CBD+ solution was the only medication used in treatment during this time

The condition has been estimated to affect *1:4000 males and 1:7000 females.Although both sexes are susceptible, males with FXS typically exhibit more severe symptoms compared with females because the single X chromosome in males is usually fully methylated and not producing FMRP6 ; females typically have some FMRP expression from the FMR1 gene on their second unaffected X chromosome.Males with FXS are far more likely than females to exhibit significant intellectual and developmental disabilities .Among individuals with the full mutation , symptoms of FXS vary by age and sex, but often include anxiety , social avoidance , stereotyped behaviors , attention-deficit/ hyperactivity disorder , autism spectrum disorders , intellectual disability , aggression , disrupted sleep patterns , and epilepsy , as well as macroorchidism , prominent ears , long faces , soft skin , and hyper extensible joints .Traditional allopathic treatment of these patients may involve medications to address issues with sleep , anxiety , hyperactivity and deficits in attention , and seizures .Yet, for many patients with FXS, the aforementioned pharmacotherapies, when used alone or in combination, have sub-optimal efficacy and tolerability,suggesting a persistent unmet medical need for novel, interventional treatment approaches for patients with FXS. Because the clinical abnormalities in these patients have been linked, at least in part, with dysregulation of the endocannabinoid system, we briefly review recent research characterizing the involvement of the endocannabinoid system in FXS and present the cases of three individuals with FXS who experienced functional benefit after treatment with cannabidiol – enriched preparations.The endocannabinoid system consists of receptors in the brain and peripheral tissues that are involved in numerous physiological processes as well as the endocannabinoids, N-arachidonoylethanolamine and 2-arachidonoylglycerol . The endocannabinoids bind to the G-protein-coupled receptors, cannabinoid 1 and 2 ,and modulate synaptic transmission throughout the central nervous system.Receptors are distributed throughout the body, with CB1 receptors abundantly expressed in the brain and present at lower concentrations in a variety of peripheral tissues and cells and CB2 receptors expressed primarily in the immune and hematopoietic systems, as well as in the brain, pancreas, and bone.CBD, the primary, noneuphoric exogenous phytocannabinoid in cannabis, may attenuate the loss of endogenous cannabinoid signaling observed in preclinical models of FXS, allowing a component of the FMRP deficiency inherent in FXS to be bypassed. Specifically, many abnormalities seen in FXS appear to be rooted in dysregulation of the endocannabinoid pathways in the central nervous system, with a reduction of endogenous stimulation of endocannabinoid receptors.CBD has the capacity to interact with an FXS-compromised endocannabinoid system. Indeed, deletion of FMRP within a mouse model of FXS led to reduced production of 2-AG, decreasing activation of CB1 receptors in the central nervous system.CBD has been shown to increase 2-AG availability,cannabis square pot potentially attenuating or reversing one of the biological mechanisms of abnormal cellular function in FXS.

Importantly, CB1 protein expression appears unaffected in FMR1 knockout mice, suggesting that the downstream elements of endocannabinoid signaling can be engaged, even in the absence of FMRP.In addition to the role of 2-AG, recent work has begun to highlight the potential importance of AEA in addressing social impairment as well as deficits in learning and memory among those with FXS. In an FMR1 KO mouse model of FXS, Qin et al. demonstrated that increased levels of AEA were associated with greater cognitive performance.Similarly, Wei et al. utilized mouse models of FXS to show that AEA-mediated signaling at CB1 receptors, driven by oxytocin, controls social reward and that increasing AEA activity resulted in reductions in social impairment.Much like its impact on 2-AG, CBD has been shown to increase levels of AEA by binding to fatty acid-binding proteins, which transport AEA to the catabolic enzyme fatty acid amide hydrolase, an enzyme that breaks down AEA.Binding to fatty acidbinding proteins is thought to increase AEA availability and CB1 activation.The mechanisms underlying the potential benefits of CBD for FXS span far beyond the endocannabinoid system. Beyond providing benefit to patients with FXS through increases in 2-AG and AEA availability, CBD may positively affect synaptic plasticity. Studies of FMR1 KO mice have identified discrete alterations in synaptic plasticity in specific brain regions, including an increase in long-term depression in the hippocampus,and preclinical data suggest that reducing LTD in FMR1 KO mice requires activation of endocannabinoid receptors.Therefore, it is hypothesized that CBD may increase synaptic plasticity in FXS, facilitating one of the basic cellular mechanisms thought to be associated with learning and improvements in cognition.More recent work has also begun to identify deficits in GABA receptor expression among those with FXS. As FMRP has been shown in animal models to enhance expression of GABA receptors, the lack of FMRP among those with FXS has been associated with fewer GABA receptors.Indeed, preclinical studies in FMR1 KO mice have consistently shown down regulation of the GABA system.As CBD acts as a positive allosteric modulator of GABA-A receptors,CBD may also act to enhance the binding affinity for GABA. The impact of CBD on serotonin represents a mechanism by which CBD may aid in reduction of social anxiety and resulting avoidance experienced by patients with FXS. Indeed, the anxiolytic effects of CBD have been reported in over 30 preclinical studies, using multiple models of anxiety ,as well as in a growing number of human studies, including within-social anxiety.Several preclinical studies have identified the serotonin 1A receptor as one mechanism through which CBD exerts its anxiolytic effects.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,trim tray 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 , electroencephalography , 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 of delta-9-tetrahydrocannabinol that delivered 50 mg of CBD per day . 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. 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.

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 due to preliminary evidence of improved language and development in young children with FXS treated with sertraline.Subsequent follow-up visits 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 , 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.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 . At 3 years of age, an updated adaptive behavior assessment was obtained . 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 FXS and an IQ score in the mid-50s. Despite a medication regimen that included 60 mg of methylphenidate hydrochloride , 2.5 mg of aripiprazole, 100 mg of sertraline, 200 mg of minocycline, and 0.2 mg of clonidine , 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 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.