Mescaline Structural Formulae Bondline
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Mescaline, also known as mescalin or mezcalin, and in chemical terms 3,4,5-trimethoxyphenethylamine, is a
naturally occurring A natural product is a natural compound or substance produced by a living organism—that is, found in nature. In the broadest sense, natural products include any substance produced by life. Natural products can also be prepared by chemical ...
psychedelic Psychedelics are a subclass of hallucinogenic drugs whose primary effect is to trigger non-ordinary mental states (known as psychedelic experiences or "trips") and a perceived "expansion of consciousness". Also referred to as classic halluci ...
protoalkaloid of the
substituted phenethylamine Substituted phenethylamines (or simply phenethylamines) are a chemical class of organic compounds that are based upon the phenethylamine structure; the class is composed of all the derivative (chemistry), derivative compounds of phenethylamine ...
class, found in
cacti A cactus (: cacti, cactuses, or less commonly, cactus) is a member of the plant family Cactaceae (), a family of the order Caryophyllales comprising about 127 genera with some 1,750 known species. The word ''cactus'' derives, through Latin, ...
like
peyote The peyote (; ''Lophophora williamsii'' ) is a small, spineless cactus which contains psychoactive alkaloids, particularly mescaline. is a Spanish word derived from the Nahuatl (), meaning "caterpillar cocoon", from a root , "to glisten". p. ...
(''Lophophora williamsii'') and San Pedro (certain species of the
Echinopsis ''Echinopsis'' is a genus of Cactus, cacti native plant, native to South America, sometimes known as hedgehog cactus, sea-urchin cactus or Easter lily cactus. , there are about 20 accepted species, ranging from large and treelike types to small ...
genus) and known for its serotonergic
hallucinogenic Hallucinogens, also known as psychedelics, entheogens, or historically as psychotomimetics, are a large and diverse class of psychoactive drugs that can produce altered states of consciousness characterized by major alterations in thought, moo ...
effects. Mescaline is typically taken orally and used recreationally, spiritually, and medically, with psychedelic effects occurring at doses from 100 to 1,000 mg, including
microdosing Microdosing, or micro-dosing, involves the administration of sub-therapeutic doses of drugs to study their effects in humans, aiming to gather preliminary data on safety, pharmacokinetics, and potential therapeutic benefits without producing s ...
below 75 mg, and it can be consumed in pure form or via mescaline-containing cacti. Mescaline induces a psychedelic experience characterized by vivid visual patterns, altered perception of time and self,
synesthesia Synesthesia (American English) or synaesthesia (British English) is a perceptual phenomenon in which stimulation of one sensory or cognitive pathway leads to involuntary experiences in a second sensory or cognitive pathway. People with sy ...
, and spiritual effects, with an onset of 0.5–0.9 hours and a duration that increases with dose, ranging from about 6 to 14 hours. Mescaline has a high
median lethal dose In toxicology, the median lethal dose, LD50 (abbreviation for " lethal dose, 50%"), LC50 (lethal concentration, 50%) or LCt50 is a toxic unit that measures the lethal dose of a given substance. The value of LD50 for a substance is the dose re ...
across species, with the human LD50 estimated at approximately 880 mg/kg, making it very difficult to consume a fatal amount.
Ketanserin Ketanserin, sold under the brand name Sufrexal, is an antihypertensive agent which is used to treat arterial hypertension and vasospasm, vasospastic disorders. It is also used in scientific research as an antiserotonergic medication, agent in th ...
blocks mescaline’s psychoactive effects, and while it's unclear if mescaline is metabolized by
monoamine oxidase Monoamine oxidases (MAO) () are a family of enzymes that catalyze the oxidation of monoamines, employing oxygen to clip off their amine group. They are found bound to the outer membrane of mitochondria in most cell types of the body. The fi ...
enzymes, preliminary evidence suggests harmala alkaloids may potentiate its effects. Mescaline primarily acts as a
partial agonist In pharmacology, partial agonists are drugs that bind to and activate a given Receptor (biochemistry), receptor, but have only partial Intrinsic activity, efficacy at the receptor relative to a full agonist. They may also be considered Ligand (bio ...
at serotonin 5-HT2A receptors, with varying affinity and efficacy across multiple
serotonin Serotonin (), also known as 5-hydroxytryptamine (5-HT), is a monoamine neurotransmitter with a wide range of functions in both the central nervous system (CNS) and also peripheral tissues. It is involved in mood, cognition, reward, learning, ...
,
adrenergic Adrenergic means "working on adrenaline (epinephrine) or noradrenaline (norepinephrine)" (or on their receptors). When not further qualified, it is usually used in the sense of enhancing or mimicking the effects of epinephrine and norepinephrine ...
,
dopamine Dopamine (DA, a contraction of 3,4-dihydroxyphenethylamine) is a neuromodulatory molecule that plays several important roles in cells. It is an organic chemical of the catecholamine and phenethylamine families. It is an amine synthesized ...
,
histamine Histamine is an organic nitrogenous compound involved in local immune responses communication, as well as regulating physiological functions in the gut and acting as a neurotransmitter for the brain, spinal cord, and uterus. Discovered in 19 ...
,
muscarinic A muscarinic acetylcholine receptor agonist, also simply known as a muscarinic agonist or as a muscarinic agent, is an agent that activates the activity of the muscarinic acetylcholine receptor. The muscarinic receptor has different subtypes, lab ...
, and trace amine receptors, but shows low affinity for most non-serotonergic targets. It is a
hydrophilic A hydrophile is a molecule or other molecular entity that is attracted to water molecules and tends to be dissolved by water.Liddell, H.G. & Scott, R. (1940). ''A Greek-English Lexicon'' Oxford: Clarendon Press. In contrast, hydrophobes are n ...
psychedelic compound structurally related to
catecholamines A catecholamine (; abbreviated CA), most typically a 3,4-dihydroxyphenethylamine, is a monoamine neurotransmitter, an organic compound that has a catechol (benzene with two hydroxyl side groups next to each other) and a side-chain amine. ...
but acting on the serotonergic system, first synthesized in 1919, with numerous synthetic methods and potent analogues developed since. Mescaline occurs naturally in various cacti species, with concentrations varying widely, and is
biosynthesized Biosynthesis, i.e., chemical synthesis occurring in biological contexts, is a term most often referring to multi-step, enzyme- catalyzed processes where chemical substances absorbed as nutrients (or previously converted through biosynthesis) serve ...
in plants from
phenylalanine Phenylalanine (symbol Phe or F) is an essential α-amino acid with the chemical formula, formula . It can be viewed as a benzyl group substituent, substituted for the methyl group of alanine, or a phenyl group in place of a terminal hydrogen of ...
via catecholamine pathways likely linked to stress responses. Mescaline-containing cacti use dates back over 6,000 years. Peyote was studied scientifically in the 19th and 20th centuries, culminating in the isolation of mescaline as its primary psychoactive compound, legal recognition of its religious use, and ongoing exploration of its therapeutic potential. Mescaline is largely illegal worldwide, though exceptions exist for religious, scientific, or ornamental use, and it has influenced many notable cultural figures through its psychoactive effects. Very few studies concerning mescaline's activity and potential therapeutic effects in people have been conducted since the early 1970s.


Uses

Mescaline is used recreationally, spiritually (as an
entheogen Entheogens are psychoactive substances used in spiritual and religious contexts to induce altered states of consciousness. Hallucinogens such as the psilocybin found in so-called "magic" mushrooms have been used in sacred contexts since ancie ...
), and medically. It is typically taken orally.


Dosage

Mescaline is used as a psychedelic at doses of 100 to 1,000mg orally. Low doses are 100 to 200mg, an intermediate or "good effect" dose is 500mg, and a high or
ego-dissolution Ego death is a "complete loss of subjective self-identity". The term is used in various intertwined contexts, with related meanings. The 19th-century philosopher and psychologist William James uses the synonymous term "self-surrender", and Jungi ...
dose is 1,000mg.
Microdosing Microdosing, or micro-dosing, involves the administration of sub-therapeutic doses of drugs to study their effects in humans, aiming to gather preliminary data on safety, pharmacokinetics, and potential therapeutic benefits without producing s ...
involves the use of subthreshold mescaline doses of less than 75mg. In addition to pure form, mescaline is used in the form of mescaline-containing
cacti A cactus (: cacti, cactuses, or less commonly, cactus) is a member of the plant family Cactaceae (), a family of the order Caryophyllales comprising about 127 genera with some 1,750 known species. The word ''cactus'' derives, through Latin, ...
such as
peyote The peyote (; ''Lophophora williamsii'' ) is a small, spineless cactus which contains psychoactive alkaloids, particularly mescaline. is a Spanish word derived from the Nahuatl (), meaning "caterpillar cocoon", from a root , "to glisten". p. ...
and San Pedro.


