Treatment of fragile x syndrome with cannabidiol

Abstract

To provide a pharmaceutical composition for use in a method of treating one or more behavioral symptoms of autism spectrum disorder in a subject.SOLUTION: A pharmaceutical composition comprises an effective amount of synthetic cannabidiol (CBD), wherein the pharmaceutical composition is formulated for transdermal administration to treat one or more behavioral symptoms of autism spectrum disorder in a subject, wherein the CBD is formulated as a permeation-enhanced gel for transdermal administration to the subject's arm, and the one or more behavioral symptoms treated by transdermal administration to the arm include irritability, social avoidance, compulsive behavior, manic / hyperactive behavior, somnolence, stereotypy, anxiety, and inappropriate speech.SELECTED DRAWING: None

Description

Technical Field

[0001] <Cross - Reference to Related Applications> This application claims the benefit and priority of U.S. Provisional Application No. 62 / 564,834, filed Sep. 28, 2017, and U.S. Provisional Application No. 62 / 632,532, filed Feb. 20, 2018. The entire content of each of these is hereby incorporated by reference into this specification.

[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 an effective amount of cannabidiol (CBD), wherein one or more behavioral symptoms of fragile X syndrome are treated in the subject.

Background Art

[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 inherited intellectual disability in males and a major cause of intellectual disability in females. 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 endogenous cannabinoid system, including a decrease in endogenous cannabinoids (2 - AG and anandamide [AEA]). This disorder affects synaptic function, plasticity, and neuronal connections, resulting in a wide range of intellectual disabilities, social anxiety, and memory impairments. There are approximately 71,000 patients in the United States affected by FXS.

[0005] "Behavioral problems are often the most significant concerns reported by parents, and increased problem behaviors in children generally accompany high levels of parental stress and depression and low levels of quality of life." 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. "As a result, reduction of behavioral problems is a major focus of ongoing clinical trials testing the effects of new drugs for FXS." Wheeler, pp. 141-142.

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

[0007] The original Aberrant Behavior Checklist (ABC) was "designed to evaluate adult behavioral problems in institutional settings." Wheeler, page 142. Since then, the original ABC has been modified to address patients not in institutions, particularly to address FXS. Id. The Aberrant Behavior Checklist - FXS Specific (ABC - FXS) scale is used by clinicians, physicians, and researchers to evaluate certain behaviors in patients with FXS. The ABC - FXS scale has six subscales including (i) irritability, (ii) hyperactivity, (iii) social unresponsiveness / somnolence, (iv) social avoidance, (v) stereotypy, and (vi) inappropriate speech. Similar to ADAMS, the ABC - FXS scale is a 4 - point Likert - type scale ranging from 0 ("no problem") to 3 ("severe problem").

Prior Art Documents

Non - Patent Documents

[0008]

Non - Patent Document 1

Summary of the Invention

Means for Solving the Problems

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

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

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

[0012] In some embodiments, the transdermal preparation can be a cream, a plaster, or an ointment. CBD can be delivered by a bandage, a pad, or a patch.

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

[0014] In some embodiments, one or more behavioral symptoms are selected from the group consisting of generalized anxiety, social avoidance, obsessive-compulsive behavior, manic / hyperactive behavior, irritability, drowsiness, stereotypy, and inappropriate speech. The behavioral symptoms that are alleviated can be any one or any combination of generalized anxiety, social avoidance, obsessive-compulsive behavior, manic / hyperactive behavior, irritability, drowsiness, stereotypy, inappropriate speech, emotional function, psychosocial health, communication by writing, socialization, play and entertainment, coping ability, 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 upper arm and shoulder of a subject. In some embodiments, CBD is administered transdermally to the thigh or back of the subject.

[0016] CBD can be synthetic CBD. CBD can be purified CBD. CBD can be plant-derived.

[0017] Administering an effective amount of cannabidiol (CBD) transdermally can reduce the intensity of at least one adverse event or side effect compared to administering CBD orally. 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 drowsiness. In some embodiments, the frequency and intensity of drowsiness are reduced as an adverse event.

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

[0019] ASD is a behavioral diagnosis with a variety of symptoms generally characterized by an impaired ability to communicate and socially interact with other people.

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

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

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

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

[0024] Relieving one or more behavioral symptoms of ASD can include improving the total score of the Anxiety, Depression, and Mood Scale (ADAMS). In some embodiments, relieving one or more behavioral symptoms of ASD can include improving one or more subscales of ADAMS.

