Treatment of fragile x-associated syndrome by cannabidiol

Abstract

To provide a method for treating one or more symptoms on action of fragile X-associated syndrome in a subject.SOLUTION: A method for treating one or more symptoms on action of fragile X-associated syndrome in a subject by percutaneously administering an effective dose of cannabidiol (CBD) to the subject.SELECTED DRAWING: None

Description

[Technical field]

[0001] <CROSS REFERENCE TO RELATED APPLICATIONS> This application claims the benefit of and priority to U.S. Provisional Application No. 62 / 564,834, filed September 28, 2017, and U.S. Provisional Application No. 62 / 632,532, filed February 20, 2018, the contents of each of which are incorporated herein by reference in their entirety.

[0002] The present disclosure relates to a method of treating one or more behavioral symptoms of Fragile X Syndrome in a subject by transdermally administering to the subject an effective amount of cannabidiol (CBD), wherein one or more behavioral symptoms of Fragile X Syndrome are treated in the subject. [Background technology]

[0003] Cannabinoids are a class of chemical compounds found in the Cannabis plant. The two main cannabinoids contained in Cannabis are cannabidiol or CBD and Δ9-tetrahydrocannabinol or THC. CBD lacks the psychoactive effects of THC. Research has shown that CBD can be used to treat disorders such as epilepsy, arthritis, and cancer.

[0004] FXS is the most common genetic intellectual disability in men and a significant cause of intellectual disability in women. FXS is caused by a mutation in the fragile X mental retardation 1 (FMR1) gene located on the X chromosome, resulting in dysregulation of the endocannabinoid system, including reduced endocannabinoids (2-AG and anandamide [AEA]). This impairment adversely affects synaptic function, plasticity and neuronal connectivity, resulting in widespread intellectual disability, social anxiety and memory impairment. There are approximately 71,000 patients in the United States who suffer from FXS.

[0005] "Behavioral problems are often the most significant concern reported by parents, and high levels of parental stress and depression and low quality of life are commonly associated with increased behavioral problems in children." Wheeler A, Raspa M, Bann C, Bishop E, Hassl D, Sacco H, Bailey DB. 2014. Anxiety attention problems, hyperactivity, and the Aberrant Behavior Checklist in fragile X syndrome. Am J Med Genet Part A 164A:141-155, 141. "Consequently, reduction of behavioral problems is a major focus of ongoing clinical trials testing the efficacy of new medications for FXS." Wheeler, pp. 141-142.

[0006] The Anxiety, Depression, and Mood Scale (ADAMS) is an instrument used by clinicians, physicians, and researchers to assess levels of anxiety, depression, and mood in patients with intellectual disabilities, including FXS. The ADAMS consists of questions divided into five subscales including: (i) generalized anxiety, (ii) social avoidance, (iii) obsessive-compulsive behavior, (iv) manic / hyperactive behavior, and (v) depressed mood. Each question is answered by the clinician / physician on a 4-point scale ranging from 0 ("no problems") to 3 ("severe problems"). In addition to the subscale scores, the ADAMS gives a total score.

[0007] The original Aberrant Behavior Checklist (ABC) was "designed to assess adult behavioral problems in an institutional setting." Wheeler, p. 142. Since then, the original ABC has been adapted to address noninstitutionalized patients, specifically to address FXS. Ibid. The Aberrant Behavior Checklist-FXS Specific (ABC-FXS) scale is used by clinicians, physicians, and researchers to assess certain behaviors in patients with FXS. The ABC-FXS scale has six subscales, including (i) irritability, (ii) hyperactivity, (iii) socially unresponsive / lethargic, (iv) social avoidance, (v) stereotypy, and (vi) inappropriate speech. Like the ADAMS, the ABC-FXS scale is a 4-point Likert-type scale ranging from 0 ("no problems") to 3 ("severe problems"). [Prior art documents] [Non-patent literature]

[0008] [Non-Patent Document 1] Wheeler A,Raspa M,Bann C,Bishop E,Hassl D,Sacco H,Bailey DB.2014.Anxiety attention problems,hyperactivity,and the Aberrant Behavior Checklist in fragile X syndrome.Am J Med Genet Part A 164A:141-155,141 Summary of the Invention [Means for solving the problem]

[0009] The present disclosure relates to a method of treating one or more behavioral symptoms of fragile X syndrome in a subject, the method comprising transdermally administering to the subject an effective amount of cannabidiol (CBD), wherein one or more behavioral symptoms of fragile X syndrome are treated in the subject.