Effects

Mescaline induces a psychedelic state comparable to those produced by
LSD Lysergic acid diethylamide, commonly known as LSD (from German ; often referred to as acid or lucy), is a semisynthetic, hallucinogenic compound derived from ergot, known for its powerful psychological effects and serotonergic activity. I ...
and
psilocybin Psilocybin, also known as 4-phosphoryloxy-''N'',''N''-dimethyltryptamine (4-PO-DMT), is a natural product, naturally occurring tryptamine alkaloid and Investigational New Drug, investigational drug found in more than List of psilocybin mushroom ...
, but with unique characteristics. Subjective effects may include altered thinking processes, an altered sense of time and self-awareness, and closed- and open-eye visual phenomena. Prominence of color is distinctive, appearing brilliant and intense. Recurring visual patterns observed during the mescaline experience include stripes, checkerboards, angular spikes, multicolor dots, and very simple
fractals In mathematics, a fractal is a Shape, geometric shape containing detailed structure at arbitrarily small scales, usually having a fractal dimension strictly exceeding the topological dimension. Many fractals appear similar at various scale ...
that turn very complex. The English writer
Aldous Huxley Aldous Leonard Huxley ( ; 26 July 1894 – 22 November 1963) was an English writer and philosopher. His bibliography spans nearly 50 books, including non-fiction novel, non-fiction works, as well as essays, narratives, and poems. Born into the ...
described these self-transforming amorphous shapes as like animated stained glass illuminated from light coming through the eyelids in his autobiographical book '' The Doors of Perception'' (1954). Like LSD, mescaline induces distortions of form and kaleidoscopic experiences but they manifest more clearly with eyes closed and under low lighting conditions.
Heinrich Klüver Heinrich Klüver (; May 25, 1897 – February 8, 1979) was a German-American biological psychologist and philosopher born in Holstein. After having served in the Imperial German Army during World War I, he studied at both the University of Ham ...
coined the term "cobweb figure" in the 1920s to describe one of the four form constant geometric visual hallucinations experienced in the early stage of a mescaline trip: "Colored threads running together in a revolving center, the whole similar to a cobweb". The other three are the chessboard design, tunnel, and spiral. Klüver wrote that "many 'atypical' visions are upon close inspection nothing but variations of these form-constants." As with LSD,
synesthesia Synesthesia (American English) or synaesthesia (British English) is a perceptual phenomenon in which stimulation of one sensory or cognitive pathway leads to involuntary experiences in a second sensory or cognitive pathway. People with sy ...
can occur especially with the help of music. An unusual but unique characteristic of mescaline use is the "geometrization" of three-dimensional objects. The object can appear flattened and distorted, similar to the presentation of a
Cubist Cubism is an early-20th-century avant-garde art movement which began in Paris. It revolutionized painting and the visual arts, and sparked artistic innovations in music, ballet, literature, and architecture. Cubist subjects are analyzed, broke ...
painting. Mescaline elicits a pattern of sympathetic arousal, with the
peripheral nervous system The peripheral nervous system (PNS) is one of two components that make up the nervous system of Bilateria, bilateral animals, with the other part being the central nervous system (CNS). The PNS consists of nerves and ganglia, which lie outside t ...
being a major target for this substance. According to a research project in the Netherlands, ceremonial San Pedro use seems to be characterized by relatively strong spiritual experiences, and low incidence of challenging experiences.


Onset and duration

The onset of the effects of mescaline given orally is 0.5 to 0.9hours on average with a range of 0.1 to 2.7hours. Its effects peak after 1.9 to 4.0hours with a range of 0.5 to 8.0hours. The duration of mescaline appears to be dose-dependent, varying from 6.4hours on average (range 3.0–10hours) at a dose of 100mg, 9.7 to 11hours on average (range 5.6–22hours) at moderate doses of 300 to 500mg, and 14hours on average (range 7.2–22hours) at a dose of 800mg.


Overdose

The LD50 of mescaline has been measured in various animals: 212–315mg/kg i.p. (mice), 132–410mg/kg i.p. (rats), 328mg/kg i.p. (guinea pigs), 54mg/kg in dogs, and 130mg/kg i.v. in
rhesus macaque The rhesus macaque (''Macaca mulatta''), colloquially rhesus monkey, is a species of Old World monkey. There are between six and nine recognised subspecies split between two groups, the Chinese-derived and the Indian-derived. Generally brown or g ...
s. For humans, the LD50 of mescaline has been reported to be approximately 880mg/kg. It has been said that it would be very difficult to consume enough mescaline to cause death in humans.


Interactions

The
serotonin Serotonin (), also known as 5-hydroxytryptamine (5-HT), is a monoamine neurotransmitter with a wide range of functions in both the central nervous system (CNS) and also peripheral tissues. It is involved in mood, cognition, reward, learning, ...
5-HT2A receptor
antagonist An antagonist is a character in a story who is presented as the main enemy or rival of the protagonist and is often depicted as a villain.ketanserin Ketanserin, sold under the brand name Sufrexal, is an antihypertensive agent which is used to treat arterial hypertension and vasospasm, vasospastic disorders. It is also used in scientific research as an antiserotonergic medication, agent in th ...
has been found to block the psychoactive effects of mescaline. It is unclear whether mescaline is
metabolized Metabolism (, from ''metabolē'', "change") is the set of life-sustaining chemical reactions in organisms. The three main functions of metabolism are: the conversion of the energy in food to energy available to run cellular processes; the co ...
by
monoamine oxidase Monoamine oxidases (MAO) () are a family of enzymes that catalyze the oxidation of monoamines, employing oxygen to clip off their amine group. They are found bound to the outer membrane of mitochondria in most cell types of the body. The fi ...
(MAO)
enzyme An enzyme () is a protein that acts as a biological catalyst by accelerating chemical reactions. The molecules upon which enzymes may act are called substrate (chemistry), substrates, and the enzyme converts the substrates into different mol ...
s or whether
monoamine oxidase inhibitor Monoamine oxidase inhibitors (MAOIs) are a drug class, class of drugs that inhibit the activity of one or both monoamine oxidase enzymes: monoamine oxidase A (MAO-A) and monoamine oxidase B (MAO-B). They are best known as effective antidepressa ...
s (MAOIs) might increase the effects of mescaline. However, there are preliminary reports that
harmala alkaloid Harmala alkaloids are several alkaloids that act as monoamine oxidase inhibitors (MAOIs). These alkaloids are found in the seeds of ''Peganum harmala'' (also known as harmal or Syrian rue), as well as ''Banisteriopsis caapi'' (ayahuasca), leave ...
s, which are reversible inhibitors of monoamine oxidase A (RIMAs), may potentiate the effects of mescaline in humans, and the combination of mescaline or mescaline-containing cacti with harmala alkaloids has been referred to as "peyohuasca". In accordance with these findings, the harmala alkaloid and RIMA harmine has been reported to augment the effects of mescaline in animals.


