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A single dose of psilocybin, a psychedelic that acutely causes distortions of space-time perception and ego dissolution, produces rapid and persistent therapeutic effects in human clinical trials1-4. In animal models, psilocybin induces neuroplasticity in cortex and hippocampus5-8. It remains unclear how human brain network changes relate to subjective and lasting effects of psychedelics. Here we tracked individual-specific brain changes with longitudinal precision functional mapping (roughly 18 magnetic resonance imaging visits per participant). Healthy adults were tracked before, during and for 3 weeks after high-dose psilocybin (25 mg) and methylphenidate (40 mg), and brought back for an additional psilocybin dose 6-12 months later. Psilocybin massively disrupted functional connectivity (FC) in cortex and subcortex, acutely causing more than threefold greater change than methylphenidate. These FC changes were driven by brain desynchronization across spatial scales (areal, global), which dissolved network distinctions by reducing correlations within and anticorrelations between networks. Psilocybin-driven FC changes were strongest in the default mode network, which is connected to the anterior hippocampus and is thought to create our sense of space, time and self. Individual differences in FC changes were strongly linked to the subjective psychedelic experience. Performing a perceptual task reduced psilocybin-driven FC changes. Psilocybin caused persistent decrease in FC between the anterior hippocampus and default mode network, lasting for weeks. Persistent reduction of hippocampal-default mode network connectivity may represent a neuroanatomical and mechanistic correlate of the proplasticity and therapeutic effects of psychedelics.

Methylphenidate (MPH) is highly efficacious in reducing symptoms of attention-deficit/hyperactivity disorder (ADHD) in children. Generally increased doses are found to result in better symptom control; however, it remains unclear whether this pattern can be observed at the individual level, given the large heterogeneity in individual dose-response relationships and observed placebo responses. A double-blind, randomized, placebo-controlled cross-over trial was used to compare weekly treatment with placebo and 5, 10, 15 and 20 mg of MPH twice daily on parent and teacher ratings of child ADHD symptoms and side effects. Participants were 5-13-year-old children with a DSM-5 diagnosis of ADHD (N = 45). MPH response was assessed at group and individual levels and predictors of individual dose-response curves were examined. Mixed model analysis showed positive linear dose-response curves at group level for parent and teacher rated ADHD symptoms and parent rated side effects, but not for teacher rated side effects. Teachers reported all dosages to improve ADHD symptoms compared to placebo, while parents only reported > 5 mg/dose as effective. At the individual level, most (73-88%) children, but not all, showed positive linear dose-response curves. Higher severity of hyperactive-impulsive symptoms and lower internalizing problems, lower weight, younger age and more positive opinions towards diagnosis and medication partly predicted steeper linear individual dose-response curves. Our study confirms that increased doses of MPH yield greater symptom control at a group level. However, large interindividual variation in the dose-response relationship was found and increased doses did not lead to greater symptom improvement for all children. This trial was registered in the Netherlands trial register (# NL8121).

Rationale: The Diagnostic and Statistical Manual of Mental Disorders (Fifth Edition) classifies attention deficit hyperactivity disorder (ADHD) as a neurodevelopmental disorder that interferes with human functioning and development. As the clinical presentation of ADHD involves a deficiency in executive function, neurocognitive deficits involving distinctive neuropathological changes must be present for clinical diagnosis. Objectives: The vesicular monoamine transporter (VMAT), specifically VMAT-2, plays a role in ADHD pathogenesis. In addition, experimental data show that the stimulants (amphetamines and methylphenidate) are first-line treatments for the condition because of their extensive interaction with VMAT-2. The interactions of peptides, bupropion, and nutritional supplements with VMAT-2 receptors have been researched, but more evidence is needed to elucidate their pharmacodynamic properties. Therefore, this literature review evaluated the current pharmacological treatment modalities, peptides, and nutritional supplements for ADHD that target the VMAT-2 system. Methods, results, and conclusions: We obtained relevant studies from several platforms, including the National Center for Biotechnology, Clinical Key, Access Medicine, and PubMed. From the results of these studies, we observed that stimulants interact highly with the VMAT-2 transporter, with omega-3 fatty acids, peptides, and bupropion exerting some modulatory activity on VMAT-2. These agents should be considered for the future treatment of ADHD, although clinical-level research involving human participants is necessary. [ABSTRACT FROM AUTHOR]

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