Pharmacodynamics Binding affinities of<unk>  for various receptors. The lower the dissociation constant (Ki), the more strongly<unk>  binds to that receptor (i.e. with higher affinity). The horizontal line represents an approximate value for human plasma concentrations of<unk> , and hence, receptor affinities that are above the line are unlikely to be involved in<unk> 's effect. Data averaged from data from the Ki Database Most serotonergic psychedelics are not significantly dopaminergic, and<unk>  is therefore atypical in this regard. The agonism of the D2 receptor by<unk>  may contribute to its psychoactive effects in humans.<unk>  binds to most serotonin receptor subtypes except for the 5-HT3 and 5-HT4 receptors. However, most of these receptors are affected at too low affinity to be sufficiently activated by the brain concentration of approximately 10–20 nM. In humans, recreational doses of<unk>  can affect 5-HT1A (Ki=1.1nM), 5-HT2A (Ki=2.9nM), 5-HT2B (Ki=4.9nM), 5-HT2C (Ki=23nM), 5-HT5A (Ki=9nM in cloned rat tissues), and 5-HT6 receptors (Ki=2.3nM). Although not present in humans, 5-HT5B receptors found in rodents also have a high affinity for<unk> . The psychedelic effects of<unk>  are attributed to cross-activation of 5-HT2A receptor heteromers. Many but not all 5-HT2A agonists are psychedelics and 5-HT2A antagonists block the psychedelic activity of<unk> .<unk>  exhibits functional selectivity at the 5-HT2A and 5HT2C receptors in that it activates the signal transduction enzyme phospholipase A2 instead of activating the enzyme phospholipase C as the endogenous ligand serotonin does. Exactly how<unk>  produces its effects is unknown, but it is thought that it works by increasing glutamate release in the cerebral cortex and therefore excitation in this area, specifically in layers IV and V.<unk> , like many other drugs of recreational use, has been shown to activate DARPP-32-related pathways. The drug enhances dopamine D2 receptor protomer recognition and signaling of D2–5-HT2A receptor complexes, which may contribute to its psychotic effects.<unk>  has been shown to have low affinity for H1 receptors, displaying antihistamine effects.<unk>  is a biased agonist that induces a conformation in serotonin receptors that preferentially recruits β-arrestin over activating G proteins.<unk>  also has an exceptionally long residence time when bound to serotonin receptors lasting hours, consistent with the long lasting effects of<unk>  despite its relatively rapid clearance. A crystal structure of 5-HT2B bound to<unk>  reveals an extracellular loop that forms a lid over the<unk>  end of the binding cavity which explains the slow rate of<unk>  unbinding from serotonin receptors. The related lysergamide lysergic<unk>  amide (LSA) that lacks the<unk>  moiety is far less hallucinogenic in comparison. Pharmacokinetics The effects of<unk>  normally last between 6 and 12 hours depending on dosage, tolerance, body weight, and age. The Sandoz prospectus for "Delysid" warned: "intermittent disturbances of affect may occasionally persist for several days." Aghajanian and Bing (1964) found<unk>  had an elimination half-life of only 175 minutes (about 3 hours). However, using more accurate techniques, Papac and Foltz (1990) reported that 1 µg/kg oral<unk>  given to a single male volunteer had an apparent plasma half-life of 5.1 hours, with a peak plasma concentration of 5 ng/mL at 3 hours post-dose. The pharmacokinetics of<unk>  were not properly determined until 2015, which is not surprising for a drug with the kind of low-μg potency that<unk>  possesses. In a sample of 16 healthy subjects, a single mid-range 200 μg oral dose of<unk>  was found to produce mean maximal concentrations of 4.5 ng/mL at a median of 1.5 hours (range 0.5–4 hours) post-administration. Concentrations of<unk>  decreased following first-order kinetics with a half-life of 3.6±0.9 hours and a terminal half-life of 8.9±5.9 hours. The effects of the dose of<unk>  given lasted for up to 12 hours and were closely correlated with the concentrations of<unk>  present in circulation over time, with no acute tolerance observed. Only 1% of the drug was eliminated in urine unchanged, whereas 13% was eliminated as the major metabolite 2-oxo-3-hydroxy-LSD (O-H-LSD) within 24 hours. O-H-LSD is formed by cytochrome P450 enzymes, although the specific enzymes involved are unknown, and it does not appear to be known whether O-H-LSD is pharmacologically active or not. The oral bioavailability of<unk>  was crudely estimated as approximately 71% using previous data on intravenous administration of<unk> . The sample was equally divided between male and female subjects and there were no significant sex differences observed in the pharmacokinetics of<unk> .
Lysergic acid diethylamide
Brevetoxin
Anatoxin-a
Bungarotoxin
Botulinum toxin
Charybdotoxin
Muscimol
N1-Methyl-lysergic acid diethylamide