of a CBD formulation once a day, or every other day, or once a week. In one embodiment, the CBD formulation is administered daily for 1-2 days, 1-3 days, 1-12 days, 4-8 days, 8-12 days, 1-24 days, 4-24 days, 8-24 days, or 12-24 days or more, or another period of time according to the invention.

[0089] The CBD formulations of the present invention may be administered in combination with a nutraceutically acceptable carrier. The active ingredient of such a formulation may comprise 1-99% by weight, or alternatively 0.1-99.9% by weight. "Nutraceutically acceptable carrier" means any carrier, diluent, or excipient that is compatible with the other ingredients of the CBD formulation and is not harmful to the user. In one embodiment, suitable nutraceutically acceptable carriers may include oils, vegetable-based oils, medium-chain triglyceride (MCT) oils, coconut oil, palm kernel oil, hemp seed oil, olive oil, avocado oil, and combinations thereof.

[0090] In certain embodiments, the dosage form is formulated as granules, pellets, microparticles, tablets, hard capsules suspended in liquid or suspended in syrup or enema. In certain embodiments, the dosage form is formulated for oral or mucosal delivery. In certain embodiments, the dosage form is formulated as or in a lozenge, candy, gum, chocolate, or cookie. In certain embodiments, the tablet or pellet is an immediate release dosage form or an extended release dosage form or a controlled release dosage form. In certain embodiments, the tablet is enteric coated or melts or dissolves in the mouth or is a mucoadhesive dosage form.

[0091] In certain embodiments, unit dosage forms that are unit particles such as tablets, capsules, granules, pellets, microparticles, and films may be enterically coated or coated with a colonic coat to protect the unit dosage form from degradation at the acidic gastric pH and to swell over time or in a pH controlled manner or both to release the CBD formulation in the distal gut as well as to release a portion of the cannabinoids in the gut for systemic absorption and a portion of the cannabinoids in the colon for local colonic pharmacological action.

[0092] In certain embodiments, the CBD formulation is formulated in a semi-solid or liquid dosage form, such as a cream, lotion, ointment, dispersion, suspension, gel, foam, spray, syrup, solution, eye drop, ear drop, enema, or oral dosage form, or topical dosage form, or topical eye drop or ophthalmic or oral or vaginal or rectal or uterine dosage form. Liquid preparations include solutions, suspensions, and emulsions, such as aqueous solutions or aqueous propylene glycol solutions. For example, parenteral injection liquid preparations can be formulated as solutions in aqueous polyethylene glycol. Thus, the chemical compounds of the present invention can be formulated for parenteral administration (e.g., by injection, e.g., bolus injection or continuous infusion), and can be presented in unit doses in ampoules, pre-filled syringes, small dose containers, or in multi-dose containers with added preservatives. The compositions may take the form of suspensions, solutions, or emulsions in oily or aqueous vehicles and may contain formulatory agents such as suspending, stabilizing, and / or dispersing agents. Alternatively, the active ingredient may be in the form of a powder obtained by aseptic isolation of sterile solid or by lyophilization from a solution which is constituted with a suitable vehicle, e.g., sterile pyrogen-free water, before use.

[0093] In certain embodiments, any one of the aforementioned compositions or any one of the aforementioned dosage forms is for use in a method of treating a sleep condition or disorder.

[0094] Preferred dosage forms include, but are not limited to, any liquid or semi-solid or solid dosage form. The CBD formulations can be formulated as pharmaceuticals by preparing topical or mucosal or oral delivery systems. Topical delivery systems can be in the form of eye drops, suspensions, ointments, creams, foams, sprays, topical patches. Oral delivery systems can be tablets or capsules or soft capsules, or sachets or granules or syrups. Mucosal delivery systems can be gels, pessaries, enemas, vaginal douches, washes, foams, mucoadhesive gels or tablets for immediate release or sustained or controlled release. The vehicle can include any acceptable solvent and inactive ingredients and preservatives, antioxidants, and colorants. The delivery form can be single dose or multiple doses, and can be microparticles, granules, nanoparticles, microcapsules, liposomes, micelles, etc., known in the pharmaceutical, cosmetic, veterinary, and formulation fields. Further details of suitable dosage forms can be obtained from any standard reference in this field including, for example, Remington's Pharmaceutical Sciences, Mack Publishing Co, Easton, Pa, USA (1980).

[0095] Thus, in one embodiment of the present invention, the CBD formulation further comprises one or more excipients selected from the group consisting of solvents, stabilizing agents, suspending agents, emulsifying agents, release modifying agents, targeting agents and viscosity agents, and combinations thereof.

[0096] Working Example

[0097] The following examples are presented to provide those of skill in the art with a complete disclosure and description of how the compounds, compositions, articles, devices, and / or methods claimed herein are made and evaluated, and are intended to be merely exemplary of the invention and are not intended to limit the scope of what the inventors regard as their invention. However, those of skill in the art should, in light of this disclosure, recognize that many changes can be made in the specific embodiments disclosed and still obtain a like or similar result without departing from the spirit and scope of the invention.

[0098] Efforts have been made to ensure accuracy with respect to numbers (e.g., amounts, temperature, etc.), but some errors and deviations should be accounted for. Unless otherwise indicated, parts are parts by weight, temperature is in degrees Celsius or is ambient temperature, and pressure is near atmospheric.

[0099] Example: Summary of data from clinical trials with CBD formulations

[0100] Two independent clinical trials have been completed to determine the effects of CBD formulations on the structure and function of sleep physiology. Each of these independent studies was conducted as a double-blind, placebo-controlled, randomized crossover trial to determine whether CBD formulations affect sleep physiology in humans.