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

[0026] CBD can be administered transdermally to the upper arm and shoulder of the subject. In some embodiments, CBD is administered transdermally to the thigh or back of the subject.

[0027] CBD can be synthetic CBD. CBD can be purified CBD. CBD can be derived from plants.

[0028] Administering an effective amount of cannabidiol (CBD) transdermally can reduce the intensity of at least one adverse event or side effect compared to administering CBD orally. At least one adverse event or side effect can be a gastrointestinal (GI) adverse event. At least one adverse event or side effect can be a liver function adverse event. In some embodiments, at least one adverse event is drowsiness. In some embodiments, the frequency and intensity of drowsiness are reduced as an adverse event.

Mode for Carrying Out the Invention

[0029] As used herein, the term "treating" or "treatment" refers to relieving, alleviating, reducing, improving, or ameliorating at least one symptom (such as behavioral symptoms) of a condition, disease, or disorder in a subject such as a human, or improving a measurable parameter associated with the condition, disease, or disorder.

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

[0031] As used herein, the term "cannabidiol" or "CBD" refers to pharmaceutically acceptable derivatives of cannabidiol, including cannabidiol; cannabidiol prodrugs; and pharmaceutically 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 pharmaceutically acceptable salts, solvates, metabolites (e.g., cutaneous 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 "administered transdermally" refers to contacting CBD with the skin of a patient or subject under conditions effective for CBD to penetrate the skin.

[0033] Fragile X syndrome (FXS) is a genetic condition that causes intellectual disability, behavioral and learning difficulties, and various physical characteristics. FXS occurs in approximately 1 in 4,000 males and 1 in 8,000 females. Patients with FXS may exhibit one or more features 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 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 ability of CBD in treating epilepsy, arthritis, cancer and fragile X syndrome. Therapeutic pharmaceuticals have been developed using innovative transdermal technologies that enable sustained and regulated delivery of therapeutic levels of CBD. Transdermal delivery of cannabinoids (e.g., CBD) allows the drug to be directly absorbed into the bloodstream through the skin and thus has advantages over oral dosing. This avoids first-pass liver metabolism, allowing for lower dosing levels of the active pharmaceutical ingredient and potentially having higher bioavailability and improved safety profiles. Transdermal delivery also avoids the gastrointestinal tract, reducing the chance of GI-related adverse events and the potential for degradation of CBD to THC by gastric acid, which can be associated with unwanted psychoactive effects. Furthermore, transdermal delivery of CBD reduces the intensity and frequency of sedative adverse events typically present with oral dosing of CBD. Transdermal delivery of CBD can avoid liver function adverse events typically present with oral dosing of CBD. In some embodiments, transdermally administering an effective amount of CBD reduces the intensity of at least one adverse event by about 15% to about 95% compared to orally administering CBD.

[0036] CBD can be in gel form and can be pharmaceutically manufactured as a clear, penetration-enhanced gel designed to provide regulated drug delivery transdermally with once or twice daily dosing. The CBD gel can be between 1% (weight / weight) CBD and 7.5% (weight / weight) CBD. The CBD gel can have, for example, 4.2% (weight / weight) CBD or 7.5% (weight / weight) CBD. The CBD gel can be topically applied by the patient or caregiver to the patient's upper arm and shoulder, back, thigh or any combination thereof.

[0037] The CBD gel can include a diluent and a carrier as well as other conventional excipients such as a wetting agent, a preservative, and a suspending and dispersing agent.

[0038] The CBD gel can include a solubilizing agent, a penetration enhancer, a solubilized substance, an antioxidant, a bulking agent, a thickening agent, and / or a pH adjusting substance. The composition of the CBD gel can be, for example, a. cannabidiol present in an amount of about 0.1% to about 20% (weight / weight) of the composition; b. a lower alcohol having 1 to 6 carbon atoms present in an amount of about 15% to about 95% (weight / weight) of the composition; c. a first penetration enhancer present in an amount of about 0.1% to about 20% (weight / weight) of the composition; and d. water in an amount sufficient to make the total composition 100% (weight / weight). Other formulations of the CBD gel can be found in WO 2010 / 127033 pamphlet, the entire content of which is 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 a 12-week study. 18 patients (14 males and 4 females) aged 6 to 17 years (mean = 11.2, standard deviation = 3.96) with fragile X, confirmed by molecular recording of the FMR1 full mutation, completed a non-blind FAB-C study over 12 weeks. CBD gel was added to other medications being administered. The first 6 weeks of the study were designed to titrate the dosing in the patients. The dosing could start at 50 mg CBD per day and increase up to 250 mg CBD per day. The 7 - 12 weeks of the study consisted of a maintenance period in which the patients were treated at the dose established at up to 250 mg CBD per day by 6 weeks. At the end of the study, the patients could enter a non-blind extension study for up to 12 months.