Pharmacology


Pharmacodynamics

In humans, mescaline acts similarly to other psychedelic agents. It acts as an agonist, binding to and activating the
serotonin Serotonin (), also known as 5-hydroxytryptamine (5-HT), is a monoamine neurotransmitter with a wide range of functions in both the central nervous system (CNS) and also peripheral tissues. It is involved in mood, cognition, reward, learning, ...
5-HT2A receptor. Its at the serotonin 5-HT2A receptor is approximately 10,000nM and at the serotonin 5-HT2B receptor is greater than 20,000nM. How activating the 5-HT2A receptor leads to psychedelic effects is still unknown, but it is likely that somehow it involves excitation of neurons in the
prefrontal cortex In mammalian brain anatomy, the prefrontal cortex (PFC) covers the front part of the frontal lobe of the cerebral cortex. It is the association cortex in the frontal lobe. The PFC contains the Brodmann areas BA8, BA9, BA10, BA11, BA12, ...
. In addition to the serotonin 5-HT2A and 5-HT2B receptors, mescaline is also known to bind to the serotonin 5-HT2C receptor and a number of other
target Target may refer to: Warfare and shooting * Shooting target, used in marksmanship training and various shooting sports ** Bullseye (target), the goal one for which one aims in many of these sports ** Aiming point, in field artille ...
s. Mescaline lacks affinity for the
monoamine transporter Monoamine transporters (MATs) are proteins that function as integral Cell membrane, plasma-membrane Neurotransmitter transporter, transporters to regulate concentrations of extracellular monoamine neurotransmitters. The three major classes are se ...
s, including the
serotonin transporter The serotonin transporter (SERT or 5-HTT) also known as the sodium-dependent serotonin transporter and solute carrier family 6 member 4 is a protein that in humans is encoded by the SLC6A4 gene. SERT is a type of monoamine transporter protein t ...
(SERT),
norepinephrine transporter The norepinephrine transporter (NET), also known as noradrenaline transporter (NAT), is a protein that in humans is encoded by the solute carrier family 6 member 2 (SLC6A2) gene. NET is a monoamine transporter and is responsible for the sodium ...
(NET), and
dopamine transporter The dopamine transporter (DAT, also sodium-dependent dopamine transporter) is a membrane-spanning protein coded for in humans by the ''SLC6A3'' gene (also known as ''DAT1''), that pumps the neurotransmitter dopamine out of the synaptic cleft ba ...
(DAT) (Ki > 30,000nM). However, it has been found to increase levels of the major serotonin
metabolite In biochemistry, a metabolite is an intermediate or end product of metabolism. The term is usually used for small molecules. Metabolites have various functions, including fuel, structure, signaling, stimulatory and inhibitory effects on enzymes, c ...
5-hydroxyindoleacetic acid (5-HIAA) at high doses in rodents. This finding suggests that mescaline might inhibit the reuptake and/or induce the release of serotonin at such doses. In any case, this possibility has not yet been further assessed or demonstrated. Besides serotonin, mescaline might also weakly induce the release of dopamine, but this is probably of modest significance, if it occurs. In accordance, there is no evidence of the drug showing
addiction Addiction is a neuropsychological disorder characterized by a persistent and intense urge to use a drug or engage in a behavior that produces natural reward, despite substantial harm and other negative consequences. Repetitive drug use can ...
or dependence. Mescaline appears to be inactive in terms of norepinephrine release induction and indirect sympathomimetic activity. Other psychedelic phenethylamines, including the closely related 2C, DOx, and TMA drugs, are inactive as
monoamine releasing agent A monoamine releasing agent (MRA), or simply monoamine releaser, is a drug that induces the release of one or more monoamine neurotransmitters from the presynaptic neuron into the synapse, leading to an increase in the extracellular concentrati ...
s and
reuptake inhibitor Reuptake inhibitors (RIs) are a type of reuptake modulators. It is a drug that inhibits the plasmalemmal transporter-mediated reuptake of a neurotransmitter from the synapse into the pre-synaptic neuron. This leads to an increase in extracel ...
s. However, an exception is trimethoxyamphetamine (TMA), the amphetamine analogue of mescaline, which is a very low-
potency Potency may refer to: * Potency (pharmacology), a measure of the activity of a drug in a biological system * Virility * Cell potency, a measure of the differentiation potential of stem cells * In homeopathic dilutions, potency is a measure of ho ...
serotonin releasing agent A serotonin releasing agent (SRA) is a type of drug that induces the release of serotonin into the neuronal synaptic cleft. A selective serotonin releasing agent (SSRA) is an SRA with less significant or no efficacy in producing neurotransmitter ...
( = 16,000nM). The possible monoamine-releasing effects of mescaline would likely be related to its
structural similarity The structural similarity index measure (SSIM) is a method for predicting the perceived quality of digital television and cinematic pictures, as well as other kinds of digital images and videos. It is also used for measuring the similarity betwe ...
to
substituted amphetamine Substituted amphetamines, or simply amphetamines, are a chemical class, class of compounds based upon the amphetamine structure; it includes all derivative (chemistry), derivative compounds which are formed by replacing, or substitution reacti ...
s and related compounds. Mescaline is a relatively low-potency psychedelic, with active doses in the hundreds of milligrams and micromolar affinities for the serotonin 5-HT2A receptor. For comparison,
psilocybin Psilocybin, also known as 4-phosphoryloxy-''N'',''N''-dimethyltryptamine (4-PO-DMT), is a natural product, naturally occurring tryptamine alkaloid and Investigational New Drug, investigational drug found in more than List of psilocybin mushroom ...
is approximately 20-fold more potent (doses in the tens of milligrams) and
lysergic acid diethylamide Lysergic acid diethylamide, commonly known as LSD (from German ; often referred to as acid or lucy), is a Semisynthesis, semisynthetic, Hallucinogen, hallucinogenic compound derived from ergot, known for its powerful psychological effects and ...
(LSD) is approximately 2,000-fold more potent (doses in the tens to hundreds of micrograms). There have been efforts to develop more potent analogues of mescaline. Difluoromescaline and
trifluoromescaline Trifluoromescaline (TF-M) is a derivative of the phenethylamine hallucinogen mescaline, which has a trifluoromethoxy group replacing the central methoxy group of mescaline. Trifluoromescaline was found to be one of the most potent compounds in t ...
are more potent than mescaline, as is its amphetamine homologue TMA.
Escaline Escaline (E), also known as 3,5-dimethoxy-4-ethoxyphenethylamine, is a psychedelic drug of the phenethylamine and scaline families related to mescaline. It is the 4- ethoxy analogue of mescaline (3,4,5-trimethoxyphenethylamine) and the pheneth ...
and
proscaline Proscaline (4-propoxy-3,5-dimethoxyphenethylamine or 4-propoxy-3,5-DMPEA) is a Psychedelic drug, psychedelic and hallucinogenic drug. It has structural properties similar to the drugs mescaline, isoproscaline, and escaline. In ''PiHKAL'', Alexan ...
are also both more potent than mescaline, showing the importance of the 4-position substituent with regard to receptor binding. Tolerance to mescaline builds with repeated usage, lasting for a few days. The drug causes
cross-tolerance Cross-tolerance is a phenomenon that occurs when tolerance to the effects of a certain drug produces tolerance to another drug. It often happens between two drugs with similar functions or effects—for example, acting on the same cell receptor ...
with other serotonergic psychedelics such as
LSD Lysergic acid diethylamide, commonly known as LSD (from German ; often referred to as acid or lucy), is a semisynthetic, hallucinogenic compound derived from ergot, known for its powerful psychological effects and serotonergic activity. I ...
and
psilocybin Psilocybin, also known as 4-phosphoryloxy-''N'',''N''-dimethyltryptamine (4-PO-DMT), is a natural product, naturally occurring tryptamine alkaloid and Investigational New Drug, investigational drug found in more than List of psilocybin mushroom ...
. The
cryo-EM Cryogenic electron microscopy (cryo-EM) is a transmission electron microscopy technique applied to samples cooled to cryogenic temperatures. For biological specimens, the structure is preserved by embedding in an environment of vitreous ice. An ...
structure A structure is an arrangement and organization of interrelated elements in a material object or system, or the object or system so organized. Material structures include man-made objects such as buildings and machines and natural objects such as ...
s of the serotonin 5-HT2A receptor with mescaline, as well as with various other psychedelics and serotonin 5-HT2A receptor agonists, have been solved and published by Bryan L. Roth and colleagues.


Pharmacokinetics


Absorption

Mescaline is usually taken orally, although it may also be insufflated,
smoked Smoking is the process of flavoring, browning, cooking, or preserving food, particularly meat, fish and tea, by exposing it to smoke from burning or smoldering material, most often wood. In Europe, alder is the traditional smoking wood, but ...
, or given
intravenously Intravenous therapy (abbreviated as IV therapy) is a medical technique that administers fluids, medications and nutrients directly into a person's vein. The intravenous route of administration is commonly used for rehydration or to provide nutr ...
. Taken orally, it is rapidly absorbed from the
gastrointestinal tract The gastrointestinal tract (GI tract, digestive tract, alimentary canal) is the tract or passageway of the Digestion, digestive system that leads from the mouth to the anus. The tract is the largest of the body's systems, after the cardiovascula ...
.
Peak Peak or The Peak may refer to: Basic meanings Geology * Mountain peak ** Pyramidal peak, a mountaintop that has been sculpted by erosion to form a point Mathematics * Peak hour or rush hour, in traffic congestion * Peak (geometry), an (''n''-3)-d ...
concentrations of mescaline occur after approximately 1.6 to 2.3hours on average (range 1.0–6.0hours). The
pharmacokinetics Pharmacokinetics (from Ancient Greek ''pharmakon'' "drug" and ''kinetikos'' "moving, putting in motion"; see chemical kinetics), sometimes abbreviated as PK, is a branch of pharmacology dedicated to describing how the body affects a specific su ...
of mescaline are dose-proportional over an
oral The word oral may refer to: Relating to the mouth * Relating to the mouth, the first portion of the alimentary canal that primarily receives food and liquid **Oral administration of medicines ** Oral examination (also known as an oral exam or ora ...
dose range of 100 to 800mg.


Distribution

Mescaline is
distributed Distribution may refer to: Mathematics *Distribution (mathematics), generalized functions used to formulate solutions of partial differential equations *Probability distribution, the probability of a particular value or value range of a varia ...
to the
liver The liver is a major metabolic organ (anatomy), organ exclusively found in vertebrates, which performs many essential biological Function (biology), functions such as detoxification of the organism, and the Protein biosynthesis, synthesis of var ...
,
spleen The spleen (, from Ancient Greek '' σπλήν'', splḗn) is an organ (biology), organ found in almost all vertebrates. Similar in structure to a large lymph node, it acts primarily as a blood filter. The spleen plays important roles in reg ...
, and
kidney In humans, the kidneys are two reddish-brown bean-shaped blood-filtering organ (anatomy), organs that are a multilobar, multipapillary form of mammalian kidneys, usually without signs of external lobulation. They are located on the left and rig ...
s at many times higher levels than blood or brain based on animal studies. It is said that a great proportion of mescaline is combined with hepatic proteins, which is said to delay its onset and
elimination half-life Biological half-life (elimination half-life, pharmacological half-life) is the time taken for concentration of a biological substance (such as a medication) to decrease from its maximum concentration ( Cmax) to half of Cmax in the blood plasma. ...
. Mescaline appears to have relatively poor
blood–brain barrier The blood–brain barrier (BBB) is a highly selective semipermeable membrane, semipermeable border of endothelium, endothelial cells that regulates the transfer of solutes and chemicals between the circulatory system and the central nervous system ...
permeability due to its low lipophilicity. However, it is still able to cross into the
central nervous system The central nervous system (CNS) is the part of the nervous system consisting primarily of the brain, spinal cord and retina. The CNS is so named because the brain integrates the received information and coordinates and influences the activity o ...
and produce
psychoactive A psychoactive drug, psychopharmaceutical, mind-altering drug, consciousness-altering drug, psychoactive substance, or psychotropic substance is a chemical substance that alters psychological functioning by modulating central nervous system acti ...
effects at sufficienty high doses.


