Patient 1 is a 3-year 6-month-old male with FXS diagnosed at age 15 months with 250 to 650 CGG repeats. He was born full-term following an uncomplicated pregnancy and delivery at seven pounds six ounces. In the newborn period, he began having problems latching for breastfeeding, and he was fed pumped breast milk and formula from a bottle; he had frequent gagging and spitting up. By 6 months of age, with introduction of soft baby foods, he was often dysphagic, choked easily, and was intolerant of chunky or textured foods. Testing for food allergies was negative, and his formula was changed multiple times over his first year of life. He grew slowly at the third to fifth percentile for weight and the 50th percentile for length until 15 months of age. He was also hypotonic with delays in gross motor skills. He had behavioral concerns, including atypical motor movements, frequent repetitive moving, stiffening and shaking of his legs, body rocking, and repetitive finger stereotypies while touching his ears. He displayed difficulty adjusting to new or noisy places and changes in routine, as well as trouble making eye contact and a short attention span during play and in social interactions; he would sometimes stare off and seem disconnected for 10 to 30 sec.

At 15 months of age, he was evaluated and underwent a brain magnetic resonance imaging (MRI), electroencephalography (EEG), creatine kinase, plasma amino acids, and thyroid and genetic testing. His MRI, EEG, microarray, and laboratory parameters were normal. His FXS DNA test results showed a full mutation for FXS with 260 to 650 fully methylated CGG repeats.

At this time, the patient's parents independently obtained and began administering an oral paste comprising 18% to 23.5% CBD and trace amounts (0.03%) of delta-9-tetrahydrocannabinol (THC) that delivered 50 mg of CBD per day (RSHO™ Blue Label; Naturewell, Inc., San Diego, CA). They combined the CBD paste with coconut oil, heated the mixture until it liquefied, and then used a syringe to administer the liquid preparation orally. During the first month of CBD+ treatment, the family noticed behavioral improvements.

After 1 month of CBD+ monotherapy, the then 16-month-old patient began specialized care in the form of speech and language therapy and occupational therapy for FXS. A baseline measure of adaptive functioning was obtained (Table 1). Over the next 3 months of daily 50-mg CBD+ treatment with adjunctive therapy, the family noted continued improvements in a wide range of clinical parameters. Feeding improved markedly with increased willingness to eat solid foods and increased intake overall. His parents also noted improvements in motor coordination, more frequent vocalizations, less rocking and kicking during feeds, more frequent and longer eye contact, an increase in positive interactions with other children, greater willingness to explore new places, and less self-stimulatory behavior. Many of the parental observations were also confirmed by the patient's occupational and speech therapists, some of whom were unaware of the initiation of CBD+ treatment. CBD+ solution was the only medication used in treatment during this time.

At the 4-month follow-up visit, the patient's weight had increased to the 15th percentile, while his length remained at the 50th percentile. Developmental progress included improved fine and gross motor skills, decreased repetitive rocking, improved social interest/engagement, improved vocalizations, and decreased hyperactivity. The patient began a regimen of sertraline (2.5 mg per day) due to preliminary evidence of improved language and development in young children with FXS treated with sertraline.^37,38 Subsequent follow-up visits (at 21 and 27 months of age) showed continued improvement in language and developmental skills. The patient started walking and self-feeding independently, exhibited more frequent and varied vocalizations, fewer repetitive and motor behaviors, fewer sensory sensitivities (e.g., tolerated noise and lights of fireworks), and more frequent initiation of joint attention with pointing. Weight increased to the 25th percentile. He continued using CBD+ solution and remained in a strong early intervention program: 1 h per week of occupational, speech, and physical therapy; 6 h per week of Early Start Denver Model behavioral therapy and applied behavioral analysis.

When the patient was 30 months of age, his parents chose to discontinue CBD+ treatment to instead explore minocycline, shown to improve behavioral symptoms in some patients with FXS.³⁹ The initiation of 25 mg per day of minocycline coupled with cessation of CBD+ treatment resulted in increased anxiety, more frequent meltdowns, and more difficulty falling and maintaining sleep.