[0101] Primary sleep physiology data was collected from study participants in a completely unbiased manner from a non-invasive sleep tracking wristband called "Whoop" (https: / / www.whoop.com), which electronically collects and transmits sleep data from study participants in the comfort of their own bed. The wristband collects hundreds of data points per second from a 3-axis accelerometer, 3-axis gyroscope, and heart rate sensor. The wristband can accurately measure sleep onset latency, total sleep time, sleep fragmentation, and time spent in each sleep stage [light, deep, rapid eye movement (REM), and wakefulness]. The wristband also collects data using photoplethysmography (PPG), a technology that involves measuring blood flow by assessing superficial changes in blood volume. Heart rate, heart rate variability, and respiration rate can all be derived from the PPG data, and all of these measurements are used in Whoop's sleep detection and staging algorithms. Two recent publications published independently of Whoop have shown that the sleep stage data collected from the Whoop device is highly accurate and correlates well with polysomnography (PSG), the gold standard for sleep tracking used in clinical trials in sleep clinics. 25、26 .

[0102] Data Test 1 Overview

[0103] In the first study, participants (N=23) were randomized to receive either a placebo control or a CBD formulation described in the figures as Defined CBD (approximately 300 mg CBD, approximately 8 mg terpenes including linalool, myrcene, phytol, limonene, α-terpinene, α-terpineol, α-pinene, and β-caryophyllene) taken once daily, one hour before bedtime, for seven consecutive nights. An example of data from one participant is shown in Figures 2A-2D. Participant DR11 showed a significant increase of approximately 0.5 hours of REM sleep, a significant increase of approximately 0.9 hours of restorative sleep (combined REM and deep sleep), and a significant increase of approximately 7% in the percentage of time spent in REM sleep, as well as a significant increase of approximately 9% in restorative sleep (Figures 2A-2D). Indeed, on average, over the 7-day treatment period, participant DR11 benefited from nearly an extra hour of restorative sleep each night compared to the placebo control (Figure 2B). Furthermore, participant DR11 was also able to perceive improvements in her sleep quality and duration compared to the placebo control when completing a clinically validated sleep survey at the end of the treatment period (shown in Table 1).

[0104] [Table 1]

[0105] In some study participants, including DR11, the CBD formulation significantly increased the percentage of time spent in REM sleep by about 7% and the percentage of time spent in restorative sleep by about 9%, whereas CBD alone appeared to only partially increase the percentage of REM sleep by about 4% and the percentage of restorative sleep by about 2%, and these effects were not statistically significant (Figures 3A-3B). This data suggests that terpenes in the CBD formulation may act synergistically with CBD to contribute to its sleep benefits.

[0106] Analysis of pooled data from all participants (N=23) from the first clinical trial showed that the CBD formulation showed a trend toward increasing the percentage of REM by approximately 2% (Figure 4A) and restorative sleep (shown in Figure 4B) by approximately 1%.

[0107] Analysis of pooled data from the first clinical trial showed that participants could be stratified into "responders" and "non-responders." Pooled data from the "responders" showed a highly significant increase in the percentage of REM of about 4% and in the percentage of restorative sleep of about 10% in study participants administered the CBD formulation compared to placebo controls (FIGS. 5A-5B). Indeed, when only the "responders" were analyzed, they exhibited an increase in restorative sleep of about 10% when treated with the CBD formulation (FIG. 5B).

[0108] After more careful scrutiny, 9 / 11 of the participants who responded to treatment with the CBD formulation were found to have a higher mean score on a clinically validated insomnia severity index (the Pittsburgh Sleep Quality Index (PSQI)) that they had completed before the clinical trial. 27 After taking the CBD formulation, participants who scored as moderately insomnia on the PSQI exhibited an increase in percentage of restorative sleep of about 3%, which narrowly missed statistical significance, and a significant increase in percentage of restorative sleep of about 6%, compared to placebo controls (Figures 6A-6B).

[0109] At the end of each treatment period in the clinical trial, participants completed a Participant Global Impression (PGI) 28Participants completed a modified version of a clinically validated questionnaire entitled "How well does the treatment affect sleep?". The PGI assessment is based on the participants' overall perception of the effect of the treatment on their sleep during each treatment period compared to their sleep during the baseline period of the study. Using the PGI assessment, participants perceived that they slept better after taking the CBD formulation, with a score of 1.4, compared to the placebo control, with a score of 1.6, but this effect was not statistically significant (Figure 7). Nevertheless, based on the post-hoc power analysis performed, this effect would achieve statistical significance with a larger sample size.

[0110] To measure the effect of the CBD formulation on anxiety, study participants completed a modified version of the Hamilton Anxiety Rating Scale, one of the first scales developed to measure the severity of anxiety symptoms and widely used in clinical and research settings. 29 The scale consists of 13 items, each defined by a set of symptoms, measuring both mental anxiety (mental agitation and psychological distress) and somatic anxiety (physical symptoms related to anxiety). Each item is scored on a scale of 0 (absent) to 4 (severe), with total scores ranging from 0 to 53, where <14 represents mild severity, 15 to 21 represents mild to moderate severity, and 22 to 27 represents moderate to severe. Based on this clinically validated anxiety rating scale, some study participants showed a reduction in anxiety with scores of 8, 5, and 3 after taking the CBD formulation, as shown by the participant's data in Figures 8A-8C.

[0111] Analysis of pooled data from the first clinical trial showed no significant effect of the CBD formulation on anxiety compared to the placebo control. However, similar to the data on sleep physiology, the data could be stratified into "responders" and "non-responders". Data from the "responders" showed that the CBD formulation significantly reduced anxiety with a score of 6 compared to the placebo control with a score of 15 or CBD alone with a score of 11 (Figure 9A). Because study participants were not asked to take the Hamilton Anxiety Rating Scale before the study, it is not clear whether the participants who benefited most from the CBD formulation were those who had the highest baseline anxiety levels. However, the mean anxiety levels of the "responders" who took the placebo were significantly higher than the "non-responders", suggesting that participants who presented with high baseline anxiety levels would benefit most from the CBD formulation, as would the effects of the CBD formulation on restorative sleep and insomnia levels (illustrated in Figure 9B).