Metabolism

The primary
metabolic pathway In biochemistry, a metabolic pathway is a linked series of chemical reactions occurring within a cell (biology), cell. The reactants, products, and Metabolic intermediate, intermediates of an enzymatic reaction are known as metabolites, which are ...
of mescaline is
oxidative deamination Oxidative deamination is a form of deamination that generates α-keto acids and other oxidized products from amine-containing compounds, and occurs primarily in the liver. Oxidative deamination is stereospecific, meaning it contains different ster ...
. The specific
enzyme An enzyme () is a protein that acts as a biological catalyst by accelerating chemical reactions. The molecules upon which enzymes may act are called substrate (chemistry), substrates, and the enzyme converts the substrates into different mol ...
s mediating the deamination of mescaline are controversial however.
Monoamine oxidase Monoamine oxidases (MAO) () are a family of enzymes that catalyze the oxidation of monoamines, employing oxygen to clip off their amine group. They are found bound to the outer membrane of mitochondria in most cell types of the body. The fi ...
(MAO), diamine oxidase (DAO; histamine oxidase), and/or other enzymes may be responsible.
Preclinical studies In drug development, preclinical development (also termed preclinical studies or nonclinical studies) is a stage of research that begins before clinical trials (testing in humans) and during which important feasibility, iterative testing and dr ...
of mescaline given in combination with inhibitors of MAO and/or DAO, such as
iproniazid Iproniazid (Marsilid, Rivivol, Euphozid, Iprazid, Ipronid, Ipronin) is a non-selective, irreversible inhibition, irreversible monoamine oxidase inhibitor (MAOI) of the hydrazine (antidepressant), hydrazine class. It is a xenobiotic that was origi ...
, pargyline, and
semicarbazide Semicarbazide is the chemical compound with the formula OC(NH2)(N2H3). It is a water-soluble white solid. It is a derivative of urea. Synthesis The compound prepared by treating urea with hydrazine:Jean-Pierre Schirmann, Paul Bourdauducq "Hydrazi ...
, have been conducted, but findings have been conflicting. Mescaline has been reported to be a poor or negligible
substrate Substrate may refer to: Physical layers *Substrate (biology), the natural environment in which an organism lives, or the surface or medium on which an organism grows or is attached ** Substrate (aquatic environment), the earthy material that exi ...
of highly purified human MAO '' in-vitro''. Mescaline appears not to be subject to metabolism by
CYP2D6 Cytochrome P450 2D6 (CYP2D6) is an enzyme that in humans is encoded by the ''CYP2D6'' gene. ''CYP2D6'' is primarily expressed in the liver. It is also highly expressed in areas of the central nervous system, including the substantia nigra. CYP2 ...
based on ''in-vitro'' studies with human liver microsomes. Similarly, the ''in-vitro''
cytotoxicity Cytotoxicity is the quality of being toxic to cells. Examples of toxic agents are toxic metals, toxic chemicals, microbe neurotoxins, radiation particles and even specific neurotransmitters when the system is out of balance. Also some types of d ...
of mescaline does not appear to be affected by
cytochrome P450 Cytochromes P450 (P450s or CYPs) are a Protein superfamily, superfamily of enzymes containing heme as a cofactor (biochemistry), cofactor that mostly, but not exclusively, function as monooxygenases. However, they are not omnipresent; for examp ...
(CYP450)
enzyme inhibitor An enzyme inhibitor is a molecule that binds to an enzyme and blocks its Enzyme activity, activity. Enzymes are proteins that speed up chemical reactions necessary for life, in which Substrate (biochemistry), substrate molecules are converted ...
s. Conversely, it was potentiated by the
MAO-A Monoamine oxidase A, also known as MAO-A, is an enzyme ( E.C. 1.4.3.4) that in humans is encoded by the ''MAOA'' gene. This gene is one of two neighboring gene family members that encode mitochondrial enzymes which catalyze the oxidative deamin ...
inhibitor clorgiline but not by the
MAO-B Monoamine oxidase B (MAO-B) is an enzyme that in humans is encoded by the ''MAOB'' gene. The protein encoded by this gene belongs to the flavin monoamine oxidase family. It is an enzyme located in the outer mitochondrial membrane. It catalyze ...
inhibitor
rasagiline Rasagiline, sold under the brand name Azilect among others, is a medication which is used in the treatment of Parkinson's disease. It is used as a monotherapy to treat symptoms in early Parkinson's disease or as an adjunct therapy in more advan ...
. These findings were in contrast to those with the related compound
2C-B 2C-B, also known as 4-bromo-2,5-dimethoxyphenethylamine or by the slang name Nexus, is a synthetic psychedelic drug of the 2C family, mainly used as a recreational drug. It was first synthesized by Alexander Shulgin in 1974 for use in psychoth ...
, which was potentiated by rasagiline but not by clorgiline. Circulating
peak Peak or The Peak may refer to: Basic meanings Geology * Mountain peak ** Pyramidal peak, a mountaintop that has been sculpted by erosion to form a point Mathematics * Peak hour or rush hour, in traffic congestion * Peak (geometry), an (''n''-3)-d ...
and area-under-the-curve concentrations of mescaline and 3,4,5-trimethoxyphenylacetic acid (TMPAA) are similar with oral administration of mescaline. Conversely, levels of ''N''-acetylmescaline (NAM) are far lower than those of mescaline or TMPAA.
Intravenous injection Intravenous therapy (abbreviated as IV therapy) is a medical technique that administers fluids, medications and nutrients directly into a person's vein. The intravenous route of administration is commonly used for rehydration or to provide nutr ...
of mescaline may result in less hepatic deamination than with oral administration.
Active metabolite An active metabolite, or pharmacologically active metabolite is a biologically active metabolite of a xenobiotic substance, such as a drug or environmental chemical. Active metabolites may produce therapeutic effects, as well as harmful effects. ...
s of mescaline might contribute to its psychoactive effects. However, both TMPAA and NAM have been said to be inactive based on human tests. Similarly, 3,4,5-trimethoxyphenylethanol (TMPE), 3,4,5-trimethoxyphenylacetaldehyde (TMPA), and NAM all failed to produce mescaline-like effects in rodent
drug discrimination Drug discrimination (DD) is a technique in behavioral neuroscience used to evaluate the discriminative stimulus properties or interoceptive cues of psychoactive drugs. In drug discrimination, a subject is trained on a training drug, and then i ...
tests. 3,4,5-Trimethoxyamphetamine (TMA), the α-
methyl In organic chemistry, a methyl group is an alkyl derived from methane, containing one carbon atom bonded to three hydrogen atoms, having chemical formula (whereas normal methane has the formula ). In formulas, the group is often abbreviated as ...
analogue of mescaline and an MAO-resistant psychedelic, is only about twice as potent as mescaline as a psychedelic in humans despite having similar
serotonin receptor 5-HT receptors, 5-hydroxytryptamine receptors, or serotonin receptors, are a group of G protein-coupled receptor and ligand-gated ion channels found in multiple tissues including the central and peripheral nervous systems. They mediate both ex ...
affinity Affinity may refer to: Commerce, finance and law * Affinity (law), kinship by marriage * Affinity analysis, a market research and business management technique * Affinity Credit Union, a Saskatchewan-based credit union * Affinity Equity Pa ...
. This suggests that the deamination of mescaline have a relatively limited impact on its potency, compared to for example the 2C series of psychedelics.


Elimination

Mescaline given orally is excreted 87% in
urine Urine is a liquid by-product of metabolism in humans and many other animals. In placental mammals, urine flows from the Kidney (vertebrates), kidneys through the ureters to the urinary bladder and exits the urethra through the penile meatus (mal ...
within 24hours and 92% in urine within 48hours. During the first hour after administration, 81.4% of mescaline is excreted unchanged while 13.2% is excreted as its deaminated metabolite 3,4,5-trimethoxyphenylacetic acid (TMPAA). However, after the first hour, the percentage excreted as unchanged mescaline declines and the percentage excreted as TMPAA rises. Ultimately, mescaline is excreted in urine 28 to 60% unchanged, 27 to 30% or more as TMPAA, 5% as ''N''-acetyl-3,4-dimethoxy-5-hydroxyphenylethylamine, and less than 0.1% as ''N''-acetylmescaline. Other minor or trace excreted metabolites have also been observed. Mescaline was originally reported to have an
elimination half-life Biological half-life (elimination half-life, pharmacological half-life) is the time taken for concentration of a biological substance (such as a medication) to decrease from its maximum concentration ( Cmax) to half of Cmax in the blood plasma. ...
of 6hours based on a study conducted in the 1960s. However, subsequent research published in the 2020s found that its half-life is actually about 3.6hours (range 2.6–5.3hours). The previous higher estimate is believed to have been due to small sample numbers and collective measurement of mescaline metabolites. The elimination half-life of mescaline does not appear to be dose-dependent. Mescaline has a similar half-life as LSD yet has a longer duration. This is due to mescaline having slower
absorption Absorption may refer to: Chemistry and biology *Absorption (biology), digestion **Absorption (small intestine) *Absorption (chemistry), diffusion of particles of gas or liquid into liquid or solid materials *Absorption (skin), a route by which su ...
and onset rather than a longer half-life.