[0010] In some embodiments, the CBD is (-)-CBD. The effective amount of CBD can be between about 50 mg and about 500 mg per day. In some embodiments, the effective amount of CBD can start at about 50 mg per day and be titrated up to about 500 mg per day. The effective amount of CBD can start at about 50 mg per day and be titrated up to about 250 mg per day. In some embodiments, the effective amount of CBD can start at 250 mg per day. The effective amount of CBD can start at 500 mg per day. In some embodiments, a daily dose of 500 mg is administered to a patient weighing more than 35 kg. CBD can be administered in a single daily dose or in a twice daily dose. In some embodiments, the effective amount of CBD can be 390 mg in a divided daily dose.

[0011] CBD may be formulated as a gel or oil. In some embodiments, CBD is formulated as a penetration-enhanced gel. The gel may contain between 1% (w / w) CBD and 7.5% (w / w) CBD. In some embodiments, the gel contains 4.2% (w / w) CBD. In some embodiments, the gel contains 7.5% (w / w) CBD.

[0012] In some embodiments, the transdermal preparation may be a cream, salve, or ointment. The CBD may be delivered by a bandage, pad, or patch.

[0013] Alleviating one or more behavioral symptoms of Fragile X Syndrome can include an improvement in the Anxiety, Depression and Mood Scale (ADAMS) total score. In some embodiments, alleviating one or more behavioral symptoms of FXS can include an improvement in one or more subscales of ADAMS. Alleviating one or more behavioral symptoms of Fragile X Syndrome can include an improvement in one or more indicators of the Aberrant Behavior Checklist for Fragile X (ABC-FXS).

[0014] In some embodiments, the one or more behavioral symptoms are selected from the group consisting of generalized anxiety, social avoidance, obsessive behavior, manic / hyperactive behavior, irritability, lethargy, stereotypy, and inappropriate speech. The behavioral symptoms to be alleviated may be any one or any combination of generalized anxiety, social avoidance, obsessive behavior, manic / hyperactive behavior, irritability, lethargy, stereotypy, inappropriate speech, emotional functioning, psychosocial well-being, written communication, socialization, play and recreation, coping skills, internalizing behavior, externalizing behavior, tantrums / mood swings, hyperactivity / impulsivity, and quality of life. In some embodiments, a single symptom is alleviated. In some embodiments, two, three, four, five, six, seven, eight, or nine symptoms are alleviated.

[0015] CBD can be administered transdermally to the subject's upper arms and shoulders. In some embodiments, CBD is administered transdermally to the subject's thighs or back.

[0016] The CBD may be synthetic CBD. The CBD may be purified CBD. The CBD may be derived from a plant.

[0017] Transdermally administering an effective amount of cannabidiol (CBD) can reduce the intensity of at least one adverse event or side effect compared to orally administering CBD. The at least one adverse event or side effect can be a gastrointestinal (GI) adverse event. The at least one adverse event or side effect can be liver function. In some embodiments, the at least one adverse event is somnolence. In some embodiments, the frequency and intensity of somnolence is reduced as an adverse event.

[0018] In another embodiment, a method is provided for treating one or more behavioral symptoms of autism spectrum disorder (ASD) in a subject by transdermally administering to the subject an effective amount of CBD, wherein one or more behavioral symptoms of ASD are treated in the subject.

