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.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 , 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.Based on its morbidity and prevalence, its association with a number of co-occurring problems, such as seizures, anxiety, and sleep disturbances,13 and the paucity of efficacious therapeutic options, FXS represents an important public health problem.The present article provides a brief review of recent research that documents the promise of CBD as a therapeutic agent for patients with FXS. Also described are the cases of one pediatric and two adult patients with FXS for whom CBD+ treatment appears to have contributed to positive changes in anxiety and/or language skills, with no observed adverse events. Before starting CBD+ treatment, Patient 1 experienced heightened symptoms of anxiety, frequent tantrums, and sleep difficulties. Over the first month of CBD+ monotherapy, and subsequent 3 months of CBD+ treatment combined with speech, language, and occupational therapy, the patient made considerable progress with feeding and weight gain,ebb and flow exhibited better oral–motor coordination, had decreased social avoidance and sensory sensitivities, and showed improvements in attention span/engagement, the frequency and severity of atypical motor movements, and general level of hyperactivity.
Upon discontinuation of CBD+ treatment, the patient’s prior symptoms reemerged. While a strong therapy program and later addition of other medications likely contributed to this patient’s overall developmental progress, the temporally related improvements in anxiety, feeding, tantrums, and sleep—evident when CBD+ treatment was initially started as monotherapy and then reinstated following cessation—are compelling support for the benefits of CBD+ treatment for this patient. By maintaining his adaptive functioning scores from 1 to 3 years of age, the patient demonstrated a significant improvement over the characteristic developmental trajectory of young male children with FXS, where a decrease in adaptive functioning scores is typically observed between 2 and 6 years of age.Patient 2 showed a similarly encouraging response to CBD+ treatment, experiencing reduced anxiety, improved use of language, and better sleep within 1 week of beginning treatment with a CBD+ solution. It is also remarkable that the patient continued to demonstrate symptom improvement over the initial 6-week treatment period, with longer-term follow-up highlighting continued use of CBD+ solution with sustained benefit. In Patient 3, the use of CBD+ solution was also associated with a positive effect in a higher functioning female with FXS and long-standing anxiety symptoms. Similar to Patient 1, treatment discontinuation was associated with a recurrence of anxiety symptoms, with reinitiation of CBD+ treatment leading to symptom improvement and resulting long-term use. The present findings, coupled with the available preclinical data, highlight the potential for CBD as an intervention for individuals with FXS. The existing literature combines to demonstrate that CBD may positively impact individuals with FXS through many mechanisms, including the endocannabinoid system, GABA, and serotonin. While a number of drugs have been developed to target specific systems , CBD has the potential to yield a multifaceted benefit to individuals with FXS due to its multiple mechanisms of action. CBD has not only been shown to be generally well tolerated relative to other treatments used in this population,but also numerous studies have documented its benefits in terms of sleep quality,anxiety ,and cognitive impairment—symptoms experienced by the individuals profiled in the present case series. These data serve as stepping stones upon which proof-of-concept open-label trials should be based. As with many patients, however, those discussed herein used orally administered botanical CBD+ solution that is not regulated by the Food and Drug Administration and, thus, inconsistencies in availability, quality, purity, and labeling make research, interpretations, and clinical recommendations challenging.
The present case series is limited by its reliance on manufacturer reported cannabinoid content as well as the lack of multi-method assessment of patient symptomatology, including clinimetric data. The observed clinical benefit of CBD+ treatment in case studies, particularly with respect to caregiver-reported behavioral outcomes, must also be interpreted with caution given the significant placebo effects that have been documented in clinical trials of CBD.Only placebo-controlled trials will be able to elucidate the true therapeutic effects of CBD/ CBD+ treatment on FXS symptomatology. Until rigorous clinical trials have demonstrated the efficacy of CBD/CBD+ treatment for FXS, current treatments for the many behavioral problems associated with FXS should be utilized before off-label use of CBD+ products. In an effort to overcome existing limitations, future studies should independently test patient samples to confirm actual constituents of each CBD+ preparation and utilize well-validated caregiver-reported assessments of anxiety and other FXS symptomatology, in addition to unstructured caregiver- and clinician based reports, in an attempt to more completely track each patient’s course while in clinical care. Due to inconsistencies observed in many oral botanical preparations, rigorous examinations of pharmaceutical-grade preparations of CBD should be explored as potential treatments for children and adolescents with FXS.Adolescence is a time of subtle, yet dynamic brain changes that occur in the context of major physiological, psychological, and social transitions. This juncture marks a gradual shift from guided to independent functioning that is analogized in the protracted development of brain structure. Growth of the prefrontal cortex, limbic system structures, and white matter association fibers during this period are linked with more sophisticated cognitive functions and emotional processing, useful for navigating an increasingly complex psychosocial environment. Despite these developmental advances, increased tendencies toward risk-taking and heightened vulnerability to psychopathology are well known within the adolescent milieu. Owing in large part to progress and innovation in neuroimaging techniques, appreciable levels of new information on adolescent neuro development are breaking ground. The potential of these methods to identify biomarkers for substance problems and targets for addiction treatment in youth are of significant value when considering the rise in adolescent alcohol and drug use and decline in perceived risk of substance exposure . What are the unique characteristics of the adolescent brain? What neural and behavioral profiles render youth at heightened risk for substance use problems, and are neurocognitive consequences to early substance use observable? Recent efforts have explored these questions and brought us to a fuller understanding of adolescent health and interventional needs. This paper will review neuro developmental processes during adolescence,dry racks discuss the influence of substance use on neuromaturation as well as probable mechanisms by which these substances influence neural development, and briefly summarize factors that may enhance risk-taking tendencies.