Chemistry

Mescaline, also known as 3,4,5-trimethoxyphenethylamine (3,4,5-TMPEA), is a
substituted phenethylamine Substituted phenethylamines (or simply phenethylamines) are a chemical class of organic compounds that are based upon the phenethylamine structure; the class is composed of all the derivative (chemistry), derivative compounds of phenethylamine ...
derivative In mathematics, the derivative is a fundamental tool that quantifies the sensitivity to change of a function's output with respect to its input. The derivative of a function of a single variable at a chosen input value, when it exists, is t ...
. It is closely structurally related to the
dopamine Dopamine (DA, a contraction of 3,4-dihydroxyphenethylamine) is a neuromodulatory molecule that plays several important roles in cells. It is an organic chemical of the catecholamine and phenethylamine families. It is an amine synthesized ...
(3,4-dihydroxyphenethylamine),
norepinephrine Norepinephrine (NE), also called noradrenaline (NA) or noradrenalin, is an organic compound, organic chemical in the catecholamine family that functions in the brain and human body, body as a hormone, neurotransmitter and neuromodulator. The ...
(3,4,β-trihydroxyphenethylamine), and
epinephrine Adrenaline, also known as epinephrine, is a hormone and medication which is involved in regulating visceral functions (e.g., respiration). It appears as a white microcrystalline granule. Adrenaline is normally produced by the adrenal glands a ...
(3,4,β-trihydroxy-''N''-methylphenethylamine). In contrast to the catecholamine neurotransmitters however, mescaline acts on the serotonergic system rather than on the
dopaminergic Dopaminergic means "related to dopamine" (literally, "working on dopamine"), a common neurotransmitter. Dopaminergic substances or actions increase dopamine-related activity in the brain. Dopaminergic pathways, Dopaminergic brain pathways facil ...
or
adrenergic Adrenergic means "working on adrenaline (epinephrine) or noradrenaline (norepinephrine)" (or on their receptors). When not further qualified, it is usually used in the sense of enhancing or mimicking the effects of epinephrine and norepinephrine ...
systems. The drug is relatively
hydrophilic A hydrophile is a molecule or other molecular entity that is attracted to water molecules and tends to be dissolved by water.Liddell, H.G. & Scott, R. (1940). ''A Greek-English Lexicon'' Oxford: Clarendon Press. In contrast, hydrophobes are n ...
with low
fat solubility Lipophilicity (from Greek λίπος "fat" and φίλος "friendly") is the ability of a chemical compound to dissolve in fats, oils, lipids, and non-polar solvents such as hexane or toluene. Such compounds are called lipophilic (translated as ...
. Its predicted log P ( XLogP3) is 0.7. The physical properties and general chemistry of mescaline have been reviewed.


Synthesis

Mescaline was first synthesized in 1919 by Ernst Späth from 3,4,5-trimethoxybenzoyl chloride. Several approaches using different starting materials have been developed since, including the following: *
Hofmann rearrangement The Hofmann rearrangement (Hofmann degradation) is the organic reaction of a primary amide to a primary amine with one less carbon atom. The reaction involves oxidation of the nitrogen followed by rearrangement of the carbonyl and nitrogen to gi ...
of 3,4,5-trimethoxyphenylpropionamide. *
Cyanohydrin reaction In organic chemistry, a cyanohydrin reaction is an organic reaction in which an aldehyde () or ketone () reacts with a cyanide anion () or a nitrile () to form a cyanohydrin (). For example: \ce + \ce \longrightarrow \ce This nucleophilic ad ...
between
potassium cyanide Potassium cyanide is a compound with the formula KCN. It is a colorless salt, similar in appearance to sugar, that is highly soluble in water. Most KCN is used in gold mining, organic synthesis, and electroplating. Smaller applications include ...
and 3,4,5-trimethoxybenzaldehyde followed by
acetylation : In chemistry, acetylation is an organic esterification reaction with acetic acid. It introduces an acetyl group into a chemical compound. Such compounds are termed ''acetate esters'' or simply ''acetates''. Deacetylation is the opposite react ...
and reduction. *
Henry reaction The Henry reaction is a classic carbon–carbon bond formation reaction in organic chemistry. Discovered in 1895 by the Belgian chemist Louis Henry (1834–1913), it is the combination of a nitroalkane and an aldehyde or ketone in the presence ...
of 3,4,5-trimethoxybenzaldehyde with
nitromethane Nitromethane, sometimes shortened to simply "nitro", is an organic compound with the chemical formula . It is the simplest organic nitro compound. It is a polar liquid commonly used as a solvent in a variety of industrial applications such as in ...
followed by nitro compound reduction of ω-nitrotrimethoxystyrene. *
Ozonolysis In organic chemistry, ozonolysis is an organic reaction where the Saturated and unsaturated compounds, unsaturated bonds are Bond cleavage, cleaved with ozone (). Multiple carbon–carbon bond are replaced by carbonyl () groups, such as aldehydes ...
of
elemicin Elemicin is a phenylpropene, a natural organic compound, and is a constituent of several plant species' essential oils. Natural occurrence Elemicin is a constituent of the oleoresin and the essential oil of '' Canarium luzonicum'' (also referre ...
followed by
reductive amination Reductive amination (also known as reductive alkylation) is a form of amination that converts a carbonyl group to an amine via an intermediate imine. The carbonyl group is most commonly a ketone or an aldehyde. It is a common method to make amine ...
. * Ester reduction of Eudesmic acid's
methyl In organic chemistry, a methyl group is an alkyl derived from methane, containing one carbon atom bonded to three hydrogen atoms, having chemical formula (whereas normal methane has the formula ). In formulas, the group is often abbreviated as ...
ester In chemistry, an ester is a compound derived from an acid (either organic or inorganic) in which the hydrogen atom (H) of at least one acidic hydroxyl group () of that acid is replaced by an organyl group (R). These compounds contain a distin ...
followed by
halogenation In chemistry, halogenation is a chemical reaction which introduces one or more halogens into a chemical compound. Halide-containing compounds are pervasive, making this type of transformation important, e.g. in the production of polymers, drug ...
,
Kolbe nitrile synthesis The Kolbe nitrile synthesis is a method for the preparation of alkyl nitriles by reaction of the corresponding organohalide, alkyl halide with a metal cyanide. A side product for this reaction is the formation of an isonitrile because the cyanide i ...
, and
nitrile reduction In nitrile reduction a nitrile is organic reduction, reduced to either an amine or an aldehyde with a suitable chemical reagent. Catalytic hydrogenation The Catalysis, catalytic hydrogenation of nitriles is often the most economical route available ...
. *
Amide reduction Amide reduction is a reaction in organic synthesis where an amide is reduced to either an amine or an aldehyde functional group. Catalytic hydrogenation Catalytic hydrogenation can be used to reduce amides to amines; however, the process often re ...
of 3,4,5-trimethoxyphenylacetamide. *Reduction of 3,4,5-trimethoxy(2-nitrovinyl)benzene with lithium aluminum hydride. * Treatment of tricarbonyl-(η6-1,2,3-trimethoxybenzene) chromium complex with acetonitrile carbanion in
THF Tetrahydrofuran (THF), or oxolane, is an organic compound with the formula (CH2)4O. The compound is classified as heterocyclic compound, specifically a cyclic ether. It is a colorless, water-miscible organic liquid with low viscosity. It is ma ...
and iodine, followed by reduction of the nitrile with lithium aluminum hydride.


Analogues

A large number of structural analogues of mescaline that act as psychedelics have been developed. These drugs often have far greater
potency Potency may refer to: * Potency (pharmacology), a measure of the activity of a drug in a biological system * Virility * Cell potency, a measure of the differentiation potential of stem cells * In homeopathic dilutions, potency is a measure of ho ...
than mescaline itself. Examples include scalines like
escaline Escaline (E), also known as 3,5-dimethoxy-4-ethoxyphenethylamine, is a psychedelic drug of the phenethylamine and scaline families related to mescaline. It is the 4- ethoxy analogue of mescaline (3,4,5-trimethoxyphenethylamine) and the pheneth ...
, 3Cs like 3,4,5-trimethoxyamphetamine (TMA or TMA-1; α-methylmescaline), 2Cs like
2C-B 2C-B, also known as 4-bromo-2,5-dimethoxyphenethylamine or by the slang name Nexus, is a synthetic psychedelic drug of the 2C family, mainly used as a recreational drug. It was first synthesized by Alexander Shulgin in 1974 for use in psychoth ...
, and DOx drugs like DOM, among others. Other notable analogues of mescaline include ''N''-methylmescaline (found in ''
Pachycereus pringlei ''Pachycereus pringlei'' (also known as Mexican giant cardon or elephant cactus) is a species of large cactus native to northwestern Mexico, in the states of Baja California, Baja California Sur, and Sonora. It is commonly known as ''cardón'', a ...
''), trichocereine (''N'',''N''-dimethylmescaline), mescaline-FLY, and NBOMe-mescaline, among others.