[0019] ASD is a heterogeneous behavioral diagnosis commonly characterized by an impaired ability to communicate and interact socially with other people.

[0020] One or more behavioral symptoms of ASD that can be treated include, for example, social avoidance, generalized anxiety, hyperactivity, depressed mood, and obsessive-compulsive behavior. Alleviating one or more behavioral symptoms of ASD can include improving the total score of the Anxiety, Depression, and Mood Scale (ADAMS). In some embodiments, alleviating one or more behavioral symptoms of ASD can include improving one or more subscales of the ADAMS.

[0021] In some embodiments, the CBD is (-)-CBD. The effective amount of CBD can be between about 50 mg and about 500 mg per day. In some embodiments, the effective amount of CBD can start at about 50 mg per day and be titrated up to about 500 mg per day. The effective amount of CBD can start at about 50 mg per day and be titrated up to about 250 mg per day. In some embodiments, the effective amount of CBD can start at 250 mg per day. The effective amount of CBD can start at 500 mg per day. In some embodiments, a daily dose of 500 mg is administered to a patient weighing more than 35 kg. CBD can be administered in a single daily dose or in a twice daily dose. In some embodiments, the effective amount of CBD can be 390 mg in a divided daily dose.

[0022] CBD may be formulated as a gel or oil. In some embodiments, CBD is formulated as a penetration-enhanced gel. The gel may contain between 1% (w / w) CBD and 7.5% (w / w) CBD. In some embodiments, the gel contains 4.2% (w / w) CBD. In some embodiments, the gel contains 7.5% (w / w) CBD.

[0023] In some embodiments, the transdermal preparation may be a cream, salve, or ointment. The CBD may be delivered by a bandage, pad, or patch.

[0024] Alleviating one or more behavioral symptoms of ASD can include an improvement in the Anxiety, Depression and Mood Scale (ADAMS) total score. In some embodiments, alleviating one or more behavioral symptoms of ASD can include an improvement in one or more subscales of the ADAMS.

[0025] In some embodiments, the one or more behavioral symptoms are selected from the group consisting of generalized anxiety, social avoidance, obsessive behavior, manic / hyperactive behavior. The behavioral symptoms alleviated may be any one of generalized anxiety, social avoidance, obsessive behavior, manic / hyperactive behavior, or any combination thereof. In some embodiments, a single symptom is alleviated. In some embodiments, two, three, or four behavioral symptoms are alleviated.

[0026] CBD can be administered transdermally to the subject's upper arms and shoulders. In some embodiments, CBD is administered transdermally to the subject's thighs or back.

[0027] The CBD may be synthetic CBD. The CBD may be purified CBD. The CBD may be derived from a plant.

[0028] Transdermally administering an effective amount of cannabidiol (CBD) can reduce the intensity of at least one adverse event or side effect compared to orally administering CBD. The at least one adverse event or side effect can be a gastrointestinal (GI) adverse event. The at least one adverse event or side effect can be a liver function adverse event. In some embodiments, the at least one adverse event is somnolence. In some embodiments, the frequency and intensity of somnolence is reduced as an adverse event. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0029] The term "treat" or "treatment" as used herein refers to reducing, ameliorating, relieving, or alleviating at least one symptom (such as a behavioral symptom) of a condition, disease, or disorder in a subject, such as a human, or the improvement in an identifiable measurement associated with a condition, disease, or disorder.

[0030] As used herein, the term "clinical efficacy" refers to the ability to produce a desired effect in humans as demonstrated through Food and Drug Administration (FDA), or any foreign counterpart, clinical trial.

