Serotonin

Psilocybin-induced psychosis in humans is due to serotonin-2A receptor activation, independently of dopamine stimulation.

experimental study

The potency of stimulants to release norepinephrine, not dopamine, correlated with the oral doses that produce amphetamine-type subjective effects in humans.

experimental study

80% of participants showed seven-day point prevalence abstinence at 6-month follow-up after psilocybin-assisted smoking cessation treatment.

open-label pilot study Sample size: 15

Crystal structures of two serotonin receptor subtypes reveal how ligand binding differences influence signaling mechanisms and biological responses.

structural biology study

Direct evidence of a decrease in a structural component of brain serotonin neurons in human MDMA users.

quantitative PET study

Binding affinities of psychoactive agents for 5-HT2 receptors strongly correlate with their hallucinogenic potencies in humans and with behavioral effects in animals.

observational study

A single dose of psilocybin led to a ∼10% increase in spine size and density in the mouse medial frontal cortex, driven by elevated spine formation, with changes occurring within 24 hours and persisting for at least one month.

observational cohort

MDA and MDMA cause selective degeneration of serotonin axon terminals in the rat forebrain, with MDA producing greater loss than MDMA at the same dose.

experimental study

MDMA stimulates serotonin efflux from both plasma membrane and secretory vesicle transporters through distinct mechanisms involving direct transporter interaction and pH gradient dissipation.

laboratory study

MDMA causes a biphasic depletion of cortical serotonin, with a reversible acute phase and a later neurotoxic phase specific to the (+)-stereoisomer, which can be blocked by fluoxetine.

experimental study

Crystal structures of two serotonin receptors reveal that subtle differences in ligand binding cause substantial differences in receptor signaling and biological responses, and that the same ligand can activate one or both of the two main signaling mechanisms depending on the receptor.

structural biology study

Psilocybin intake leads to significant 5-HT2AR occupancy in the human brain, and both psilocin plasma levels and 5-HT2AR occupancy are closely associated with subjective intensity ratings.

observational cohort Sample size: 8

A hallucinogenic 5-HT2A/2C receptor agonist differentially regulated BDNF mRNA expression in hippocampus and neocortex, an effect blocked by a selective 5-HT2A receptor antagonist.

experimental study

Intracellular 5-HT2ARs, not cell-surface ones, mediate the plasticity-promoting effects of psychedelics, explaining why serotonin does not engage similar plasticity mechanisms.

experimental study

LSD's slow binding kinetics at serotonin receptors may be due to a 'lid' formed by extracellular loop 2, and a mutation that increases lid mobility accelerates binding and selectively dampens β-arrestin2 recruitment.

experimental study with structural biology and molecular dynamics simulations

Proposes that daily low-dose psilocybin may induce progressive 5-HT2A receptor desensitization, with fading subjective effects marking an adaptive state rather than therapeutic failure; the hypothesis is not evidence of efficacy and requires testing.

theoretical or philosophical paper

Psilocin reverses social behavior deficits in stressed mice through activation of the serotonin 5-HT2A receptor.

experimental study using a mouse model

25CN-NBOH increases spontaneous excitatory and inhibitory synaptic transmission via action potential-dependent, 5-HT2A-independent mechanisms, while elevating intracellular calcium through 5-HT2A-dependent and glutamatergic presynaptic pathways, with no change in neuronal firing.

experimental study

Argues that 5-HT2A receptor stimulation promotes disintegration of the default mode network and increased global brain integration, facilitating a state of higher neural entropy, and proposes that this modulation is the primary neurobiological determinant of therapeutic benefits.

systematic review

Psilocybin selectively reconfigures burst coding rather than mean firing rates across cortical, thalamic, and hippocampal circuits, with most effects abolished by ketanserin, suggesting partial 5-HT2A receptor dependence.

observational cohort Sample size: 35

Argues that isotryptamines, including isoDMT, have a long history of study and are gaining renewed interest due to their potential therapeutic applications, with an isoDMT analog now in clinical trials.

review

Psilocybin, LSD, and 2C-B each induce distinct acute brain metabolic patterns, with LSD-specific hypometabolism in retrosplenial and hippocampal regions and a 2C-B-specific hypermetabolic cluster in the midbrain; one week after administration, LSD and psilocybin, but not 2C-B, show modest hypometabolism across cortical, limbic, and midbrain structures.

preclinical experimental study

Psilocybin's activation of 5-HT2A receptors and subsequent neuroplasticity mechanisms may synergistically regulate excitatory and inhibitory neurotransmitter systems relevant to tinnitus.

review

LSD and the non-brain-penetrant 5-HT2AR agonist IHCH-8110 suppress colorectal cancer growth by activating 5-HT2AR on enteric glial cells, inducing CXCL10 and IL-18 to promote CD8+ T cell recruitment and effector polarization, thereby enhancing PD-1 blockade efficacy.

preclinical study

Argues that sex and endocrine state can modulate serotonergic mechanisms relevant to psychedelic action, and that many clinical and preclinical studies lack design to test sex-by-treatment effects, limiting understanding of variability in responses.

review