Mescaline

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Mescaline (3,4,5-trimethoxyphenethylamine) is a substance of plant origin. It belongs to phenylethylamine group and entheogenic class of psychoactive substances. It has mostly psychedelic effects like LSD and, to some extent, psilocybin, however, one of mescaline distinctive effects is higher level of sociability. This substance is found in cacti genera Lophophora and Echinopsis (known before as trichocereus). The most common species of the above-mentioned cacti are Peyote, San Pedro, and Peruvian Torch. These species of plants have slow goth rate, they are most commonly found in southern parts of the USA, Mexico, Central and South America. Also, some acacia species can contain certain amounts of mescaline, for example, Acacia Berlandieri and Fernasiana, however, aside from mescaline they contain significantly higher concentrations of other psychoactive substances, Chronology of mescaline use goes back at least 5000 years, there is archaeological data evident of that. Initially, either fast-growing cacti San Pedro, which tower over mountainous desert shrubs in the Andes, or slow-growing creeping Peyote were consumed. Europeans first encountered Peyote at the beginning of sixteenth century when Spain defeated Mexico. Missionaries’ attempts to ban the use of cacti turned out to be successful. In fact, it resulted in various Peyote-using rituals spreading among Native Americans (e.g. Osage Nation) after they had to move to reservations. Up to twentieth century there was only small number of people who knew about mescaline and neither belonged to nor shared the culture of the American indigenous peoples. Their reports about this substance effects provoked huge interest in medicine and spirituality. In traditional rites, the phase of hallucinations is described as “constantly shifting/drifting”. In 1887, a doctor from Texas John Raleigh Briggs (1851–1907) first described in a medical magazine his own symptoms during use of this substance, which were pronounced and intense including, among other symptoms, increased heart rate and difficulty breathing after eating a small part of “Peyote button”- dried top of the cactus. Pharmaceutical company Parke-Davis in Detroit, which was researching botanical sources of potential medicine of South America and other countries, took note of this information because they were searching for cocaine alternative. In 1983 representatives of this company offered Peyote tincture as a psychostimulant. After that, by trial and error studies of mescaline began with no ethical and safety considerations at that point.

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In 1895, two reports describing unpredictability of this substance came out from the organization, which is now called George Washington University in Washington. In one of them a young chemist chewed a ” Peyote button”, then described the following symptoms: nausea, followed by pleasant visions, which he had control over to some extent, then depression and insomnia occurred which lasted 8 hours. In 1897, German chemist Arthur Carl Wilhelm Heffter first managed to isolate and identify mescaline from Peyote. In 1913, pharmacologists Alwyn Knauer and William Maloney carried out rather big study at that time on 23 participants; they hoped that mescaline could reveal the mystery of schizophrenia and most of the other psychotic events. However, the experiments didn't reveal any pattern that could help solve their problem. In 1919 Ernst Späth first synthesized mescaline. At that time mescaline was one of the first psychedelics used by western intellectuals, such as Aldous Huxley, (who was offered mescaline by his psychiatrist Humphry Osmond) who described its effects in his essay "The Doors of Perception" in 1954. Huxley gave a very sincere feedback, calling mescaline “a window to the world as it really is, not the way people perceive it”. According to his words, mescaline use is a priceless experience for everybody, especially for intellectuals. But the epic milestones of history do not end there. In 1955, Osmond gave 400 mg to a member of British Parliament Christopher Mayhew in BBC documentary film, but the footage of this episode was excluded from the show. Now this historic moment is available for watching here. Mayhew called this experience “the most interesting thing that he has ever done”. At that moment, governments of many countries were interested in mescaline, but their interest was exclusively political. It was known from history that mescaline was used as truth serum by the nazi in concentration camps during the World War II. CIA had this information and funded the CHATTER project, continuing