Natural occurrence

It occurs naturally in several species of
cacti A cactus (: cacti, cactuses, or less commonly, cactus) is a member of the plant family Cactaceae (), a family of the order Caryophyllales comprising about 127 genera with some 1,750 known species. The word ''cactus'' derives, through Latin, ...
. It is also reported to be found in small amounts in certain members of the bean family,
Fabaceae Fabaceae () or Leguminosae,International Code of Nomen ...
, including ''
Senegalia berlandieri ''Senegalia berlandieri'' (Berlandier acacia, guajillo acacia, guajillo, huajillo, huajilla) is a shrub native to the Southwestern United States and northeast Mexico that belongs to the Mimosoid clade of Fabaceae. It grows tall, with blossoms ...
'' (syn. ''Acacia berlandieri''), although these reports have been challenged and have been unsupported in any additional analyses. As shown in the accompanying table, the concentration of mescaline in different specimens can vary largely within a single species. Moreover, the concentration of mescaline within a single specimen varies as well. In plants, mescaline may be the end-product of a pathway utilizing catecholamines as a method of stress response, similar to how animals may release such compounds and others such as
cortisol Cortisol is a steroid hormone in the glucocorticoid class of hormones and a stress hormone. When used as medication, it is known as hydrocortisone. Cortisol is produced in many animals, mainly by the ''zona fasciculata'' of the adrenal corte ...
when stressed. The ''in vivo'' function of catecholamines in plants has not been investigated, but they may function as
antioxidant Antioxidants are Chemical compound, compounds that inhibit Redox, oxidation, a chemical reaction that can produce Radical (chemistry), free radicals. Autoxidation leads to degradation of organic compounds, including living matter. Antioxidants ...
s, as developmental signals, and as integral cell wall components that resist degradation from pathogens. The deactivation of catecholamines via methylation produces alkaloids such as mescaline.


Biosynthesis

Mescaline is
biosynthesized Biosynthesis, i.e., chemical synthesis occurring in biological contexts, is a term most often referring to multi-step, enzyme- catalyzed processes where chemical substances absorbed as nutrients (or previously converted through biosynthesis) serve ...
from
tyrosine -Tyrosine or tyrosine (symbol Tyr or Y) or 4-hydroxyphenylalanine is one of the 20 standard amino acids that are used by cells to synthesize proteins. It is a conditionally essential amino acid with a polar side group. The word "tyrosine" is ...
, which, in turn, is derived from
phenylalanine Phenylalanine (symbol Phe or F) is an essential α-amino acid with the chemical formula, formula . It can be viewed as a benzyl group substituent, substituted for the methyl group of alanine, or a phenyl group in place of a terminal hydrogen of ...
by the enzyme phenylalanine hydroxylase. In ''Lophophora williamsii'' (
Peyote The peyote (; ''Lophophora williamsii'' ) is a small, spineless cactus which contains psychoactive alkaloids, particularly mescaline. is a Spanish word derived from the Nahuatl (), meaning "caterpillar cocoon", from a root , "to glisten". p. ...
),
dopamine Dopamine (DA, a contraction of 3,4-dihydroxyphenethylamine) is a neuromodulatory molecule that plays several important roles in cells. It is an organic chemical of the catecholamine and phenethylamine families. It is an amine synthesized ...
converts into mescaline in a biosynthetic pathway involving ''m''-''O''-methylation and aromatic hydroxylation. Tyrosine and phenylalanine serve as metabolic precursors towards the synthesis of mescaline. Tyrosine can either undergo a decarboxylation via tyrosine decarboxylase to generate
tyramine Tyramine ( ) (also spelled tyramin), also known under several other names, is a naturally occurring trace amine derived from the amino acid tyrosine. Tyramine acts as a catecholamine releasing agent. Notably, it is unable to cross the bl ...
and subsequently undergo an oxidation at carbon 3 by a monophenol hydroxylase or first be hydroxylated by
tyrosine hydroxylase Tyrosine hydroxylase or tyrosine 3-monooxygenase is the enzyme responsible for catalyzing the conversion of the amino acid L-tyrosine to L-3,4-dihydroxyphenylalanine (L-DOPA). It does so using molecular oxygen (O2), as well as iron (Fe2+) and ...
to form
L-DOPA -DOPA, also known as -3,4-dihydroxyphenylalanine and used medically as levodopa, is made and used as part of the normal biology of some plants and animals, including humans. Humans, as well as a portion of the other animals that utilize -DO ...
and decarboxylated by
DOPA decarboxylase Aromatic L-amino acid decarboxylase (AADC or AAAD), also known as DOPA decarboxylase (DDC), tryptophan decarboxylase, and 5-hydroxytryptophan decarboxylase, is a lyase enzyme (), located in region 7p12.2-p12.1. Mechanism The enzyme uses pyri ...
. These create dopamine, which then experiences methylation by a
catechol-O-methyltransferase Catechol-''O''-methyltransferase (COMT; ) is one of several enzymes that degrade catecholamines (neurotransmitters such as dopamine, epinephrine, and norepinephrine), catecholestrogens, and various drugs and substances having a catechol struct ...
(COMT) by an ''S''-adenosyl methionine (SAM)-dependent mechanism. The resulting intermediate is then oxidized again by a hydroxylase enzyme, likely monophenol hydroxylase again, at carbon 5, and methylated by COMT. The product, methylated at the two meta positions with respect to the alkyl substituent, experiences a final methylation at the 4 carbon by a guaiacol-O-methyltransferase, which also operates by a SAM-dependent mechanism. This final methylation step results in the production of mescaline. Phenylalanine serves as a precursor by first being converted to L-tyrosine by L-amino acid hydroxylase. Once converted, it follows the same pathway as described above.


History

Archaeological evidence from sites in the United States, Mexico, and Peru indicates that mescaline-containing cacti have been used for over 6,000 years. Europeans recorded use of peyote in Native American religious ceremonies upon early contact with the
Huichol people The Huichol () or Wixárika () are an Indigenous people of Mexico living in the Sierra Madre Occidental range in the states of Nayarit, Jalisco, Zacatecas, and Durango, with considerable communities in the United States, in the states of Califor ...
in Mexico. Other mescaline-containing cacti such as the San Pedro have a long history of use in South America, from Peru to Ecuador. While religious and ceremonial peyote use was widespread in the
Aztec Empire The Aztec Empire, also known as the Triple Alliance (, Help:IPA/Nahuatl, �jéːʃkaːn̥ t͡ɬaʔtoːˈlóːjaːn̥ or the Tenochca Empire, was an alliance of three Nahuas, Nahua altepetl, city-states: , , and . These three city-states rul ...
and northern Mexico at the time of the Spanish conquest, religious persecution confined it to areas near the Pacific coast and up to southwest Texas. However, by 1880, peyote use began to spread north of South-Central America with "a new kind of peyote ceremony" inaugurated by the Kiowa and Comanche people. These religious practices, incorporated legally in the United States in 1920 as the Native American Church, have since spread as far as Saskatchewan, Canada. In traditional peyote preparations, the top of the cactus is cut off, leaving the large tap root along with a ring of green photosynthesizing area to grow new heads. These heads are then dried to make disc-shaped buttons. Buttons are chewed to produce the effects or soaked in water to drink. However, the taste of the cactus is bitter, so modern users will often grind it into a powder and pour it into capsules to avoid having to taste it. The typical dosage is 200–400 milligrams of mescaline sulfate or 178–356 milligrams of mescaline hydrochloride. The average peyote button contains about 25mg mescaline. Some analyses of traditional preparations of San Pedro cactus have found doses ranging from 34mg to 159mg of total alkaloids, a relatively low and barely psychoactive amount. It appears that patients who receive traditional treatments with San Pedro ingest sub-psychoactive doses and do not experience psychedelic effects. Botanical studies of peyote began in the 1840s and the drug was listed in the Mexican
pharmacopeia A pharmacopoeia, pharmacopeia, or pharmacopoea (or the typographically obsolete rendering, ''pharmacopœia''), meaning "drug-making", in its modern technical sense, is a reference work containing directions for the identification of compound med ...
. The first use of mescal buttons was published by John Raleigh Briggs in 1887. In 1887, the German pharmacologist
Louis Lewin Louis Lewin (9 November 1850 - 1 December 1929) was a German pharmacologist. In 1887 he received his first sample of the Peyote, Peyote cactus from Dallas, Texas-based physician John Raleigh Briggs (1851-1907), and later published the first metho ...
received his first sample of the peyote cactus, found numerous new alkaloids and later published the first methodical analysis of it. Mescaline was first isolated and identified in 1897 by the German chemist Arthur Heffter. He showed that mescaline was exclusively responsible for the psychoactive or hallucinogenic effects of peyote. However, other components of peyote, such as hordenine, pellotine, and anhalinine, are also
active Active may refer to: Music * ''Active'' (album), a 1992 album by Casiopea * "Active" (song), a 2024 song by Asake and Travis Scott from Asake's album ''Lungu Boy'' * Active Records, a record label Ships * ''Active'' (ship), several com ...
. Mescaline was first synthesized in 1919 by Ernst Späth. In 1955, English politician
Christopher Mayhew Christopher Paget Mayhew, Baron Mayhew (12 June 1915 – 7 January 1997) was a British politician who was a Labour Member of Parliament (MP) from 1945 to 1950 and from 1951 to 1974, when he left the Labour Party to join the Liberals. In 1981 ...
took part in an experiment for
BBC The British Broadcasting Corporation (BBC) is a British public service broadcaster headquartered at Broadcasting House in London, England. Originally established in 1922 as the British Broadcasting Company, it evolved into its current sta ...
's ''
Panorama A panorama (formed from Greek language, Greek πᾶν "all" + ὅραμα "view") is any Obtuse angle, wide-angle view or representation of a physical space, whether in painting, drawing, photography (panoramic photography), film, seismic image ...
'', in which he ingested 400mg of mescaline under the supervision of psychiatrist
Humphry Osmond Humphry Fortescue Osmond (1 July 1917 – 6 February 2004) was an English psychiatrist who moved to Canada and later the United States. He is known for inventing the word '' psychedelic'' and for his research into interesting and useful applicat ...
. Though the recording was deemed too controversial and ultimately omitted from the show, Mayhew praised the experience, calling it "the most interesting thing I ever did". Studies of the potential therapeutic effects of mescaline started in the 1950s. The mechanism of action of mescaline, activation of the
serotonin Serotonin (), also known as 5-hydroxytryptamine (5-HT), is a monoamine neurotransmitter with a wide range of functions in both the central nervous system (CNS) and also peripheral tissues. It is involved in mood, cognition, reward, learning, ...
5-HT2A receptors, became known in the 1990s.


