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Background: Psilocybin, a psychoactive serotonin receptor partial agonist, has been reported to acutely reduce clinical symptoms of depressive disorders. Psilocybin’s effects on cognitive function have not been widely or systematically studied. Aim: The aim of this study was to explore the safety of simultaneous administration of psilocybin to healthy participants in the largest randomised controlled trial of psilocybin to date. Primary and secondary endpoints assessed the short- and longer-term change in cognitive functioning, as assessed by a Cambridge Neuropsychological Test Automated Battery (CANTAB) Panel, and emotional processing scales. Safety was assessed via endpoints which included cognitive function, assessed by CANTAB global composite score, and treatment-emergent adverse event (TEAE) monitoring. Methods: In this phase 1, randomised, double-blind, placebo-controlled study, healthy participants ( n = 89; mean age 36.1 years; 41 females, 48 males) were randomised to receive a single oral dose of 10 or 25 mg psilocybin, or placebo, administered simultaneously to up to six participants, with one-to-one psychological support – each participant having an assigned, dedicated therapist available throughout the session. Results: In total, 511 TEAEs were reported, with a median duration of 1.0 day; 67% of all TEAEs started and resolved on the day of administration. There were no serious TEAEs, and none led to study withdrawal. There were no clinically relevant between-group differences in CANTAB global composite score, CANTAB cognitive domain scores, or emotional processing scale scores. Conclusions: These results indicate that 10 mg and 25 mg doses of psilocybin were generally well tolerated when given to up to six participants simultaneously and did not have any detrimental short- or long-term effects on cognitive functioning or emotional processing. Clinical Trial Registration: EudraCT ( https://www.clinicaltrialsregister.eu/ ) number: 2018-000978-30.

An in-vitro superfusion system was used to study the effects of the endogenous opioid peptides [Met]-enkephalin (and its long-lasting analogue [D-Ala2,Met]-enkephalinamide), [Leu]-enkephalin and beta-endorphin and of the opiate antagonist naloxone, on the secretion of LHRH from the mediobasal hypothalamus of the cockerel. The effects of the compounds on both basal release of LHRH and on release stimulated by a depolarizing pulse of increased extracellular potassium ion (64 mmol/l) were investigated. None of the endogenous opioid peptides altered basal release of LHRH; however, both [Met]-enkephalin (10 mumol/l) and [D-Ala2,Met]-enkephalinamide (1 mumol/l) significantly (P less than 0.05) reduced the response to depolarization. Neither [Leu]-enkephalin nor beta-endorphin (0.1-10 mumol/l) were effective. Naloxone (1 mumol/l) administered alone significantly (P less than 0.05) increased basal release of LHRH and abolished the inhibitory effects of [Met]-enkephalin and [D-Ala2,Met]-enkephalinamide on depolarization-induced release. These results suggest that the endogenous opioid peptides exert a tonic inhibitory influence on LHRH secretion by the mediobasal hypothalamus of the cockerel.

Opiatergic inhibition of [Gln8]LHRH secretion from the mediobasal hypothalamus of the cockerel (Gallus domesticus) was studied during sexual maturation in a hypothalamic superfusion system. The basal and depolarization-induced release of [Gln8]LHRH in the presence and absence of the opiate agonists [D-Ala2,N-Phe4-Gly-ol5]enkephalin (DAGO), which binds selectively to the mu-receptor subtype, and [D-Thr2,L-Leu5] enkephalyl-Thr (DTLET), which binds selectively to the delta-receptor subtype, and of the opiate antagonist naloxone was assessed in tissue obtained from birds at 4, 8, 12, 16, 20, and 24 weeks of age. Concentrations of LH and testosterone in plasma obtained from cockerels at the same ages rose progressively from 8-16 weeks of age. Between 16 and 20 weeks of age testosterone increased about 3-fold, whereas LH decreased significantly. Thereafter, LH rose in the face of sustained plasma testosterone concentrations. The initial rise in plasma LH concentrations was associated with a rise in the basal release of [Gln8]LHRH and a decrease in the ability of DAGO to inhibit and of naloxone to stimulate [Gln8]LHRH release. The delta-agonist DTLET did not affect secretion at any time. The fall in plasma LH at 20 weeks occurred despite an increased release of [Gln8]LHRH, whereas the subsequent rise in LH release occurred at a time when the pattern of [Gln8]LHRH release remained unchanged. These observations support the proposition that a decrease in tonic opioid inhibition of [Gln8]LHRH secretion during sexual maturation may explain why plasma LH concentrations rise in the face of sustained plasma testosterone concentrations. The changes in plasma LH concentrations that occur in the immediate pubertal period may be due, however, to a direct action of testosterone on the anterior pituitary lobe.