the trials of mescaline as truth serum etc. In 1953, this project was officially discontinued after 6 years from its start. Also, mescaline is an important part of Alexander Shulgin’s life, who used it as a starting point of synthesis of dozens of new psychedelic phenylethylamine compounds, which belong to the families 2С-х and DOx, working under the auspices of Dow Chemical Company in the 1960s. Mescaline is a part of the so - called "magical half-dozen", which includes the most important phenylethylamine compounds. Peyote became more famous in 1960s due to anthropologists officially documenting the sacred hunt for Peyote with Indians Huichol. American anthropologist and writer Carlos Castaneda became one of the important popularizers of mescaline after he published his own Peyote trip in the book "The Teachings of Don Juan: A Yaqui Way of Knowledge", which became a bestseller. The other name, associated with mescaline at that time, was Hunter Stockton Thompson, who described his experience with mescaline in the well-known book "Fear and Loathing in Las Vegas: A Savage Journey to the Heart of the American Dream". It is interesting to note, that if you track Google queries on mescaline and Peyote, the most publications on the subject will peak in 1940-1950s, then there will be a sharp spike in 1960-1970s just after Carlos Castaneda’s book. Then, in thje 1990s the number of publications will rise again, presumably, due to Peyote listing as endangered species by Mexican government and the 1994 amendment to American Indian Religious Freedom Act. Meanwhile, since 2004 search queries on Peyote has shown an increase related to mescaline, this can be explained by a presence of Peyote in a game Grand Theft Auto V. There is a myth that mescal beans contain mescaline. However, this is not true. Though “mescal beans” Sophora secundiflora have certain psychoactive properties, they do not contain mescaline at all. The term "mescal" was initially misinterpreted and applied to Peyote, more specifically to its tops, “buttons”; actually this word comes from "mexcalli", which in the Aztec language Nahuatl means «agave». In recent history, according to Global Drug Survey as of 2014, mescaline and Peyote have been in top 20 the most popular psychoactive drugs exclusively in Mexico. Nowadays popularity of mescaline is very little, nevertheless, relevance and significance of the substance from the moment of its discovery still remains.

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Mescaline has been documented in many species aside from Lophophora williamsii (the actual peyote) and T. pachanoi (wachuma, San Pedro, San Pedro hembra). Nevertheless, this alkaloid is seldom abundant and, because of its low psychedelic potency (oral doses of about 300 mg of the free base are required for a full-blown hallucinogenic experience), L. williamsii and T. pachanoi are the only widely consumed botanical sources. T. peruvianus (Peruvian torch, San Pedro macho) and T. bridgesii (Bolivian torch), both also called wachuma, are used, though less frequently. An exhaustive list of mescaline-containing cacti and their chemistry was compiled by Trout. Regarding the nomenclature of these cacti, the genus Lophophora was only segregated from Anhalonium by Coulter in 1894, explaining why peyote was called Anhalonium williamsii or A. lewinii in the early literature. The homeopathic pharmacopoeia still retains the older name. Today, there are only two generally recognized Lophophora species, L. williamsii and L. diffusa (Queret́aro peyote). The latter contains little mescaline, and the tetrahydroisoquinoline pellotine is the main alkaloid. This may have been the material first analyzed by Heffter. His “pellote” paper includes two beautiful illustrations by R. Sperling of Anhalonium williamsii and Anhalonium lewinii. Studying a sample of plants founds in commerce in Japan and probably not representative of wild populations, it was suggested that there are two different forms of L. williamsii, one of them lacking mescaline, that can be distinguished from each other and from L. dif f usa morphologically, on the basis of their mescaline content and by the length of a chloroplast DNA sequence.19 Trichocereus is a South American genus comprising about 45 species. It has been proposed that Trichocereus be included in the related Echinopsis, but this change is not supported by DNA analysis.20,21 As a consequence, T. pachanoi sometimes appears in the literature as E. pachanoi, T. peruvianus as E. peruviana and, more confusingly, T. bridgesii as E. lageniformis. Moreover, T. pachanoi and T. peruvianus have recently been combined into a single species as T. macrogonus var. pachanoi and