[0112] Summary of data from study 2

[0113] After the successful completion of the first clinical trial, we attempted to replicate the results of the first clinical trial in an independent cohort of participants. While data from the first clinical trial indicated that participants with insomnia benefited most from treatment with the CBD formulation, the second clinical trial showed that participants with insomnia benefited most from treatment with the clinically validated Insomnia Severity Index (PSQI) 27 Only participants with moderate or severe insomnia as defined by the WHO guidelines were enrolled.

[0114] In the second study, participants (N=13) were randomized to receive either a placebo control or a CBD formulation (approximately 300 mg CBD, approximately 8 mg terpenes including linalool, myrcene, phytol, limonene, α-terpinene, α-terpineol, α-pinene, and β-caryophyllene) taken once daily, one hour before bedtime, at least four nights per week for a total treatment period of three weeks.

[0115] Pooled data from the second study showed that the CBD formulation increased the percentage of REM sleep by about 2% and the percentage of restorative sleep by about 3% in participants treated with the CBD formulation compared to placebo controls, with the increase in restorative sleep reaching statistical significance by about 3%, as shown in Figures 10A-10B. As with the first clinical trial, this data represents a successful replication of the first clinical trial in a completely independent patient cohort. Furthermore, based on the post-hoc power analysis performed, the effect of the CBD formulation on REM sleep would reach statistical significance with a larger sample size.

[0116] The two clinical trials were conducted in a decentralized manner, with study participants administering the treatments themselves and tracking their sleep data in the comfort of their own homes. The effect of the CBD formulation on sleep physiology was quantified when combining data from the two clinical trials. The CBD formulation significantly increased the percentage of time study participants spent in REM by approximately 2% and the percentage of time spent in restorative sleep by approximately 2% in the combined data set, as shown in Figures 11A-11B. The effect of the CBD formulation on deep sleep in the combined data narrowly missed statistical significance, but the CBD formulation increased deep sleep by approximately 2% as shown in Figure 11C.

[0117] As mentioned above, based on the post-hoc power analysis performed, the effect of CBD formulations on deep sleep would achieve statistical significance with a larger sample size. In fact, the power analysis indicated that the magnitude of statistical significance of these findings would likely increase with a larger sample size, and a further final clinical trial with 150 participants will be conducted.

[0118] Conclusions and clinical significance of the study findings

[0119] Clinical data with the CBD formulation shows that it significantly increases the percentage of time people spend in REM and restorative (deep + REM) sleep, and that these effects are most pronounced in people suffering from insomnia. Importantly, the effect of the CBD formulation on parameters of sleep physiology was replicated in two independent patient cohorts. Furthermore, participants who took the CBD formulation were also able to perceive the benefits of the treatment on their sleep quality.

[0120] REM and restorative sleep are believed to be crucial for good brain health, and their absence in human populations is often associated with chronic illness and disease. For example, REM sleep plays an essential role in learning and memory processes in the hippocampus, and disruption of REM sleep can lead to cognitive impairment and other symptoms. 30 During sleep, the brain can repair and grow cells, tissues, and nerves that regenerate and strengthen the hormone and immune systems. Along with good nutrition, exercise, and stress reduction, restorative sleep is essential for people's optimal physical, mental, and emotional health. Insufficient restorative sleep increases the risk of disorders such as hypertension, diabetes, obesity, stroke, and depression. It is also associated with cognitive decline and Alzheimer's disease.

[0121] The CBD formulation is composed of CBD and terpenes that have been shown to significantly increase REM and restorative sleep in people with insomnia, and these people were able to accurately perceive benefits from the treatment (even though they were blinded to the treatment). In addition to this reported effect, another major advantage of the CBD formulation as a potential sleep aid is its superior safety profile, especially compared to commonly prescribed sleep medications, including zolpidem (Ambien), which have many serious undesirable adverse reactions.

[0122] Example 2: A double-blind, placebo-controlled, randomized crossover clinical trial to determine whether a CBD formulation, a capsule containing a custom formulation of cannabidiol (CBD) and terpenes, affects sleep physiology

[0123] A novel CBD-based formulation in the form of a small capsule administered orally increases the percentage of time participants spend in deep sleep (SWS) and REM sleep, as measured by an objective sleep tracking device called "Whoop". The research study, entitled Le Reve 3.0, is a double-blind, placebo-controlled, randomized crossover trial to determine whether a CBD formulation or a custom-formulated CBD capsule labeled with CBD-terpenes affects sleep physiology. The capsule does not contain delta-9-THC. The study is designed only to evaluate the effect of the CBD formulation on the structure and function of sleep physiology, and the phase of the study is not applicable.

[0124] The Le Reve 3.0 study involves a crossover design in which study participants cycle through two independent treatments, each for 4 weeks (treatment 1: placebo; treatment 2: CBD formulation). The placebo looks, smells, and tastes the same as the CBD formulation capsules. Study participants are initially randomized with respect to treatment arm, and all participants cycle through both treatment arms. A double-blind design is used in which both the inventors and study participants are blinded to the treatment. Baseline data for each participant are collected 2 weeks prior to the start of treatment and during a 1-week washout period after each treatment arm. The total study duration is 12 weeks, as shown in FIG. 12.

[0125] Le Reve's primary data comes in a completely unbiased way from a non-invasive sleep-tracking wrist-worn device called "Whoop" (https: / / www.whoop.com), which electronically collects and transmits sleep data from study participants in the comfort of their own bed.

[0126] The wristband collects hundreds of data points per second from a three-axis accelerometer, a three-axis gyroscope, and a heart rate sensor. The wristband can accurately measure sleep onset latency, total sleep time, sleep fragmentation, and the time spent in each sleep stage (light, deep, rapid eye movement (REM), and wakefulness). The device also collects data using photoplethysmography (PPG), a technique that involves measuring blood flow by measuring superficial changes in blood volume. Heart rate, heart rate variability, and respiration rate can all be derived from the PPG data, and all of these metrics are used in Whoop's sleep detection and staging algorithms. Importantly, two recent publications published independently of Whoop have shown that the data on sleep stages collected from the Whoop device is highly accurate and correlates well with polysomnography (PSG), the gold standard for sleep tracking used in clinical trials conducted in sleep clinics.