[0031] The term "cannabidiol" or "CBD" as used herein refers to cannabidiol; cannabidiol prodrugs; pharma- ceutically acceptable derivatives of cannabidiol, including pharma- ceutically acceptable salts of cannabidiol, cannabidiol prodrugs, and cannabidiol derivatives. CBD includes 2-[3-methyl-6-(1-methylethenyl)-2-cyclohexen-1-yl]-5-pentyl-1,3-benzenediol and its pharma- ceutically acceptable salts, solvates, metabolites (e.g., skin metabolites), and metabolic precursors. The synthesis of CBD is described, for example, in Petilka et al., Helv. Chim. Acta, 52:1102 (1969) and Mechoulam et al., J. Am. Chem. Sco., 87:3273 (1965), which are incorporated herein by reference.

[0032] As used herein, the term "transdermally administering" refers to contacting the CBD with the skin of a patient or subject under conditions effective for the CBD to penetrate the skin.

[0033] Fragile X syndrome (FXS) is a genetic condition that causes intellectual disability, behavioral and learning difficulties, and a variety of physical characteristics. FXS affects 1 in 4,000 males and 1 in 8,000 females. Patients with FXS may exhibit one or more characteristics of ASD.

[0034] The present disclosure relates to a method of treating one or more behavioral symptoms of Fragile X Syndrome in a subject by transdermally administering to the subject an effective amount of cannabidiol (CBD), wherein one or more behavioral symptoms of Fragile X Syndrome are treated in the subject.

[0035] Clinical and preclinical data support the potential of CBD in treating epilepsy, arthritis, cancer and fragile X syndrome. Therapeutic medicines have been developed that use innovative transdermal technology to allow sustained and regulated delivery of therapeutic levels of CBD. Transdermal delivery of cannabinoids (e.g., CBD) has advantages over oral dosing because it allows the drug to be absorbed directly into the bloodstream through the skin. This allows for lower dosage levels of the active pharmaceutical ingredient, potentially with higher bioavailability and improved safety profile, since it avoids first-pass hepatic metabolism. Transdermal delivery also avoids the gastrointestinal tract, thus reducing the chance of GI-related adverse events and the potential for the breakdown of CBD to THC by stomach acid, which may involve undesirable psychoactive effects. Additionally, transdermal delivery of CBD reduces the intensity and frequency of somnolence adverse events that are typically present with oral dosing of CBD. Transdermal delivery of CBD can avoid liver function adverse events that are typically present with oral dosing of CBD. In some embodiments, administering an effective amount of CBD transdermally reduces the intensity of at least one adverse event by about 15% to about 95% compared to administering CBD orally.

[0036] CBD can be in gel form and can be pharma- ceutical manufactured as a clear, permeation-enhanced gel designed to provide controlled drug delivery transdermally with once or twice daily dosing. CBD gel can be between 1% (w / w) CBD and 7.5% (w / w) CBD. CBD gel can have, for example, 4.2% (w / w) CBD or 7.5% (w / w) CBD. CBD gel can be applied topically by the patient or a caregiver to the patient's upper arms and shoulders, back, thighs, or any combination thereof.

[0037] The CBD gel may contain diluents and carriers as well as other conventional excipients such as wetting agents, preservatives, and suspending and dispersing agents.

[0038] The CBD gel may include solubilizers, penetration enhancers, solubilizing agents, antioxidants, bulking agents, thickening agents, and / or pH modifiers. The composition of the CBD gel may be, for example, a. cannabidiol present in an amount of about 0.1% to about 20% (w / w) of the composition; b. a lower alcohol having between 1 and 6 carbon atoms present in an amount of about 15% to about 95% (w / w) of the composition; c. a first penetration enhancer present in an amount of about 0.1% to about 20% (w / w) of the composition; and d. water in an amount sufficient to bring the composition to a total of 100% (w / w). Other formulations of CBD gels can be found in WO 2010 / 127033, the entire contents of which are incorporated herein by reference. EXAMPLES

[0039] Example 1: Study design and data A total of 20 patients (mean age = 10.8, standard deviation = 4.0) participated in the 12-week study. Eighteen patients (14 males, 4 females) aged 6-17 years (mean = 11.2, standard deviation = 3.96) with fragile X, confirmed by molecular documentation of FMR1 pan-mutation, completed the open-label FAB-C study throughout the 12 weeks. CBD gel was added to other medications being administered. The first 6 weeks of the study were designed to titrate the medication in the patients. Dosing was initiated at 50 mg CBD per day and could be increased to 250 mg CBD per day. Weeks 7-12 of the study consisted of a maintenance period in which patients were treated with the dose established by week 6, up to a maximum of 250 mg CBD per day. Upon completion of the study, patients could enter an open-label extension study for up to 12 months.