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

[0041] Results for the primary outcome measure are summarized in Table 1, which details the mean (standard deviation) values of the efficacy measures at baseline and 12 weeks for the ADAMS total score.

[0042]

Table 1

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

[0044]

Table 2

[0045] Compared to the baseline total score, patients treated with CBD transdermal gel had a 44% decrease in the ADAMS total score (p < 0.0001). Furthermore, patients treated with CBD transdermal gel had statistically and clinically significant improvements at 12 weeks compared to baseline in all but one of the ADAMS subscales (i.e., manic / hyperactive behavior, social avoidance, general anxiety, and compulsive behavior). No significant change was observed for the depressive mood subscale of the ADAMS.

[0046] Abnormal Behavior Checklist - FXS Specific (ABC-FXS), Pediatric Anxiety Rating Scale (PARS-R), Visual Analog Scale (VAS) for anxiety, hyperactivity and tantrums / mood lability, Vineland Adaptive Behavior (VLD) III, and Pediatric Quality of Life (PedsQL) TM A number of secondary efficacy assessment items including (). Both the PARS-R and the Vineland scale are evaluated by clinicians, while the other scales are evaluated by caregivers.

[0047] The primary and secondary assessment items were evaluated before drug administration and 12 weeks after drug administration. The results of the secondary assessment items reinforce the results demonstrated in ADAMS. Consistent with the findings from ADAMS, patients taking CBD transdermal gel showed a statistically and clinically significant 12-week decrease in all subscales of ABC-FXS (i.e., irritability, hyperactivity, socially unresponsive / somnolence, social avoidance, stereotypy, and inappropriate speech) and both total score calculated values of PARS-R (i.e., 5 and 7 items).

[0048] Except for the physical function, school adaptation, and social adaptation subscales of PedsQL and some subscales of VLD (e.g., communication, daily living skills), patients also showed significant improvement between the baseline and 12-week scores for all remaining scales. Both VLD and ADAMS are also being conducted in the extension phase 2 of the trial.

[0049] The results obtained from ABC-FXS are summarized in Table 3, which details the mean (standard deviation) values of the efficacy scales at baseline and 12 weeks.

[0050]

Table 3

[0051] The results obtained from PARS-R are summarized in Table 4, which details the baseline and mean (standard deviation) values of the efficacy measures at 12 weeks.

[0052] [Table 4]

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

[0054] [Table 5]

[0055] The results obtained from PedsQL are summarized in Table 6, which details the baseline and mean (standard deviation) values of the efficacy measures at 12 weeks.

[0056] [Table 6]

[0057] The results obtained from VLDIII are summarized in Table 7, which details the baseline and mean (standard deviation) values of the efficacy measures at 12 weeks.

[0058] [Table 7]

[0059] Among the 18 patients who completed the 12-week treatment, the mean improvement in overall anxiety and depression (ADAMS total score) reached 44% (p < 0.01), and particular benefit was observed for generalized anxiety (51%; p < 0.01) and the obsessive-compulsive subscale (48%; p < 0.05). Furthermore, there was a range from 28% (hyperactivity subscale; p0 <.05) to 60% (constancy subscale; p0 <.01) for the ABC FXSThe improvements measured by [method] were observed in abnormal behaviors, and during the treatment period, social avoidance (p<0.01) and the social non-responsiveness / somnolence subscale improved by 55% each (p<0.01). Beyond individual symptoms, quality of life improved by 17% (p=0.01).

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

[0061] After the 12-week open-label study, patients were permitted to enter a 1-year open-label extension study. 72% (n=13) of the 18 patients who completed the initial 12-week study entered the extension study. The open-label extension study is ongoing, and some data have been collected over 38 weeks (12 weeks of the initial study and up to 6 months of the extension study). Results from the extension study demonstrate continued progress on two measures collected (ADAMS and ABC FXS ). In fact, those who completed the 38-week visit (n=4) showed significant progress from screening for general anxiety and depression, and participants experienced an average improvement of 74% in the total ADAMS score. Similar improvements ranging from 75% (irritability subscale) to 96% (social avoidance subscale) and 97% (socially non-responsive / somnolence subscale) were observed at 38 weeks for abnormal behaviors.