[0127] Exam description

[0128] Insomnia is a disorder in which people have inadequate or insufficient quality sleep due to many factors, such as difficulty falling asleep, frequent awakenings during the night with difficulty falling asleep again, waking too early in the morning, or waking unrefreshed. The CBD formulation is a capsule that is composed of highly pure (>99.9% pure) cannabis-derived CBD and terpenes (>98% pure). The CBD formulation does not contain delta-9-tetrahydrocannabinol (delta-9-THC). The research trial, entitled Le Reve 3, is designed to evaluate the effectiveness of the CBD formulation on sleep physiology.

[0129] The primary objective was to determine whether CBD formulations affected objective measures of sleep physiology. The secondary objective was to determine whether CBD formulations affected subjective measures of sleep physiology.

[0130] The primary outcome measure was the percentage of sleep spent in deep sleep [slow-wave sleep (SWS)] and rapid eye movement (REM) sleep as determined using an objective wrist-worn sleep tracking device called Whoop. Secondary outcomes were total sleep time, sleep latency, number of sleep disruptions, time spent in each sleep stage, percentage of time spent in each sleep stage, and subjective measures of sleep physiology collected via participant surveys.

[0131] Study Population: 150 study participants will be enrolled who demonstrate chronic insomnia, defined as self-reported difficulty falling asleep (latency to sustained sleep >30 minutes) and / or difficulty maintaining sleep (waking >30 minutes or waking >30 minutes earlier than desired awakening time) for at least 3 nights per week for at least 3 months. Participants will also complete a brief, clinically validated Insomnia Severity Index, and only participants with an Insomnia Severity Index score >15 will be enrolled in Le Reve 3.0. Men and women aged 25-70 years living in the United States who meet the inclusion and exclusion criteria will be enrolled.

[0132] Description of the test procedure

[0133] Le Reve 3.0 is a decentralized study conducted by participants in the comfort of their own homes. Recruitment, enrollment, informed consent, and distribution of study materials to participants will all be managed by the contract research organization (CRO) 83 Bar, Inc.

[0134] The study intervention included a CBD formulation or placebo control taken orally (po) as two small capsules one hour before bedtime. The CBD formulation was a capsule made in GMP standard material composed of vegetable cellulose (gluten-free, non-GMO, vegan, kosher, halal certified) containing 300mg of >99.9% pure hemp-derived CBD made in a GMP certified laboratory dissolved in coconut oil (USDA organic, non-GMO, non-dairy, gluten-free, vegan coconut oil). The CBD formulation is a custom chemical formulation containing low concentration (1 mg each) highly pure (>98% pure) forms of the terpenes linalool, myrcene, phytol, limonene, α-terpinene, α-terpineol, α-pinene, and β-caryophyllene [Food Grade (GRAS), natural, organic, non-GMO, non-dairy, gluten-free, vegan], also made in a GMP certified laboratory. The CBD formulation does not contain Δ-9-tetrahydrocannabinol (Δ-9-THC). The safety of CBD1 and these terpenes at the doses found in the CBD formulation has been well established.

[0135] Test period

[0136] The estimated time from when Le Reve 3.0 begins enrollment to when data analysis is completed is 20 weeks.

[0137] Participant Retention Period: After enrolment, participant retention for the entire study will be 12 weeks.

[0138] An overview of the clinical trial is shown in Figure 12.

[0139] [Table 2]

[0140] [Table 3] JPEG2025503837000007.jpg103159

[0141] Study population

[0142] To be eligible to participate in the study, individuals must meet all of the following criteria: have provided a signed and dated informed consent form; have had the presence of chronic insomnia, defined as self-reported difficulty falling asleep (latency to persistent sleep >30 minutes) and / or difficulty maintaining sleep (three or more midnight awakenings per week >30 minutes or awakenings >30 minutes earlier than desired awakening time), for at least 3 months; and have an Insomnia Severity Index score >15.

[0143] Male or female aged 25-70

[0144] Wear a sleep-tracking device on your wrist for the entire study Ensure that you connect the sleep tracking device to your smartphone via Bluetooth each day so that your sleep data can be collected daily. Ensure that you charge your sleep tracking device before going to bed each night to ensure that your sleep data is collected daily. Willingness to receive and respond to daily text (SMS) notifications for the entire duration of the clinical trial Willingness to undergo treatment for at least 4 nights each week during the treatment phase of the study Willingness to comply with all testing methods across all studies, including

[0145] Participants were willing to abstain from excessive alcohol consumption (>2 drinks per day) on the night of their procedure.

[0146] were amenorrhea for at least one year prior to the first interview and were postmenopausal, or surgically infertile, or if of childbearing potential, agreed to use an effective method of contraception or to abstain completely from sexual intercourse from the time of signing the informed consent until the last dose of study treatment; self-reported a bedtime between 9 pm and midnight for 4 to 7 nights per week; and owned a smartphone.

[0147] Lifestyle Considerations During this study, participants are required to refrain from consuming more than two standard servings of alcohol per day during the study period; refrain from consuming more than 400 g / day of caffeine during the study period; refrain from consuming caffeine after 3:00 p.m. during the study period; and refrain from consuming more than five cups or glasses of xanthine-containing beverages (i.e., tea, coffee, energy drinks, or colas) per day during the study period.

[0148] 6.1 Administration of Study Treatment

[0149] The CBD formulation consists of small capsules made from vegetable cellulose (gluten-free, non-GMO, vegan, kosher, halal certified) containing >99.9% pure hemp-derived CBD dissolved in coconut oil (USDA organic, non-GMO, non-dairy, gluten-free, vegan coconut oil) with a custom chemical formulation that also contains highly purified (>98% pure) forms of the terpenes linalool, myrcene, phytol, limonene, α-terpinene, α-terpineol, α-pinene, and β-caryophyllene (Food Grade (GRAS)), natural, organic, non-GMO, non-dairy, gluten-free, vegan). Participants are asked to take two small capsules one hour before bedtime. These capsules contain a total of 300mg of CBD and 8mg of terpenes (1mg of terpene each). The CBD formulation does not contain delta-9-THC. The capsules containing the placebo control look, feel, and smell exactly like the capsules containing the CBD formulation, but contain no CBD or terpenes.