[0040] The primary outcome of the study was change from baseline to week 12 in the Anxiety, Depression, and Mood Scale (ADAMS) total score. The ADAMS is a 28-item scale designed to assess generalized anxiety, social avoidance, obsessive-compulsive behavior, manic / hyperactive behavior, and depressed mood. The ADAMS has been validated in patients with FXS.

[0041] Results for the primary endpoints are summarized in Table 1, which details the baseline and 12 week efficacy scale mean (standard deviation) values ​​for the ADAMS total score.

[0042] [Table 1]

[0043] The ADAMS subscales are summarized in Table 2, which details the efficacy scale mean (standard deviation) values ​​at baseline and 12 weeks.

[0044] [Table 2]

[0045] Compared to baseline total score, patients treated with CBD transdermal gel had a 44% reduction in ADAMS total score (p<0.0001). Additionally, patients treated with CBD transdermal gel had statistically and clinically significant improvements compared to baseline in all but one ADAMS subscale (i.e., manic / hyperactive behavior, social avoidance, generalized anxiety, and obsessive-compulsive behavior) at 12 weeks. No significant changes were observed for the ADAMS depressed mood subscale.

[0046] Abnormal Behavior Checklist-FXS Specific (ABC-FXS), Pediatric Anxiety Rating Scale (PARS-R), Visual Analogue Scales (VAS) for Anxiety, Hyperactivity and Tantrum / Mood Lability, Vineland Adaptive Behavior (VLD) III and Pediatric Quality of Life (PedsQL) TM Both the PARS-R and the Vineland Scale are clinician-rated, whereas the other scales are caregiver-rated.

[0047] Primary and secondary endpoints were assessed prior to and 12 weeks after drug administration. The secondary endpoint results reinforce the findings demonstrated in ADAMS. Consistent with findings from ADAMS, patients taking CBD transdermal gel demonstrated statistically and clinically significant 12-week reductions in all subscales of the ABC-FXS (i.e., irritability, hyperactivity, socially unresponsive / lethargic, social avoidance, stereotypy and inappropriate speech) and both calculated total scores of the PARS-R (i.e., items 5 and 7).

[0048] With the exception of the physical functioning, school adjustment, and social adjustment subscales of the PedsQL and some subscales of the VLD (e.g., communication, daily living skills), patients also showed significant improvements between baseline and 12-week scores on all remaining scales. Both the VLD and ADAMS are also being administered in the extension phase 2 of the study.

[0049] Results from the ABC-FXS are summarized in Table 3, which details efficacy measure mean (standard deviation) values ​​at baseline and 12 weeks.

[0050] [Table 3]

[0051] Results from the PARS-R are summarized in Table 4, which details the efficacy scale mean (standard deviation) values ​​at baseline and 12 weeks.

[0052] [Table 4]

[0053] The results from the VAS for anxiety, hyperactivity and tantrums / mood variability are summarized in Table 5.

[0054] [Table 5]

[0055] Results from the PedsQL are summarized in Table 6, which details the efficacy scale mean (standard deviation) values ​​at baseline and 12 weeks.

[0056] [Table 6]

[0057] Results from the VLDIII are summarized in Table 7, which details the efficacy measure mean (standard deviation) values ​​at baseline and 12 weeks.