[0062] The open-label extension study continues, and data are being collected over 51 weeks. Results are summarized in Table 8 (ABC FXS ), and 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 existing eczema. Other adverse events did not lead 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 infections (n = 5). However, during the 12-week treatment period, patients did not experience drug-related GI events and THC was not detected in plasma.

[0066] The clinical results of this trial are important for many FXS patients worldwide who currently have no approved therapeutic options to treat their symptoms. This data, in particular, the improvement in anxiety, social avoidance, and irritability measured by ADAMS, ABC-FXS, and PARS-R is important. The CBD gel was extremely well tolerated in children and adolescents with FXS.

[0067] [Example 2]: Report of patient studies by parents This is a report on a 7-year-old child who participated in the above study and continued in the extension study, as reported by the caregiver. The caregiver's son has full mutation fragile X syndrome. He was reported to have severe intellectual disability, visual impairment, not yet using words, still requiring diapers, and extremely severe gastrointestinal problems that required nutritional supplementation by a feeding tube every two hours before this trial. Before starting this trial, this child had no eye contact, rarely left home without significant mental distress, never initiated any form of communication, extremely disliked being touched including by his parents, did not even allow family members to sit next to him, and left the room when someone walked into the room.

[0068] Within the first two weeks of the trial, this patient began to make more eye contact, initiated physical contact with his family, such as holding his mother's hand, started emotional contact with his family, such as seeking to be in the same room as his family, and showed improvement in his ability to go out to the extent that the family could take their first vacation together.

[0069] At the end of the initial trial and several weeks into the extended trial, the caregiver recorded another major change in the patient. He began greeting his family, started engaging in more complex games, showed / shared a preference for things instead of simply rejecting all choices, and began accepting the family pet. He also allowed the doctor to touch and hold him without flinching. The patient truly began using physical cues (sign language) for the first time. The patient truly began expressing his longing for his mother in a very clear manner for the first time and strongly desired to be hugged and held by his mother.

[0070] The patient is reported to be happier, more relaxed, able to interact with the world in ways he couldn't before, and able to learn new skills he couldn't before. The patient's teachers, therapists, and assistants also noted the changes in the patient.

Claims

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 the one or more behavioral symptoms of fragile X syndrome are treated in the subject.

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

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

4. The method of claim 1, wherein the effective amount of CBD is initiated at 50 mg per day and titrated up to 500 mg per day.

5. The method of claim 1, wherein the effective amount of CBD is initiated at 50 mg per day and titrated up to 250 mg per day.

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

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

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

9. The method of claim 8, wherein the CBD is formulated as a penetration-enhanced gel.

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

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

12. The method of claim 1, wherein alleviating one or more behavioral symptoms of fragile X syndrome comprises improving the total score of the Anxiety, Depression, and Affective Scale (ADAMS).

13. The method of claim 1, wherein alleviating one or more behavioral symptoms of fragile X syndrome comprises improving one or more metrics of the Aberrant Behavior Checklist for Fragile X (ABC-FXS).

14. The method of claim 1, wherein 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.

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

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

17. The method of claim 1, wherein the behavioral symptom being alleviated is obsessive behavior.

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

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

20. The method according to claim 1, wherein the behavioral symptom to be alleviated is drowsiness.

21. The method according to claim 1, wherein the behavioral symptom to be alleviated is unresponsiveness.

22. The method according to claim 1, wherein the behavioral symptom to be alleviated is stereotypy.

23. The method according to claim 1, wherein the behavioral symptom to be alleviated is inappropriate speech.

24. The method according to claim 1, wherein the behavioral symptom to be alleviated is epilepsy / mood swings.

25. The method according to claim 1, wherein the behavioral symptom to be alleviated is hyperactivity / impulsivity.

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

27. The method according to claim 1, wherein CBD is synthetic CBD.

28. The method according to claim 1, wherein CBD is purified CBD.

29. The method according to claim 1, wherein CBD is derived from plants.

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

31. The method according to claim 30, wherein the at least one adverse event is selected from the group consisting of drowsiness, psychostimulant effects, liver function, and gastrointestinal-related adverse events.

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