[0150] In the study, participants will take two small capsules containing a total of 300 mg of CBD and 8 mg of terpenes (1 mg each of the terpenes linalool, myrcene, phytol, limonene, α-terpinene, α-terpineol, α-pinene, and β-caryophyllene) orally with a glass of water one hour before bedtime. Participants will be required to take the study medication a minimum of four nights per week for each of the four-week treatment phases of the study.

[0151] Administration

[0152] In the study, participants will take two small capsules containing a total of 300 mg of CBD and 8 mg of terpenes (1 mg each of the terpenes linalool, myrcene, phytol, limonene, α-terpinene, α-terpineol, α-pinene, and β-caryophyllene) orally with a glass of water one hour before bedtime. Participants will be required to take the study medication a minimum of four nights per week for each of the four-week treatment phases of the study.

[0153] Efficacy assessment

[0154] One hundred fifty study participants will be enrolled who present with chronic insomnia, defined as self-reported difficulty falling asleep (latency to sustained sleep >30 minutes) and / or difficulty staying asleep (waking >30 minutes or waking >30 minutes earlier than desired wake time) for at least three nights per week for at least three months. Participants will also complete a brief, clinically validated Insomnia Severity Index, and only participants with an Insomnia Severity Index score >15 will be enrolled in Le Reve 3.0. Men and women aged 25-70 years living in the United States who meet the inclusion and exclusion criteria will be enrolled.

[0155] Le Reve 3.0 will be conducted in a fully decentralized manner: Le Reve 3.0's primary data will be obtained in a completely unbiased manner from a non-invasive wrist-worn sleep tracking device called "Whoop" (https: / / www.whoop.com), which electronically collects and transmits sleep data from study participants in the comfort of their own bed.

[0156] The wristband collects hundreds of data points per second from a three-axis accelerometer, three-axis gyroscope, and heart rate sensor. The wristband can accurately measure sleep onset latency, total sleep time, sleep fragmentation, and time spent in each sleep stage: light, deep, rapid eye movement (REM), and wakefulness. The device also collects data using photoplethysmography (PPG), a technique that involves measuring blood flow by assessing superficial changes in blood volume. Heart rate, heart rate variability, and respiration rate can all be derived from the PPG data, and all of these metrics are used in Whoop's sleep detection and staging algorithms. Importantly, two recent publications published independently of Whoop have shown that the data on sleep stages collected from the Whoop device is highly accurate and correlates well with polysomnography (PSG), the gold standard for sleep tracking used in clinical trials conducted in sleep clinics.

[0157] The primary efficacy endpoint for Le Reve 3.0 is the percentage of time spent in slow-wave (deep) sleep and REM sleep, as collected by a non-invasive wrist-worn sleep tracking device called Whoop.

[0158] Additional objective secondary outcome measures collected by the Whoop device include total sleep time, sleep latency, number of sleep disruptions, time spent in each sleep stage, and percentage of time spent in each sleep stage.

[0159] A modified version of a clinically validated questionnaire titled PGI19 will be used to track subjective measures of sleep physiology. This data will be collected from study participants in the form of a brief, five-minute survey completed on their smartphones at the end of each four-week treatment period.

[0160] Example 2: A double-blind, placebo-controlled, randomized crossover clinical trial to determine whether prescription CBD, custom-formulated cannabidiol (CBD) capsules affect sleep physiology

[0161] overview

[0162] A total of 126 participants were enrolled, with 63 completing the study. An initial analysis of the study data showed that the clinical trial's primary endpoint - the percentage of time participants spent in SWS sleep + REM (restorative) sleep - showed statistically significant positive results. The secondary endpoint of the percentage of time participants spent in SWS sleep was met as well. An independent analysis of the data will confirm the initial findings.

[0163] Exam description

[0164] Insomnia is a disorder in which people have inadequate or insufficient quality sleep due to many factors, such as difficulty falling asleep, frequent waking during the night with difficulty falling asleep again, waking too early in the morning, or waking unrefreshed. Formula CBD (labeled CBD-Terpenes in the drawings) is a capsule formulation composed of highly pure (>99.9% pure) cannabis-derived CBD and terpenes (>98% pure). Formula CBD does not contain delta-9-tetrahydrocannabinol (delta-9-THC). The research study, entitled Le Reve 3.0, is designed to evaluate the effectiveness of formula CBD on sleep physiology. The study is not intended to treat, diagnose, prevent, or cure any disease.

[0165] The primary objective is to determine whether prescribed CBD affects objective measures of sleep physiology. The secondary objective is to determine whether prescribed CBD affects subjective measures of sleep physiology.

[0166] The primary outcome measure was the percentage of sleep spent in deep sleep [slow-wave sleep (SWS)] and rapid eye movement (REM) sleep as determined using an objective wrist-worn sleep tracking device called Whoop. Secondary outcomes included total sleep time, sleep latency, number of sleep disruptions, time spent in each sleep stage, percentage of time spent in each sleep stage, and subjective measures of sleep physiology collected via participant surveys.

[0167] One hundred fifty study participants will be enrolled who present with chronic insomnia, defined as self-reported difficulty falling asleep (latency to sustained sleep >30 minutes) and / or difficulty staying asleep (waking >30 minutes or waking >30 minutes earlier than desired wake time) for at least three nights per week for at least three months. Participants will also complete a brief, clinically validated Insomnia Severity Index, and only participants with an Insomnia Severity Index score >15 will be enrolled in Le Reve 3.0. Men and women aged 25-70 years living in the United States who meet the inclusion and exclusion criteria will be enrolled.

