Neuropharmacology
July 18, 2015
Aisling Spain, Clare Howarth, Alexandre A. Khrapitchev et al.
45 citations
Psilocin, the active metabolite of psilocybin, causes region-specific changes in brain activity measured by pharmacological MRI (phMRI). In rats, a high dose (2 mg/kg) increased phMRI signals in olfactory, limbic, and visual areas while decreasing signals in somatosensory and motor cortices. However, direct comparison of neuronal activity (local field potentials) and blood flow showed that psilocin reduced neuronal responses to sensory stimuli but enhanced the accompanying blood flow response. This dissociation indicates that phMRI signal changes reflect not only neuronal activity but also drug-induced alterations in neurovascular coupling, complicating the interpretation of hemodynamic neuroimaging data in pharmacological studies.
Current topics in behavioral neurosciences
January 1, 2024
Trevor Sharp, Helen Collins
40 citations
SSRIs remain widely prescribed for depression and anxiety, but their therapeutic action is now understood to involve more than simply raising serotonin levels. The current view is that increased serotonin initiates downstream signaling that triggers neural plasticity—functional and structural changes in the brain. These plasticity changes are thought to help relearn emotional experiences, improving mood. This framework also informs research on fast-acting antidepressants like ketamine and psychedelics. However, direct evidence linking plasticity changes to behavioral effects is lacking, and predictions about broader medical applications remain unfulfilled. The mechanisms behind SSRI discontinuation syndrome are less understood, though evidence of rebound increases in serotonin neuron excitability after stopping treatment offers a starting point for future research, drawing parallels with withdrawal from other psychotropic drugs.
Translational Psychiatry
February 23, 2022
Trevor Sharp, Christopher W. Thomas, Cristina Blanco‐duque et al.
40 citations
Psilocin, a serotonergic psychedelic, alters sleep architecture and cortical activity in mice. Acute administration delays REM sleep onset, reduces NREM sleep maintenance for about three hours, and enhances a 4 Hz EEG oscillation. No long-term changes in sleep-wake quantity occur. Psilocin does not affect the overall homeostatic sleep rebound after sleep deprivation, but it slows the recovery of slow-wave activity in the medial prefrontal and surrounding cortex. These findings suggest psilocin influences both global vigilance state control and local sleep homeostasis, which may relate to its antidepressant effects.
British journal of pharmacology
June 22, 2025
Aurelija Ippolito, Sridhar Vasudevan, Shaun Hurley et al.
9 citations
Serotonergic psychedelic drugs are being studied as treatments for psychiatric disorders like major depression. All such drugs activate the 5-HT2A receptor, but some 5-HT2A receptor agonists are not psychedelic. This investigation tested six psychedelic drugs (psilocin, 5-MeO-DMT, LSD, mescaline, 25B-NBOMe, and DOI) and three non-psychedelic drugs (lisuride, TBG, and IHCH-7079) for their effects on Gq-coupled and β-arrestin2 signaling pathways in cells expressing human 5-HT2A receptors. All psychedelic drugs were unbiased partial agonists at both pathways. The non-psychedelic drugs were not distinguished by signaling bias but showed the lowest signaling efficacy among all drugs tested, a finding confirmed in rat C6 cells. Low 5-HT2A receptor signaling efficacy may explain why some agonists lack psychedelic effects.
British journal of pharmacology
May 23, 2025
Trevor Sharp, Aurelija Ippolito
8 citations
Psychedelic drugs like LSD and psilocin, once banned and stigmatized, are now being studied for their long-lasting benefits in mental illnesses such as depression, addictions, and anxiety disorders. Their powerful hallucinatory effects are thought to be mediated by agonist action at 5-HT2A receptors, but the link between the psychedelic experience and therapeutic outcomes remains uncertain. Recent research has identified a new class of 5-HT2A receptor agonists that may retain therapeutic potential without inducing hallucinations, with biased signalling, partial agonism, and increased neuroplasticity offering possible explanations for their effects. This article explores the neuropsychopharmacological properties of both hallucinogenic and non-hallucinogenic 5-HT2A receptor agonists as potential novel psychiatric treatments.
bioRxiv (Cold Spring Harbor Laboratory)
December 11, 2022
Benjamin J. B. Bréant, José Prius-Mengual, David M. Bannerman et al.
5 citations
preprint
Psychedelics like 5-MeO-DMT induce a dissociated state of arousal that combines features of waking and sleep. In freely moving adult male mice, the drug produced sleep-like slow waves in the cortex alongside marked pupil dilation, even while animals were awake and moving. REM sleep was strongly suppressed, similar to the effect of conventional antidepressants. This mixed brain state may explain psychedelic effects such as dream-like hallucinations and reopening of the critical period for plasticity.
bioRxiv (Cold Spring Harbor Laboratory)
December 11, 2022
Benjamin J. B. Bréant, José Prius-Mengual, David M. Bannerman et al.
5 citations
preprint
Psychedelics like 5-MeO-DMT induce a dissociated state of arousal that combines features of waking and sleep. In freely moving adult male mice, the drug produced sleep-like slow waves in the cortex alongside marked pupil dilation, even while animals were awake and moving. REM sleep was strongly suppressed, similar to the effect of conventional antidepressants. This mixed brain state may explain psychedelic effects such as dream-like hallucinations and reopening of the critical period for plasticity.
bioRxiv Preprint Server
February 16, 2021
Christopher W. Thomas, Cristina Blanco-Duque, Benjamin Bréant et al.
4 citations
preprint
A single dose of psilocin, the active compound in psychedelic mushrooms, alters sleep architecture in mice. Psilocin delayed the onset of REM sleep and reduced NREM sleep maintenance for about three hours after injection, without causing long-term changes in sleep quantity. The acute brain response featured enhanced oscillations around 4 Hz. When mice were sleep-deprived, psilocin did not change the overall amount of sleep rebound, but it slowed the recovery of slow wave activity in the medial prefrontal cortex. These findings suggest that psilocin affects both global vigilance and local sleep homeostasis, which may relate to its potential antidepressant effects.
bioRxiv (Cold Spring Harbor Laboratory)
June 16, 2024
Aurelija Ippolito, Sridhar R. Vasudevan, Shaun Hurley et al.
1 citation
preprint
All psychedelic drugs tested were unbiased, partial agonists at the 5-HT2A receptor, activating G-protein and β-arrestin2 pathways equally. Non-psychedelic drugs lisuride and TBG were not biased either, but they showed the lowest signalling efficacy among all compounds. Low efficacy at the 5-HT2A receptor, not biased signalling, may explain why some 5-HT2A agonists are not psychedelic.
bioRxiv (Cold Spring Harbor Laboratory)
June 16, 2024
Aurelija Ippolito, Sridhar R. Vasudevan, Shaun Hurley et al.
1 citation
preprint
All psychedelic drugs tested were unbiased, partial agonists at the 5-HT2A receptor, activating G-protein and β-arrestin2 pathways equally. Non-psychedelic drugs lisuride and TBG were not biased either, but they showed the lowest signalling efficacy among all compounds. Low efficacy at the 5-HT2A receptor, not biased signalling, may explain why some 5-HT2A agonists are not psychedelic.