Society and culture


Legal status


United States

In the United States, mescaline was made illegal in 1970 by the Comprehensive Drug Abuse Prevention and Control Act, categorized as a Schedule I hallucinogen. The drug is prohibited internationally by the 1971
Convention on Psychotropic Substances The Convention on Psychotropic Substances of 1971 is a United Nations treaty designed to control psychoactive drugs such as amphetamine-type stimulants, barbiturates, benzodiazepines, and psychedelics signed in Vienna, Austria on 21 February ...
. Mescaline is legal only for certain religious groups (such as the
Native American Church The Native American Church (NAC), also known as Peyotism and Peyote Religion, is a Syncretism, syncretic Native American religion that teaches a combination of traditional Native Americans in the United States, Native American beliefs and eleme ...
by the American Indian Religious Freedom Act of 1978) and in scientific and medical research. In 1990, the
Supreme Court In most legal jurisdictions, a supreme court, also known as a court of last resort, apex court, high (or final) court of appeal, and court of final appeal, is the highest court within the hierarchy of courts. Broadly speaking, the decisions of ...
ruled that the state of Oregon could ban the use of mescaline in Native American religious ceremonies. The
Religious Freedom Restoration Act The Religious Freedom Restoration Act of 1993, Pub. L. No. 103-141, 107 Stat. 1488 (November 16, 1993), codified at through (also known as RFRA, pronounced "rifra"), is a 1993 United States federal law that "ensures that interests in religio ...
(RFRA) in 1993 allowed the use of peyote in religious ceremony, but in 1997, the Supreme Court ruled that the RFRA is unconstitutional when applied against states. Many states, including the state of
Utah Utah is a landlocked state in the Mountain states, Mountain West subregion of the Western United States. It is one of the Four Corners states, sharing a border with Arizona, Colorado, and New Mexico. It also borders Wyoming to the northea ...
, have legalized peyote usage with "sincere religious intent", or within a religious organization, regardless of race. Synthetic mescaline, but not mescaline derived from cacti, was officially decriminalized in the state of Colorado by ballot measure Proposition 122 in November 2022. While mescaline-containing cacti of the genus ''
Echinopsis ''Echinopsis'' is a genus of Cactus, cacti native plant, native to South America, sometimes known as hedgehog cactus, sea-urchin cactus or Easter lily cactus. , there are about 20 accepted species, ranging from large and treelike types to small ...
'' are technically controlled substances under the
Controlled Substances Act The Controlled Substances Act (CSA) is the statute establishing federal government of the United States, federal drug policy of the United States, U.S. drug policy under which the manufacture, importation, possession, use, and distribution of ...
, they are commonly sold publicly as
ornamental plant Ornamental plants or ''garden plants'' are plants that are primarily grown for their beauty but also for qualities such as scent or how they shape physical space. Many flowering plants and garden varieties tend to be specially bred cultivars th ...
s.


United Kingdom

In the United Kingdom, mescaline in purified powder form is a Class A drug. However, dried cactus can be bought and sold legally.


Australia

Mescaline is considered a schedule 9 substance in Australia under the Poisons Standard (February 2020).Poisons Standard February 2020
comlaw.gov.au
A schedule 9 substance is classified as "Substances with a high potential for causing harm at low exposure and which require special precautions during manufacture, handling or use. These poisons should be available only to specialised or authorised users who have the skills necessary to handle them safely. Special regulations restricting their availability, possession, storage or use may apply."


Other countries

In Canada, France, The Netherlands and Germany, mescaline in raw form and dried mescaline-containing cacti are considered illegal drugs. However, anyone may grow and use peyote, or ''Lophophora williamsii'', as well as ''Echinopsis pachanoi'' and ''Echinopsis peruviana'' without restriction, as it is specifically exempt from legislation. In Canada, mescaline is classified as a schedule III drug under the
Controlled Drugs and Substances Act Control may refer to: Basic meanings Economics and business * Control (management), an element of management * Control, an element of management accounting * Comptroller (or controller), a senior financial officer in an organization * Controll ...
, whereas peyote is exempt. In Russia mescaline, its derivatives and mescaline-containing plants are banned as narcotic drugs (Schedule I).