[0168] Le Reve 3.0 is a decentralized study conducted by participants in the comfort of their own homes. Recruitment, enrollment, informed consent, and distribution of study materials to participants will all be managed by the contract research organization (CRO) 83 Bar, Inc.

[0169] Description of the study procedure

[0170] Study treatments included either prescribed CBD or a placebo control taken orally (po) as two small capsules one hour before bedtime. The prescribed CBD was a capsule made to GMP standard material composed of vegetable cellulose (gluten-free, non-GMO, vegan, kosher, halal certified) containing 300mg of >99.9% pure hemp-derived CBD made in a GMP certified laboratory dissolved in coconut oil (USDA organic, non-GMO, non-dairy, gluten-free, vegan coconut oil). Regular CBD is a custom chemical formulation made in a GMP certified laboratory containing low concentration (1 mg each) highly pure (>98% pure) forms of the terpenes linalool, myrcene, phytol, limonene, α-terpinene, α-terpineol, α-pinene, and α-caryophyllene [Food Grade (GRAS), natural, organic, non-GMO, non-dairy, gluten-free, vegan]. Regular CBD does not contain delta-9-tetrahydrocannabinol (Δ-9-THC). The safety of CBD and these terpenes at the doses found in Regular CBD has been well established.

[0171] The trial duration, which is the estimated time from when Le Reve 3.0 begins enrollment to when data analysis is completed, is 20 weeks. Participant retention for the entire study is 12 weeks from enrollment.

[0172] result

[0173] 13A-13F are graphs showing that CBD-terpene formulations increase the percentage of time spent in SWS+REM sleep (restoration sleep) for DR24 (FIG. 13A), DR45 (FIG. 13B), DR51 (FIG. 13C), DR111 (FIG. 13D), DR112 (FIG. 13E), and DR128 (FIG. 13F). * p<0.05(t-test); ** p<0.01(t-test); *** p<0.001; ****p<0.0001 (t-test). n=15-28 days per treatment group. Values ​​are mean±SEM]. Participant DR24 showed approximately a 3% increase in SWS+REM sleep compared to placebo; participant DR45 showed approximately a 3% increase in SWS+REM sleep; participant DR51 showed approximately a 7% increase in SWS+REM sleep; participant DR111 showed approximately a 3% increase in SWS+REM sleep; participant DR112 showed approximately a 9% increase in SWS+REM sleep; and participant DR128 showed approximately a 13% increase in SWS+REM sleep.

[0174] 14A-14F are graphs showing that a CBD-terpene formulation increases the percentage of time spent in (FIG. 14A) REM, (FIG. 14B) SWS, (FIG. 14C) SWS+REM (restorative sleep) in study participant DR51, as well as (FIG. 14D) REM and (FIG. 14E) SWS, and (FIG. 14F) SWS+REM (restorative sleep). ** p < 0.01; *** p<0.001 (t-test). n=19-25 days per treatment group. Values ​​are mean±SEM]. Participant DR51 demonstrated approximately a 30 minute increase in REM sleep compared to placebo; participant DR51 demonstrated approximately a 22 minute increase in SWS sleep; participant DR51 demonstrated approximately a 51 minute increase in SWS+REM sleep; participant DR51 demonstrated approximately a 7% increase in REM sleep; participant DR51 demonstrated approximately a 5% increase in SWS sleep; participant DR51 demonstrated approximately a 13% increase in SWS+REM sleep.

[0175] 15A-15F are graphs showing that CBD-terpene formulations increase the percentage of time spent in (FIG. 15A) REM, (FIG. 15B) SWS, (FIG. 15C) SWS+REM (restorative sleep) in study participant DR128, and (FIG. 15D) REM and (FIG. 15E) SWS, and (FIG. 15F) SWS+REM (restorative sleep). * p<0.05(t-test); *** p<0.001; ****p<0.0001 (t-test). n=15-28 days per treatment group. Values ​​are mean±SEM]. Participant DR128 demonstrated approximately a 30 minute increase in REM sleep compared to placebo; participant DR128 demonstrated approximately a 19 minute increase in SWS sleep; participant DR128 demonstrated approximately a 50 minute increase in SWS+REM sleep; participant DR128 demonstrated approximately a 13% increase in REM sleep; participant DR128 demonstrated approximately an 8% increase in SWS sleep; participant DR128 demonstrated approximately an 18% increase in SWS+REM sleep.

[0176] Self-identified as having insomnia and a clinically validated Insomnia Severity Index 13 Six participants who were scored as having severe clinical insomnia (>22) on the ANOVA were administered capsules containing 300mg of pure CBD and 8mg of terpenes, or a placebo control, for a minimum of four nights per week over a four-week period. After a one-week washout period, participants were administered the second treatment (i.e., capsules with CBD-terpenes or a placebo control) for a second four-week treatment period.

[0177] CBD-terpenes capsules are clinically proven 14、15 All six participants significantly increased the percentage of time spent in SWS+REM sleep (restorative sleep) as quantified by a wrist-worn sleep tracking device (Figures 13A-13F). The magnitude of the increase in the percentage of restorative sleep in these participants varied from 5-18%, but this represented an absolute increase of 38-51 minutes per night over the one-month period (an absolute increase of approximately 19-26 hours of restorative sleep over the one-month treatment period). Furthermore, the capsules containing CBD-terpenes reduced the percentage of time spent in light sleep in all six participants compared to the placebo control (Figures 16A-16F), but had no effect on total sleep time (Figures 17A-17F).