[0058] [Table 7]

[0059] Among the 18 patients who completed 12 weeks of treatment, the mean improvement in overall anxiety and depression (ADAMS total score) reached 44% (p<0.01), with particular benefits observed for the generalized anxiety (51%; p<0.01) and obsessive-compulsive behavior subscales (48%; p<0.05). Furthermore, the mean improvement in ABC scores ranged from 28% (hyperactivity subscale; p0<0.05) to 60% (stereotypy subscale; p0<0.01). FXSImprovements were observed in abnormal behavior, as measured by the Social Avoidance (p<0.01) and Social Unresponsiveness / Sleepiness subscales, which improved by 55% (p<0.01), respectively, during the treatment period. Beyond the individual symptoms, quality of life improved by 17% (p=0.01).

[0060] The study successfully met its primary endpoint, achieving a 44% improvement in total ADAMS score (P<0.0001) at week 12 compared to baseline. The study also achieved clinically significant improvements in all indices of the ABC-FXS, which describes the core symptoms of FXS, including irritability, hyperactivity, social unresponsiveness, social avoidance, stereotypy, and inappropriate speech.

[0061] After the 12-week open-label study, patients were allowed to enter a 1-year open-label extension study. Of the 18 patients who completed the initial 12-week study, 72% (n=13) entered the extension study. The open-label extension study is ongoing, with some data collected over 38 weeks (12 weeks in the initial study and up to 6 months in the extension study). Results from the extension study were based on two collected measures (ADAMS and ABC). FXS ) demonstrate continued progress. Indeed, those completing the 38-week visit (n=4) showed significant progress from screening in global anxiety and depression, with participants experiencing a mean improvement in ADAMS total score of 74%. Similar improvements were observed for aberrant behaviors, ranging from 75% (irritability subscale) to 96% (social avoidance subscale) and 97% (socially unresponsive / lethargic subscale) at 38 weeks.

[0062] The open-label extension study continues to progress, with data being collected through 51 weeks. The results are shown in Table 8 (ABC FXS ) and summarized in a table (ADAMS).

[0063] [Table 8]

[0064] [Table 9]

[0065] The CBD gel was well tolerated and had excellent skin tolerability. One patient discontinued due to exacerbation of pre-existing eczema. No other adverse events led to discontinuation and the adverse events were not considered severe. The most common adverse events were mild to moderate gastroenteritis (n=6) and upper respiratory tract infection (n=5). However, during the 12-week treatment period, no patients experienced drug-related GI events and THC was not detectable in plasma.

[0066] The clinical results of this study are important for the many FXS patients around the world who currently have no approved therapeutic options to treat their symptoms. The data are significant, especially the improvements in anxiety, social avoidance, and irritability as measured by ADAMS, ABC-FXS, and PARS-R. CBD gel was extremely well tolerated by children and adolescents with FXS.

[0067] Example 2: Parent-reported patient profiles This is a caregiver-reported report of a 7-year-old child who participated in the above study and is continuing in the extension study. The caregiver's son has full mutation fragile X syndrome. He was reported prior to the study to be non-verbal, severely intellectually disabled, visually impaired, and had extremely severe gastrointestinal problems that required him to still wear diapers and be fed by feeding tube every 2 hours. Prior to starting the study, the child had never made eye contact, was rarely able to leave the house without significant emotional distress, never initiated any form of communication, and had an extreme aversion to being touched, including by his parents, would not allow even family members to sit next to him and would leave the room if anyone walked in.

[0068] Within the first 2 weeks of the study, the patient began to make more eye contact, initiated physical contact with his family, e.g., began holding his mother's hand, initiated emotional contact with his family, such as asking to be in the same room as them, and showed improvement in his ability to go out to places such as the family being able to take their first vacation together.

[0069] After the end of the initial study and several weeks into the extended study, the caregivers noted other significant changes in the patient. He began to greet family members, initiated and engaged in more complex games, showed / shared preferences for things instead of simply refusing all choices, and began to accept the family pet. He also allowed the physician to touch and hold him without flinching. Patient began to use physical cues (sign language) for the very first time. Patient communicated his longing for his mother very clearly for the very first time and longed to be held and held by her.