Notable individuals

*
Salvador Dalí Salvador Domingo Felipe Jacinto Dalí i Domènech, Marquess of Dalí of Púbol (11 May 190423 January 1989), known as Salvador Dalí ( ; ; ), was a Spanish Surrealism, surrealist artist renowned for his technical skill, precise draftsmanship, ...
experimented with mescaline believing it would enable him to use his subconscious to further his art potential. *
Antonin Artaud Antoine Maria Joseph Paul Artaud (; ; 4September 18964March 1948), better known as Antonin Artaud, was a French artist who worked across a variety of media. He is best known for his writings, as well as his work in the theatre and cinema. Widely ...
wrote 1947's ''The Peyote Dance'', where he describes his peyote experiences in Mexico a decade earlier. *
Jerry Garcia Jerome John Garcia (August 1, 1942 – August 9, 1995) was an American musician who was the lead guitarist and a vocalist with the rock band Grateful Dead, which he co-founded and which came to prominence during the counterculture of the 196 ...
took peyote prior to forming
The Grateful Dead The Grateful Dead was an American rock band formed in Palo Alto, California, in 1965. Known for their eclectic style that fused elements of rock, blues, jazz, folk, country, bluegrass, rock and roll, gospel, reggae, and world music with psyc ...
but later switched to
LSD Lysergic acid diethylamide, commonly known as LSD (from German ; often referred to as acid or lucy), is a semisynthetic, hallucinogenic compound derived from ergot, known for its powerful psychological effects and serotonergic activity. I ...
and
DMT Dimethyltryptamine (DMT), also known as ''N'',''N''-dimethyltryptamine (''N'',''N''-DMT), is a serotonergic hallucinogen and investigational drug of the tryptamine family that occurs naturally in many plants and animals, including humans. D ...
since they were easier on the stomach. *
Allen Ginsberg Irwin Allen Ginsberg (; June 3, 1926 – April 5, 1997) was an American poet and writer. As a student at Columbia University in the 1940s, he began friendships with Lucien Carr, William S. Burroughs and Jack Kerouac, forming the core of th ...
took peyote. Part II of his poem "Howl" was inspired by a peyote vision that he had in San Francisco. *
Ken Kesey Ken Elton Kesey (; September 17, 1935 – November 10, 2001) was an American novelist, essayist and Counterculture of the 1960s, countercultural figure. He considered himself a link between the Beat Generation of the 1950s and the hippies o ...
took peyote prior to writing ''
One Flew Over the Cuckoo's Nest One Flew Over the Cuckoo's Nest may refer to: * ''One Flew Over the Cuckoo's Nest'' (novel), a 1962 novel by Ken Kesey * ''One Flew Over the Cuckoo's Nest'' (play), a 1963 stage adaptation of the novel starring Kirk Douglas * ''One Flew Over the ...
''. *
Jean-Paul Sartre Jean-Paul Charles Aymard Sartre (, ; ; 21 June 1905 – 15 April 1980) was a French philosopher, playwright, novelist, screenwriter, political activist, biographer, and literary criticism, literary critic, considered a leading figure in 20th ...
took mescaline shortly before the publication of his first book, '' L'Imaginaire''; he had a bad trip during which he imagined that he was menaced by sea creatures. For many years following this, he persistently thought that he was being followed by lobsters, and became a patient of
Jacques Lacan Jacques Marie Émile Lacan (, ; ; 13 April 1901 – 9 September 1981) was a French psychoanalyst and psychiatrist. Described as "the most controversial psycho-analyst since Sigmund Freud, Freud", Lacan gave The Seminars of Jacques Lacan, year ...
in hopes of being rid of them. Lobsters and crabs figure in his novel ''
Nausea Nausea is a diffuse sensation of unease and discomfort, sometimes perceived as an urge to vomit. It can be a debilitating symptom if prolonged and has been described as placing discomfort on the chest, abdomen, or back of the throat. Over 30 d ...
''. *
Havelock Ellis Henry Havelock Ellis (2 February 1859 – 8 July 1939) was an English physician, eugenicist, writer, Progressivism, progressive intellectual and social reformer who studied human sexuality. He co-wrote the first medical textbook in English on h ...
was the author of one of the first written reports to the public about an experience with mescaline (1898). * Stanisław Ignacy Witkiewicz, Polish writer, artist and philosopher, experimented with mescaline and described his experience in a 1932 book ''Nikotyna Alkohol Kokaina Peyotl Morfina Eter''. *
Aldous Huxley Aldous Leonard Huxley ( ; 26 July 1894 – 22 November 1963) was an English writer and philosopher. His bibliography spans nearly 50 books, including non-fiction novel, non-fiction works, as well as essays, narratives, and poems. Born into the ...
described his experience with mescaline in the essay " The Doors of Perception" (1954). *
Jim Carroll James Dennis Carroll (August 1, 1949 – September 11, 2009) was an American author, poet, and punk musician. Carroll was best known for his 1978 autobiographical work '' The Basketball Diaries'', which inspired a 1995 film of the same title ...
in '' The Basketball Diaries'' described using peyote that a friend smuggled from Mexico. *
Quanah Parker Quanah Parker (, ; – February 23, 1911) was a war leader of the Kwahadi ("Antelope") band of the Comanche Nation. He was likely born into the Nokoni ("Wanderers") band of Tabby-nocca and grew up among the Kwahadis, the son of Kwahadi Coman ...
, appointed by the federal government as principal chief of the entire
Comanche The Comanche (), or Nʉmʉnʉʉ (, 'the people'), are a Tribe (Native American), Native American tribe from the Great Plains, Southern Plains of the present-day United States. Comanche people today belong to the List of federally recognized tri ...
Nation, advocated the syncretic Native American Church alternative, and fought for the legal use of peyote in the movement's religious practices. *
Hunter S. Thompson Hunter Stockton Thompson (July 18, 1937 – February 20, 2005) was an American journalist and author, regarded as a pioneer of New Journalism along with Gay Talese, Truman Capote, Norman Mailer, Joan Didion, and Tom Wolfe. He rose to prom ...
wrote an extremely detailed account of his first use of mescaline in "First Visit with Mescalito", and it appeared in his book '' Songs of the Doomed'', as well as featuring heavily in his novel ''
Fear and Loathing in Las Vegas ''Fear and Loathing in Las Vegas: A Savage Journey to the Heart of the American Dream'' is a 1971 novel in the gonzo journalism style by Hunter S. Thompson. The book is a ''roman à clef'', rooted in autobiographical incidents. The story fol ...
''. * Psychedelic research pioneer
Alexander Shulgin Alexander Theodore "Sasha" Shulgin (June 17, 1925 – June 2, 2014) was an American biochemist, broad researcher of synthetic psychoactive compounds, and author of works regarding these, who independently explored the organic chemistry and ph ...
said he was first inspired to explore psychedelic compounds by a mescaline experience. In 1974, Shulgin synthesized
2C-B 2C-B, also known as 4-bromo-2,5-dimethoxyphenethylamine or by the slang name Nexus, is a synthetic psychedelic drug of the 2C family, mainly used as a recreational drug. It was first synthesized by Alexander Shulgin in 1974 for use in psychoth ...
, a psychedelic phenylethylamine derivative, structurally similar to mescaline, and one of Shulgin's self-rated most important phenethylamine compounds together with Mescaline,
2C-E 2C-E is a Psychedelic drug, psychedelic phenethylamines, phenethylamine of the 2C (psychedelics), 2C family. It was first synthesized by Alexander Shulgin and documented in his book ''PiHKAL''. Like the other substances in its family, it produces ...
,
2C-T-7 2C-T-7, also known as 4-propylthio-2,5-dimethoxyphenethylamine, is a psychedelic phenethylamine of the 2C family. In his book '' PiHKAL: A Chemical Love Story'', Alexander Shulgin lists the dosage range as 10–30  mg. 2C-T-7 is generall ...
, and 2C-T-2. * Bryan Wynter produced ''Mars Ascends'' after trying the substance for the first time. *
George Carlin George Denis Patrick Carlin (May 12, 1937 – June 22, 2008) was an American stand-up comedian, social critic, actor and author. Regarded as one of the greatest and most influential comedians of all time, he was dubbed "the dean of countercultur ...
mentioned mescaline use during his youth while being interviewed in 2008. *
Carlos Santana Carlos Humberto Santana Barragán (; born July 20, 1947) is an American guitarist, best known as a founding member of the Rock music, rock band Santana (band), Santana. Born and raised in Mexico where he developed his musical background, he r ...
told about his mescaline use in a 1989 ''
Rolling Stone ''Rolling Stone'' is an American monthly magazine that focuses on music, politics, and popular culture. It was founded in San Francisco, California, in 1967 by Jann Wenner and the music critic Ralph J. Gleason. The magazine was first known fo ...
'' interview. * Disney animator
Ward Kimball Ward Walrath Kimball (March 4, 1914 – July 8, 2002) was an American animator employed by Walt Disney Animation Studios. He was part of Walt Disney's main team of animators, known collectively as Disney's Nine Old Men. His films have been honor ...
described participating in a study of mescaline and peyote conducted by
UCLA The University of California, Los Angeles (UCLA) is a public land-grant research university in Los Angeles, California, United States. Its academic roots were established in 1881 as a normal school then known as the southern branch of the C ...
in the 1960s. *
Michael Cera Michael Austin Cera ( ; ; born June 7, 1988) is a Canadian actor. Over his career he has received nominations for a British Academy Film Award, three Critics' Choice Movie Awards, four Screen Actors Guild Awards, and a Tony Award. Cera beca ...
used real mescaline for the movie '' Crystal Fairy & the Magical Cactus'', as expressed in an interview. * Philip K. Dick was inspired to write '' Flow My Tears, the Policeman Said'' after taking mescaline. * Arthur Kleps, a psychologist turned drug legalization advocate and writer whose Neo-American Church defended use of marijuana and hallucinogens such as LSD and peyote for spiritual enlightenment and exploration, bought, in 1960, by mail from Delta Chemical Company in New York 1 g of mescaline sulfate and took 500mg. He experienced a psychedelic trip that caused profound changes in his life and outlook.


Research

Mescaline has a wide array of suggested medical usage, including treatment of depression, anxiety, PTSD, and
alcoholism Alcoholism is the continued drinking of alcohol despite it causing problems. Some definitions require evidence of dependence and withdrawal. Problematic use of alcohol has been mentioned in the earliest historical records. The World He ...
. However, its status as a Schedule I controlled substance in the
Convention on Psychotropic Substances The Convention on Psychotropic Substances of 1971 is a United Nations treaty designed to control psychoactive drugs such as amphetamine-type stimulants, barbiturates, benzodiazepines, and psychedelics signed in Vienna, Austria on 21 February ...
limits availability of the drug to researchers. Because of this, very few studies concerning mescaline's activity and potential therapeutic effects in people have been conducted since the early 1970s.


See also

* List of psychedelic plants **
Mind at Large The mind is that which thinks, feels, perceives, imagines, remembers, and wills. It covers the totality of mental phenomena, including both conscious processes, through which an individual is aware of external and internal circumstances, ...
(concept in ''The Doors of Perception'') * '' The Psychedelic Experience: A Manual Based on the Tibetan Book of the Dead'' (1964) * '' Der Meskalinrausch, seine Geschichte und Erscheinungsweise'' (1927)


References


Further reading

* * *


External links

*
Mescaline: The Chemistry and Pharmacology of its Analogs
an essay by
Alexander Shulgin Alexander Theodore "Sasha" Shulgin (June 17, 1925 – June 2, 2014) was an American biochemist, broad researcher of synthetic psychoactive compounds, and author of works regarding these, who independently explored the organic chemistry and ph ...

Mescaline on the Mexican Border
{{Chemical classes of psychoactive drugs 5-HT2A agonists 5-HT2B agonists 5-HT2C agonists Alexander Shulgin Alkaloids found in Fabaceae Cacti Entheogens Experimental hallucinogens Native American Church Phenethylamine alkaloids Scalines Serotonin receptor agonists TAAR1 modulators