[0178] In participants DR51 and DR128, CBD-terpene capsules also significantly increased the absolute time spent in REM, SWS, and SWS+REM sleep, as well as the percentage of time spent in REM, SWS, and SWS+REM sleep (Figures 14 and 15). In participant DR51, who only had an average of 45 minutes of SWS+REM sleep per night in the placebo control, treatment with CBD-terpene capsules increased SWS+REM sleep by an average of 52 minutes per night (an average increase of more than 6 hours of recovery sleep per week or an increase of more than 24 hours over the 4-week treatment period) (Figure 5). Similarly, in participant DR128, CBD-terpene capsules increased SWS+REM sleep by 49 minutes per night (an average increase of about 6 hours per week or an increase of more than 24 hours over the 4-week treatment period) (Figure 14). No adverse events were reported by any participant during this study.

[0179] Consideration

[0180] The use of CBD in humans and animals has increased significantly over the past decade. Although consumers have used CBD to ostensibly self-treat a variety of common ailments, including chronic pain, anxiety, and insomnia, there is little clinical evidence supporting its use to effectively treat any of these conditions. Furthermore, medical practitioners are increasingly being asked by patients whether they should use CBD to treat these conditions, but in the absence of rigorous clinical studies, physicians are simply unable to provide informed guidance to patients on the appropriate use of CBD.

[0181] In this case series, we report that daily administration of capsules containing pure CBD and terpenes significantly increased the percentage of time spent in SWS+REM sleep in six participants with severe clinical insomnia. The combination of SWS and REM sleep stages is commonly referred to as "restorative" sleep. 16Numerous studies have shown that SWS and REM sleep stages are crucial for strengthening the immune system, increasing cell and tissue regeneration, increasing clearance of brain metabolites, replenishing energy stores, as well as for learning, memory, attention, and executive function. 16、17 SWS is associated with decreased heart rate, blood pressure, sympathetic nerve activity, and cerebral glucose utilization compared with wakefulness. 16 Additionally, during SWS, human growth hormone is released and the stress hormone cortisol is inhibited. 16 In particular, the percentage of time spent in SWS and REM sleep decreases with age. 17、18 Clinical trials have shown that many commonly prescribed hypnotic drugs, including barbiturates, benzodiazepines, zolpidem, zopiclone, and neuroactive steroids, reduce sleep latency, and many of these medications reduce SWS and REM sleep. 19 .

[0182] The CBD-containing capsules used in this case series also contain small amounts (1 mg each) of terpenes. These small molecules are commonly found in plants and are currently classified by the FDA as Generally Regarded As Safe (GRAS) for human consumption and are commonly used as flavor additives in food. Preclinical studies in animals have shown that the high concentrations of terpenes used in this study have sedative effects in animals. 8-12,20 However, these potential effects on human sleep physiology have not been established and are the subject of future research.

[0183] The CBD-terpene capsules used in this study contained no detectable delta-9-THC. Recent studies have suggested that treatment with a complex mixture of THC, CBD, and other cannabinoids improves some subjective sleep outcomes in patients with insomnia. 21 If THC induces euphoria and increases heart rate at the concentrations tested, it is difficult to infer causation from this study. 22It is difficult to argue that the study was truly placebo-controlled when participants could identify which treatment arm had the active treatment. In particular, the study showed no effect of cannabinoid treatment on objective measures of sleep physiology. 22 .

[0184] In summary, the results from this case series demonstrate that capsules containing a pure CBD-terpene mixture lacking delta-9-THC increased the percentage of time spent in restorative sleep stages in six patients with insomnia. The inventors did not observe any adverse events during the course of this case series, and current research to date indicates that CBD is a significant alternative to most commonly prescribed sleep medications, which clearly have a well-documented serious side effect profile. 24 has been shown to have a relatively favorable safety profile compared with 23 If the results reported in this case series can be replicated in a strict placebo-controlled setting, the current results suggest that CBD may represent a safer alternative as a promising treatment for insomnia that enhances rather than diminishes restorative sleep.

[0185] Published literature

[0186] 1- Ford et al., Sleep Med. 2015; 16(3):372-8. 2- Chagas et al., J Psychopharmacol. 2013; 27(3):312-6. 3-Carlini and Cunha, J Clin Pharmacol. 1981; 21(S1):417S-427S. 4-Shannon et al, Perm J 2019; 23:18-041. 5-Linck et al., Phytomedicine. 2009; 16(4):303-7. 6-Buchbauer et al., J Pharm Sci. 1993; 82(6):660-4. 7-Lee et al., Biomol Ther (Seoul). 2018; 26(4): 368-373. 8-do Vale et al., Phytomedicine. 2002;9(8):709-14. 9-Freitas et al., Braz J Med Biol Res. 1993; 26(5):519-23. 10-Tan et al., Trends Neurosci. 2011; 34(4):188-197. 11-Yang et al., Mol Pharmacol. 2016; 90(5):530-539. 12-Costa et al., Brain Res. 2014; 1547:34-42. 13-Kessler et al., Mol Nutr Food Res. 2014; 58(4):851-862. 14-Rodrigues de Almeida Costa et al., Journal of Ethnopharmacology. 2011; 137(1):828-836. 15-Watt et al., Eur J Pharmacol. 2008; 590(1-3):120-126. 16-Bang et al., Archives of Pharmacal Res. 2002; 25:643-646. 17-Zhou et al., J Nutr Sci Vitaminol (Tokyo). 2009; 55(4):367-373. 18-Elisabetsky et al., Phytotherapy. 1995; 66(5):407-414. 19-Galdino et al., Prog Neuropsychopharmacol Biol Psychiatry. 2012; 38(2):276-284. 20-Bahi et al., Physiol Behav. 2014; 135:119-124. 21-Sharpe et al., J Transl Med. 2020; 18:374-395. 22-Bergamaschi et al., Neuropsychopharmacol. 2011; 36(6):1219-1226. 23-Zuardi et al., Psychopharmacol. 1982; 76(3):245-250. 24-Fusar-Poli et al., Arch Gen Psychiatry. 2009; 66(1):95-105. 25-Berryhill et al., J Clin Sleep Med. 2020; 16(5):775-783. 26-Miller et al., Journal of Sports Sciences. 2020; 38(22):2631-2636. 27-Buysse et al., Psychiatry Res. 1989; 28(2):192-213. 28-Krystal et al., Sleep. 2008; 31:79-90. 29-Hamilton, Br J Med Psychol. 1959; 32:50-55. 30-Krause et al., Nat Rev Neurosci. 2017; 18(7):404-418.