[0070] Patients are reported to be happier, more relaxed, able to interact with the world in ways they were not able to before, and able to learn new skills they were not able to before. The patient's teachers, therapists, and aides also noted changes in the patient.

Claims

1. 1. A method of treating one or more behavioral symptoms of Fragile X Syndrome in a subject, comprising transdermally administering to the subject an effective amount of cannabidiol (CBD), wherein one or more behavioral symptoms of Fragile X Syndrome are treated in the subject.

2. 2. The method of claim 1, wherein the CBD is (-)-CBD.

3. 10. The method of claim 1, wherein the effective amount of CBD is between about 50 mg and about 500 mg total per day.

4. 10. The method of claim 1, wherein the effective amount of CBD starts at 50 mg per day and titrates up to 500 mg per day.

5. 10. The method of claim 1, wherein the effective amount of CBD starts at 50 mg per day and titrates up to 250 mg per day.

6. 10. The method of claim 1, wherein the effective amount of CBD is initiated at 250 mg per day.

7. 10. The method of claim 1, wherein the effective amount of CBD is initiated at 500 mg per day.

8. 10. The method of claim 1, wherein the CBD is formulated as a gel.

9. 10. The method of claim 8, wherein the CBD is formulated as a permeation enhancing gel.

10. 10. The method of claim 1, wherein the CBD is administered as a single daily dose.

11. 10. The method of claim 1, wherein the CBD is administered as a twice daily dose.

12. 10. The method of claim 1, wherein alleviating one or more behavioral symptoms of Fragile X Syndrome comprises an improvement in the Anxiety, Depression and Mood Scale (ADAMS) total score.

13. 10. The method of claim 1, wherein alleviating one or more behavioral symptoms of Fragile X Syndrome comprises improvement in one or more indicators of the Aberrant Behavior Checklist for Fragile X (ABC-FXS).

14. 2. The method of claim 1, wherein the one or more behavioral symptoms are selected from the group consisting of generalized anxiety, social avoidance, obsessive-compulsive behavior, manic / hyperactive behavior, irritability, lethargy, stereotypies, and inappropriate speech.

15. 10. The method of claim 1, wherein the behavioral symptom that is alleviated is generalized anxiety.

16. 10. The method of claim 1, wherein the behavioral symptom that is alleviated is social avoidance.

17. 10. The method of claim 1, wherein the behavioral symptom that is alleviated is obsessive-compulsive behavior.

18. 10. The method of claim 1, wherein the behavioral symptom that is alleviated is manic / hyperactive behavior.

19. 10. The method of claim 1, wherein the behavioral symptom that is alleviated is irritability.

20. 10. The method of claim 1, wherein the behavioral symptom that is alleviated is lethargy.

21. 2. The method of claim 1, wherein the behavioral symptom that is alleviated is unresponsiveness.

22. 10. The method of claim 1, wherein the behavioral symptom that is alleviated is stereotypy.

23. 10. The method of claim 1, wherein the behavioral symptom that is alleviated is inappropriate speech.

24. 10. The method of claim 1, wherein the behavioral symptom that is alleviated is tantrums / mood swings.

25. 10. The method of claim 1, wherein the behavioral symptom that is alleviated is hyperactivity / impulsivity.

26. 10. The method of claim 1, wherein the CBD is administered transdermally to the subject's arm.

27. 2. The method of claim 1, wherein the CBD is synthetic CBD.

28. 2. The method of claim 1, wherein the CBD is purified CBD.

29. 2. The method of claim 1, wherein the CBD is derived from a plant.

30. 10. The method of claim 1, wherein administering an effective amount of cannabidiol (CBD) transdermally reduces the intensity of at least one adverse event compared to administering CBD orally.

31. 31. The method of claim 30, wherein the at least one adverse event is selected from the group consisting of somnolence, psychoactive effects, liver function, and gastrointestinal related adverse events.

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