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Psilocybin (a serotonin 2A, or 5-HT 2A , receptor agonist) has shown preliminary efficacy as a treatment for mood and substance use disorders. The current report utilized positron emission tomography (PET) with the selective 5-HT 2A receptor inverse agonist radioligand [ 11 C]MDL 100,907 (a.k.a. M100,907) and cortical regions of interest (ROIs) derived from resting-state functional connectivity-based brain parcellations in 4 healthy volunteers (2 females) to determine regional occupancy/target engagement of 5-HT 2A receptors after oral administration of a psychoactive dose of psilocybin (10 mg/70 kg). Average 5-HT 2A receptor occupancy across all ROIs was 39.5% (± 10.9% SD). Three of the ROIs with greatest occupancy (between 63.12 and 74.72% occupancy) were within the default mode network (subgenual anterior cingulate and bilateral angular gyri). However, marked individual variability in regional occupancy was observed across individuals. These data support further investigation of the relationship between individual differences in the acute and enduring effects of psilocybin and the degree of regional 5-HT 2A receptor occupancy., Competing Interests: RG is on the Board of Directors of the Heffter Research Institute. YZ is employed by the company United Imaging Intelligence. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Barrett, Zhou, Carbonaro, Roberts, Smith, Griffiths and Wong.)

Novel synthetic compounds have been available for decades as quasi-legal alternatives to controlled substances. The hallucinogen-like effects of eight novel substituted tryptamines were evaluated to determine their potential abuse liability. Male Sprague-Dawley rats were trained to discriminate 2,5-dimethoxy-4-methylamphetamine (DOM, 0.5 mg/kg, i.p., 30 min) from saline. 4-Acetoxy- N , N -diethyltryptamine (4-AcO-DET), 4-hydroxy- N -methyl- N -ethyltryptamine (4-OH-MET), 4-hydroxy- N , N -diethyltryptamine (4-OH-DET), 4-acetoxy- N -methyl- N -isopropyltryptamine (4-AcO-MiPT), 4-acetoxy- N , N -dimethyltryptamine (4-AcO-DMT), 4-hydroxy- N , N -dimethyltryptamine (4-OH-DMT, psilocin), 5-methoxy- N -methyl- N -isopropyltryptamine (5-MeO-MiPT), 4-acetoxy- N , N -diisopropyltryptamine (4-AcO-DiPT), and 4-hydroxy- N , N -diisopropyltryptamine (4-OH-DiPT) were tested for their ability to substitute for the discriminative stimulus effects of DOM. All test compounds fully substituted for DOM with potencies less than or equal to that of DOM. 4-OH-MET, 4-OH-DET, 4-OH-DMT, and 4-AcO-DMT decreased response rate at doses that fully substituted. Because the test compounds produced DOM-like discriminative stimulus effects, they may have similar abuse liability as DOM. 4-Acetoxy substituted compounds were less potent than 4-hydroxy substituted compounds, and the N , N -diisopropyl compounds were less potent than the dimethyl, diethyl, N -methyl- N -ethyl, and N -methyl- N -isopropyl compounds., Competing Interests: The authors declare no competing financial interest., (© 2020 American Chemical Society.)