[0187] All publications and patent applications mentioned in this specification are herein incorporated by reference to the same extent as if each individual publication or patent application was specifically and individually indicated to be incorporated by reference.

[0188] While the invention has been described in connection with various embodiments, it will be understood that the invention is capable of further modifications. This application is generally intended to cover all variations, uses, or adaptations of the invention in accordance with the principles of the invention, including departures from the present disclosure within known and customary practice in the art to which this invention pertains.

Claims

1. A composition for use in a method for increasing REM sleep or increasing restorative sleep in a subject in need thereof, the method comprising the steps of providing a formulation comprising CBD and a plurality of terpenes, the plurality of terpenes including linalool, myrcene, phytol, limonene, α-terpinene, α-terpineol, α-pinene, and β-caryophyllene, and administering an effective amount of the formulation to the subject, thereby increasing REM sleep or increasing restorative sleep in the subject.

2. The composition of claim 1, wherein the formulation contains approximately 150 mg of CBD, the plurality of terpenes contains approximately 0.5 mg of each terpene, and does not contain delta-9-tetrahydrocannabinol.

3. The composition described in claim 1, wherein the increase in REM sleep comprises an increase of at least 20% in the subject compared to a baseline measurement measured in the subject prior to administration of the effective amount to the subject.

4. The composition described in claim 1, wherein the effective amount is administered to the subject once daily, one hour before going to bed, for at least seven consecutive nights.

5. The composition described in claim 1, wherein the formulation is orally administered to the subject.

6. The composition described in claim 1, wherein administration of the effective amount to the subject is carried out for a period of four weeks, and slow wave sleep (SWS) and rapid eye movement (REM) sleep are increased by an average of 50 minutes per night over the four week period.

7. The CBD is selected from the group consisting of: (1) Δ 5 -cannabidiol (2-(6-isopropenyl-3-methyl-5-cyclohexen-1-yl)-5-pentyl-1,3-benzenediol), (2) Δ 4 -cannabidiol (2-(6-isopropenyl-3-methyl-4-cyclohexen-1-yl)-5-pentyl-1,3-benzenediol), (3) Δ 3 -cannabidiol (2-(6-isopropenyl-3-methyl-3-cyclohexen-1-yl)-5-pentyl-1,3-benzenediol), (4) Δ 3,7 -cannabidiol (2-(6-isopropenyl-3-methylenecyclohex-1-yl)-5-pentyl-1,3-benzenediol), and (5) Δ 2 7. The composition of claim 6, wherein the cannabidiol is selected from (6) Δ 1 -cannabidiol (2-(6-isopropenyl-3-methyl-2-cyclohexen-1-yl)-5-pentyl-1,3-benzenediol), (6) Δ 1 -cannabidiol (2-(6-isopropenyl-3-methyl-1-cyclohexen-1-yl)-5-pentyl-1,3-benzenediol), and (7) Δ 6 -cannabidiol (2-(6-isopropenyl-3-methyl-6-cyclohexen-1-yl)-5-pentyl-1,3-benzenediol).

8. A composition for use in a method for treating anxiety in a subject in need thereof, the method comprising the steps of providing a formulation comprising CBD and a plurality of terpenes, the plurality of terpenes comprising linalool, myrcene, phytol, limonene, α-terpinene, α-terpineol, α-pinene, and β-caryophyllene; and administering an effective amount of the formulation to the subject, wherein administration of the effective amount to the subject reduces the subject's anxiety score on the Hamilton Anxiety Rating Scale compared to a baseline anxiety score on the Hamilton Anxiety Rating Scale assessed in the subject prior to administration of the effective amount to the subject.

9. The composition described in claim 8, wherein the formulation contains approximately 150 mg of CBD and the plurality of terpenes contains approximately 0.5 mg of each terpene.

10. The composition described in claim 9, wherein the effective amount is administered to the subject once daily, one hour before going to bed, for at least seven consecutive nights.

11. The CBD is selected from the group consisting of (1) Δ 5 -cannabidiol (2-(6-isopropenyl-3-methyl-5-cyclohexen-1-yl)-5-pentyl-1,3-benzenediol), (2) Δ 4 -cannabidiol (2-(6-isopropenyl-3-methyl-4-cyclohexen-1-yl)-5-pentyl-1,3-benzenediol), (3) Δ 3 -cannabidiol (2-(6-isopropenyl-3-methyl-3-cyclohexen-1-yl)-5-pentyl-1,3-benzenediol), (4) Δ 3,7 -cannabidiol (2-(6-isopropenyl-3-methylenecyclohex-1-yl)-5-pentyl-1,3-benzenediol), and (5) Δ 2 9. The composition of claim 8, wherein the cannabidiol is selected from (6) Δ 1 -cannabidiol (2-(6-isopropenyl-3-methyl-2-cyclohexen-1-yl)-5-pentyl-1,3-benzenediol), (6) Δ 1 -cannabidiol (2-(6-isopropenyl-3-methyl-1-cyclohexen-1-yl)-5-pentyl-1,3-benzenediol), and (7) Δ 6 -cannabidiol (2-(6-isopropenyl-3-methyl-6-cyclohexen-1-yl)-5-pentyl-1,3-benzenediol).

12. The composition of claim 8, wherein the formulation is orally administered to the subject.

13. The composition of claim 1, wherein the formulation contains approximately 300 mg of CBD and the plurality of terpenes contains approximately 1.0 mg of each terpene.

14. The composition described in claim 8, wherein the subject's anxiety score on the Hamilton Anxiety Rating Scale is less than 8 after administration of the effective amount to the subject.

15. The composition of claim 8, wherein the formulation contains approximately 300 mg of CBD and the plurality of terpenes contains approximately 1.0 mg of each terpene.

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