During a clinic visit when the patient was 3 years of age, it was noted that the patient continued to engage and make slow progress, although anxiety, frequent meltdowns, and difficulties with sleep persisted, and increasing challenges with transitions and attention span were observed. The patient's medical treatments included a daily regimen of 4 mg of sertraline and 25 mg of minocycline. He also continued to receive intensive early intervention services (as described above). At 3 years of age, an updated adaptive behavior assessment was obtained (Table 1). After discussion with his family and medical team, the patient was restarted on CBD+ treatment, 50 mg per day. Following reinitiation of CBD+ treatment, his parents noted reductions in anxiety, fewer meltdowns, and improvements in his ability to fall and stay asleep. The patient has now transitioned into a small preschool where he is continuing to do well and has remained on his CBD+ treatment.

Patient 2 is a 26-year-old male with full-mutation (>200 CGG repeats) FXS and an IQ score in the mid-50s. Despite a medication regimen that included 60 mg of methylphenidate hydrochloride (once daily), 2.5 mg of aripiprazole, 100 mg of sertraline, 200 mg of minocycline, and 0.2 mg of clonidine (at bedtime), the patient experienced significant symptoms of attention-deficit/hyperactivity disorder, including hyperactivity, inattention, and impulsivity. He also suffered from anxiety, which led to avoidant behavior and sleep disturbances, and some significant features of autism, including social avoidance, poor eye contact, perseverative behavior, hand stereotypies, and tactile defensiveness.

Due to ongoing symptomatology, the patient began taking a liquid preparation containing 63.9% CBD, 4% cannabichromene, 3.4% THC, and 0.7% phenylbiguanide, delivered orally by a 1-mL syringe. The patient's parents obtained the solution independent of their physician. Between 0.05 and 0.1 mL (i.e., 32.0–63.9 mg CBD) of the oral solution was delivered in the morning, once per day for 6 weeks, during which time other therapies remained unchanged.

During the first week of treatment with the CBD+ solution, the patient's family noticed that his anxiety level was reduced and he was able to explore and participate in more activities with less social avoidance. His facility with language increased, as shown by greater capacity to engage in longer more meaningful conversations. The quality and duration of his sleep also improved; he no longer awoke and wandered in the middle of the night. His symptoms of anxiety and linguistic skills continued to improve over the 6-week course of treatment with the CBD+ solution. His parents have continued him on a stable dose of 0.1 mL daily now for 2 years and have observed sustained symptom improvement.

Patient 3 is a 22-year-old female who was diagnosed with FXS at 9 years of age with a full mutation of >200 CGG repeats. She met all of her early milestones appropriately, but at around 3 to 4 years of age, she developed quite significant anxiety and panic attacks. There was mild benefit associated with initiation of psychological therapies, although her mother described difficulties with new settings, social anxiety, frequent negative perseverative thoughts, and ongoing panic attacks that would vary in frequency depending on her routine and social supports.

Starting in the fourth grade, she had mild academic challenges that were supported with a 504 educational plan through the end of high school. Ongoing anxiety was present and trials of St. John's Wort and other supplements were minimally helpful. She did not receive any other medication treatment. She graduated from college with academic supports, with continued periods of significant anxiety symptoms, social withdrawal, and panic attacks. After college, she began work as an educational aide in a public school, with an exacerbation of anxiety due to this transition into adulthood and pressures of increased independence.

At 22 years of age, her parents provided her with a liquid formulation of hemp oil containing ∼43 mg of CBD daily (Charlotte's Web™ Everyday Advanced; CWB Holdings, Inc., Denver, CO), which she began taking. She described feeling calmer, with fewer perseverative worries, and a cessation of panic attacks. This led to more interactions and activities with peers and improved performance at work. Her mother also noted that she became more engaged socially, calmed more easily when frustrated, and was less likely to fixate on negative aspects of various situations. She missed about 1 week of dosing when on a family vacation out of town, and after a few days without treatment, she experienced recurrence of anxiety symptoms and reemergence of panic attacks. These resolved after she was home and able to restart her CBD+ treatment. She is currently working full time and living independently. She has continued CBD+ treatment for two and a half years with sustained therapeutic benefit.