Finally, we will conclude with suggestions for future research directions.The developmental trajectory of grey matter follows an inverted parabolic curve, with cortical volume peaking, on average, around ages 12–14, followed by a decline in volume and thickness over adolescence . Widespread supratentorial diminutions are evident, but show temporal variance across regions . Declines begin in the striatum and sensorimotor cortices , progress rostrally to the frontal poles, then end with the dorsolateral prefrontal cortex , which is also late to myelinate . Longitudinal charting of brain volumetry from 13–22 years of age reveals specific declines in medial parietal cortex, posterior temporal and middle frontal gyri, and the cerebellum in the right hemisphere, coinciding with previous studies showing these regions to develop late into adolescence . Examination of developmental changes in cortical thickness from 8–30 years of age indicates a similar pattern of nonlinear declines, with marked thinning during adolescence. Attenuations are most notable in the parietal lobe, and followed in effect size by medial and superior frontal regions, the cingulum, and occipital lobe . The mechanisms underlying cortical volume and thickness decline are suggested to involve selective synaptic pruning of superfluous neuronal connections, reduction in glial cells, decrease in neuropil and intra-cortical myelination . Regional variations in grey matter maturation may coincide with different patterns of cortical development, with allocortex, including the piriform area, showing primarily linear growth patterns, compared to transition cortex demonstrating a combination of linear and quadratic trajectories, and isocortex demonstrating cubic growth curves . Though the functional implications of these developmental trajectories are unclear, isocortical regions undergo more protracted development and support complex behavioral functions. Their growth curves may reflect critical periods for development of cognitive skills as well as windows of vulnerability for neurotoxic exposure or other developmental perturbations.In contrast to grey matter reductions, white matter across the adolescent years shows growth and enhancement of pathways . This is reflected in white matter volume increase, particularly in fronto-parietal regions . Diffusion tensor imaging , a neuroimaging technique that has gained widespread use over the past decade, relies on the intrinsic diffusion properties of water molecules and has afforded a view into the more subtle microstructural changes that occur in white matter architecture. Two common scalar variables derived from DTI are fractional anisotropy , which describes the directional variance of diffusional motion, and mean diffusivity , an indicator of the overall magnitude of diffusional motion. These measures index relationships between signal intensity changes and underlying tissue structure, and provide descriptions of white matter quality and architecture . High FA reflects greater fiber organization and coherence, myelination and/or other structural components of the axon, and low MD values suggest greater white matter density . Studies of typically developing adolescents show increases in FA and decreases in MD. These trends continue through early adulthood in a nearly linear manner , though recent data suggest an exponential pattern of anisotropic increase that may plateau during the late-teens to early twenties . Areas with the most prominent FA change during adolescence are the superior longitudinal fasciculus, superior corona radiata, thalamic radiations, and posterior limb of the internal capsule . Other projection and association pathways including the corticospinal tract, arcuate fasciculus, cingulum, corpus callosum, superior and mid-temporal white matter, and inferior parietal white matter show anisotropic increases as well . Changes in subcortical and deep grey matter fibers are more pronounced, with less change in compact white matter tracts comprising highly parallel fibers such as the internal capsule and corpus callosum . Fiber tracts constituting the fronto-temporal pathways appear to mature relatively later , though comparison of growth rates among tracts comes largely from cross-sectional data that present developmental trends. The neurobiological mechanisms contributing to FA increases and MD decreases during adolescence are not entirely understood, but examination of underlying diffusion dynamics point to some probable processes. For example, decreases in radial diffusivity , diffusion that occurs perpendicular to white matter pathways, suggests increased myelination, axonal density, and fiber compactness , but have not been uniformly observed to occur during adolescence. Similarly, changes in axial diffusivity , diffusion parallel to the fibers’ principle axis, show discrepant trends, with some studies documenting decreases , and others increases in this index . Decreases in AD may be attributable to developing axon collaterals, whereas increases may reflect growth in axon diameter, processes which are both likely to occur during adolescence. Technical and demographic differences such as imaging parameters, inter-scan intervals, age range, and gender ratios may account for divergent findings. Both grey matter volume decreases and FA increases in frontoparietal regions occur well into adolescence, suggesting a close spatiotemporal relationship .