Mescaline
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🧬 Receptor activity
| Target | Action | Affinity | Source | |
|---|---|---|---|---|
| 5-hydroxytryptamine receptor 2C | — | Ki 302.8 nM | CHEMBL | Target5-hydroxytryptamine receptor 2C Action— AffinityKi 302.8 nM SourceCHEMBL |
| 5-hydroxytryptamine receptor 2A | — | Ki 360 nM | CHEMBL | Target5-hydroxytryptamine receptor 2A Action— AffinityKi 360 nM SourceCHEMBL |
| 5-hydroxytryptamine receptor 2B | — | Ki 795.1 nM | CHEMBL | Target5-hydroxytryptamine receptor 2B Action— AffinityKi 795.1 nM SourceCHEMBL |
| 5-hydroxytryptamine receptor 1A | — | Ki 6900 nM | CHEMBL | Target5-hydroxytryptamine receptor 1A Action— AffinityKi 6900 nM SourceCHEMBL |
Mechanism of action
Hallucinogens, including mescaline, psilocybin, and lysergic acid diethylamide (LSD), profoundly affect perception, cognition, and mood. All known drugs of this class are 5-HT(2A) receptor (2AR) agonists, yet closely related 2AR agonists such as lisuride lack comparable psychoactive properties. Why only certain 2AR agonists are hallucinogens and which neural circuits mediate their effects are poorly understood. By genetically expressing 2AR only in cortex, we show that 2AR-regulated pathways on cortical neurons are sufficient to mediate the signaling pattern and behavioral response to hallucinogens. Hallucinogenic and nonhallucinogenic 2AR agonists both regulate signaling in the same 2AR-expressing cortical neurons. However, the signaling and behavioral responses to the hallucinogens are distinct. While lisuride and LSD both act at 2AR expressed by cortex neurons to regulate phospholipase C, LSD responses also involve pertussis toxin-sensitive heterotrimeric G(i/o) proteins and Src. These studies identify the long-elusive neural and signaling mechanisms responsible for the unique effects of hallucinogens.
The mechanism of action of mescaline is unknown. Hallucinogenic effects are believed to be due to stimulation of serotonin and dopamine receptors in the CNS.
Mescaline (3,4,5-trimethoxyphenylethylamine; MES) and its analogs, anhalinine (ANH) and methylenemescaline trimer (MMT) were investigated, using sciatic-sartorius preparations of the frog and cortical tissue from the rat. The effects of MES and its analogs were examined with respect to muscle twitch, resting membrane potential and nicotinic receptor binding. Mescaline and its analogs (10-100 microM) blocked both directly and neurally evoked twitches but their effects on neurally evoked twitches were greater than those on directly evoked twitches. Mescaline, ANH and MMT decreased amplitude of the miniature endplate and endplate potentials, decreased acetylcholine (ACh) quantal content, hyperpolarized the resting membrane potential and prolonged duration of the action potential. They did not significantly displace the binding of [125I]-alpha-bungarotoxin (alpha-BTX) to nicotinic receptors, at concentrations which blocked neuromuscular transmission. These Mescaline (3,4,5-trimethoxyphenylethylamine; MES) and its analogs, anhalinine (ANH) and methylenemescaline trimer (MMT) were investigated, using sciatic-sartorius preparations of the frog and cortical tissue from the rat. The effects of MES and its analogs were examined with respect to muscle twitch, resting membrane potential and nicotinic receptor binding. Mescaline and its analogs (10-100 microM) blocked both directly and neurally evoked twitches but their effects on neurally evoked twitches were greater than those on directly evoked twitches. Mescaline, ANH and MMT decreased amplitude of the miniature endplate and endplate potentials, decreased acetylcholine (ACh) quantal content, hyperpolarized the resting membrane potential and prolonged duration of the action potential. They did not significantly displace the binding of [125I]-alpha-bungarotoxin (alpha-BTX) to nicotinic receptors, at concentrations which blocked neuromuscular transmission. These results suggest that MES and its analogs inhibit cholinergic neuromuscular transmission by blocking release of ACh; they also affect K+ conductance.
Pharmacokinetics
Absorption
Mescaline binds to liver proteins but not to plasma proteins. It is rapidly and widely distributed into the peripheral tissues. The volume of distribution is not specifically known but is believed to be on the order of several L/kg.
Sixty percent of mescaline is excreted unchanged in a 24 hour urine, and the rest is excreted as metabolites.
Peyote is rapidly absorbed after ingestion. The onset of action is between 30 minutes and 2 hours, and peak blood levels occur 2 hours after ingestion. The duration of the effect usually ranges from 6 to 12 hours but may last up to 14 hours. /Peyote/
Rats of 1, 4, 8, 12, 20, and 60 days postnatal age were injected ip with (14)C-mescaline (50 nCi/g). The levels of mescaline and its deaminated metabolite, 3,4,5-trimethoxyphenylacetic acid, were examined in the brain, liver, heart, spleen, lung, and kidney at 30, 60, 90, and 120 min. Mescaline was rapidly taken up by all the organs examined. In general, the organs of younger rats accumulated much larger amounts than those of adult animals. Brain concentrated the lowest amounts in comparison with other tissues. In the brain, the uptake was the highest in 1-day-old rats and decreased with age. The disappearance of mescaline in various organs was comparatively slower in younger animals than in 20-day or older rats. Rats immediately after birth and uptake was the highest in 1-day-old rats and decreased with age. The disappearance of mescaline in various organs was comparatively slower in younger animals than in 20-day or older rats. Rats immediately after birth and up to 20 days of age metabolized mescaline less efficiently than adults. From the data, it appears that the blood-brain barrier for mescaline develops gradually with age but is not completely impermeable in adults.
Metabolism
It is metabolized in the liver by mescaline oxidase into numerous inactive metabolites. These include 3,4,5-trimethoxyphenylacetic acid; 3,4,5-trimethoxybenzoic acid; 3,4-dihydroxy-5-methoxy-phenyl-lacetyl glutamine; 3-hydroxy-4,5-dimethoxyphenylethylamine; N-acetylmescaline; and N-acetyl-3,4-dimethoxy-5-hydroxyphenylethylamine.
Metabolism of mescaline by several rabbit tissues was examined in vitro. Mescaline-oxidizing activity (micromoles/ per milligram of protein/15 min) of lung homogenates was 4 times greater than that of either liver or kidney. Brain and plasma each had comparatively little capacity to metabolize mescaline. Mescaline metabolism in vitro was sensitive to inhibition by semicarbazide. Removal of mescaline from the medium perfusing the isolated rabbit lung was explained by intrapulmonary metabolism. Semicarbazide (10(-3) M pargyline. Semicarbazide-treated lungs accumulated more mescaline than did untreated lungs. Mescaline efflux from lung was slower than that of its metabolite. These results indicate that the intact lung removes perfused mescaline and may be important in the disposition of circulating mescaline in vivo.
Fact-sheets from PsychonautWiki. Harm-reduction reference only — not medical advice.