T. macrogonus var. peruvianus. In this review, we retained the traditional name Trichocereus. As early as 1898, Heffter remarked that the upper chlorophyll containing part of what he called Anhalonium williamsii is very bitter, while the roots are hardly bitter at all. An analysis carried out on cacti received “fresh from Saltillo” showed that the green tops contained 6−7 times higher concentrations of total alkaloids than the rest of the plant. Klein et al. reported that 10 individual peyote plants from a southern Texan population contained (calculated on dry weight) 1.82−5.5% mescaline in the crown and 1−2 orders of magnitude less in the nonchlorophyllous stem and root, lending modern support to Heffter’s work and the traditional use of the tops. Nevertheless, a recent paper reported the analysis of the crown and the root of a single L. williamsii plant, which gave similar total alkaloid contents in both parts but with radically different compositions. Practically all the mescaline (15.7% of the alkaloids) was found in the crown with the simple isoquinolines anhalidine, pellotine, lophophorine, and anhalonine making up most of the rest (14.6,19.8,13.3 and 6.0%, respectively), and very little of these in the “root”, where the phenethylamine hordenine was by far the major alkaloidal component. Natural sources of mescaline include: lophophora williamsii (mescaline 3-6%) lophophora diffusa (hordenine 0.5% of total alkaloid, N-methyltyramine 0.1% of total alkaloid, mescaline - trace); echinopsis pachanoi(mescaline 0.006-0.12%); echinopsis peruviana (mescaline 0.0005%-0.12%); echinopsis lageniformis (mescaline 0.025%,3,4-Dimethoxyphenylethylamine 1%, 3-Methoxytyramine 1%, tyramine 1%); echinopsis macrogona (mescaline - 0.01-0.05%);echinopsis tacaquirensis (mescaline - 0.005-0.025%); echinopsis terscheckii (mescaline - 0,005-0,025%); echinopsis valida (mescaline - 0.025%); opuntia basilaris (mecaline - 0.01%); cylindropuntia spinosior (mescaline - 0.00004%).

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Back in his early years, Heffter began to study mescaline by synthesis of various salts, including neutral sulfate dihydrate. Surprisingly, he reported a free base, which had an appearance of a solid substance softening at the temperature exceeding 100 °C, with a melting point about 150 °C. Unfortunately, the substance wasn't analyzed and presumably was a carbonate, because mescaline, as it is known, easily absorbs CO2 and water. Mescaline itself as a pure substance has an appearance of white crystalline or powdery substance. A more complicated method of extraction produces more concentrated and pure substance, such as mescaline sulfate or hydrochloride. The substance has a chemical structure of substituted phenylethylamine, which contains a phenyl ring, bound to the amino-NH2 group via an ethyl chain. Also mescaline has three metoxy- functional groups, attached to carbon atoms at R3-R5 of the phenyl ring. The full name of mescaline is 2-(3,4,5-trimethoxyphenyl)-ethanamine. Boiling point is 180 °С at 12 mmHg., melting point 35.5 °С, moderately soluble in water (with calculated parameters 8.41X10+4 mg/L at 25 °C), in ethanol (poorly soluble in lignin), chloroform and benzene, but almost insoluble in the ether and petroleum ether; log Kow = 0.78; Henry's Law constant = 1.68X10-10 atm-cu m/mol at 25 °C; рКа=9.56; needles: melting point 181 °C; soluble in water, alcohol.

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Pharmacokinetics and pharmacodynamics.
Biosynthesis process of mescaline starts from tyrosine, which is produced from phenylethylamine by phenylalanine hydroxylase. In Lophophora williamsii dopamine transforms into mescaline through a pathway, which includes m-O-methylation and aromatic hydroxylation. Tyrosine and phenylalanine act as metabolic precursors in mescaline biosynthesis. Tyrosine either undergoes decarboxylation by tyrosine decarboxylase producing tyramine or, first, is hydroxylated by tyrosine hydroxylase into L-DOPA and then decarboxylated into DOPA. They create dopamine, which is methylated by COMT, and the resulting intermediate product is again oxidized by hydroxylase, then by monophenol hydroxylase at 5 carbon atoms, then it is again methylated by COMT. The resulting product, methylated in two meta-positions with respect to the alkyl substituent, undergoes final methylation at 4 carbon atoms mediated by guaiacol-O-methyltransferase by a SAM-dependent mechanism, which yields mescaline. Mescaline is rapidly absorbed in gastrointestinal tract, a significant amount of the dose is distributed in kidneys and liver, it binds to the respectable liver proteins, keeping the concentration in blood and increasing half-life. This "delays" the onset of psychoactive effect. Mescaline has poor ability to pass the blood-brain barrier, high doses are needed for that to happen. Usually, the onset of effects is within 30 minutes since use, the peak of psychedelic effect is after two hours with a gradual decline for ten hours. Peak of effects doesn't always coincide with peak concentrations of mescaline in the brain, which allows us to assume that mescaline undergoes bioactivation for it to reach maximum efficacy. In studies with prior administration of chloropromasine 30 minutes before administration of trance-dosage of mescaline, a significant retention of hallucinogen in the brain and other studied tissues occurred due to blockade of mescaline elimination from different tissues. Half life period of mescaline after oral administration is about six hours in humans, about 80% is excreted unchanged in urine during the first hour. About 13% of the dose is excreted in a form of 3,4,5-trimethoxypheny-lacetic acid, elimination rate of this metabolite increases with time. 87% TMP-A is eliminated within the first 24 hours and reaches 96% at 48 hours. Mescaline can be detected in urine within 3 days, in hair samples – within 90 days. In blood tests, mescaline can be detected approximately within 24 hours since use, in saliva – within 10 days. According to the data of numerous studies, insignificant amount of other metabolites can be detected in urine as well, for example: N-acetyl-3,4-dimethoxy-5-hydroxyphenylethylamine, 3,4,5-trimethoxybenzoic acid, 3,4-dimethoxy-5-hydroxyphenethylamine and 3,4-dihydroxy-5- methoxyphenacetylglutamine. Mescaline undergoes metabolism mostly through the oxidative deamination pathway yielding an intermediate unstable aldehyde - 3,4,5-trimethoxyphenylacetaldehyde, which, in turn, is rapidly oxidized into inactive TMP-A or reducted into inactive 3,4,5-trimethoxyphenylethanol. The fact that there is inconsistency in peak of mescaline effects and its brain concentrations is evident of mescaline metabolites contributing to its hallucinogenic effects. The enzyme responsible for deamination of mescaline into aldehyde derivative remains unknown to this day. This process can be mediated by both monoamine oxidase and diamine oxidase. However, it has been proved that this metabolic pathway is inhibited by TPN, nicotinamide, iproniazide and semicrbazide. TMP-A is metabolized into 3,4-dihydroxy-5- methoxyphenylacetic acid or 3,4,5-trimethoxybenzoic acid. The first metabolite of mescaline is formed as a result of demethylation of TMP-A, then it combines with glutamine by glutamine N-acyltransferase and is excreted in urine in the form of 3,4-dihydroxy-5-methoxyphenacetylglutamine. This reaction is similar to amphetamine degradation yielding benzoic acid, which combines with glycine and is eliminated from the body. The highest concentration of 3,4,5-TMPA is detected in the brain compared to the other tissues (liver, heart and kidneys), this explains the position of the enzyme catalyzing the formation of TMP-A, which is located in the nuclear and microsomal fractions of this organ. MAO and DAO inhibitors do not affect the formation of this metabolite. N-acetylation of mescaline is the most important metabolic pathway in the brain, which results in the formation of such metabolites as N-acetylmescaline, N-acetyl-3,5-dimethoxy-4-hydroxy-phenylethylamine and N-acetyl-3,4-dimethoxy-5-hydroxy-phenylethylamine. The above-mentioned derivatives comprise about 30% of the total number of metabolites excreted in urine, and N-acetylation is the main pathway of detoxication of mescaline in the central nervous system. Secondary metabolic pathways include its demethylation by O-demethylase to 3,5-dimethoxy-4-hydroxyphenethylamine and 3,4-dimethoxy-5-hydroxy-phenethylamine, yielding formaldehyde. The above-mentioned reaction doesn't depend on CYP2D6 metabolism. Minor metabolite 3,4-dihydroxy-5-methoxyphene-thylamine is methylated into 3,5-dimethoxy-4-hydroxyphene-thylamine by catecholamine O-methyl transferase. As other biogenic amines, mescaline has the ability to be bioactivated by dopamine-β-hydroxylase, which, in the end, leads to formation of β-hydroxymescaline. However, to this date, this metabolite hasn't been identified in humans.
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5-HT2A/2B and /2С receptor subfamilies, characterized by significant homology: 46-50% in the total amino acid sequence and more than 70% in transmembrane domains, regulate excitatory neurotransmission through the G-protein family (predominantly Gaq or Gq/11), which activate phospholipase C, leading to hydrolysis of phosphatidylinositol 4,5-bisphosphate into soluble inositol-1,4,5-triphosphate, thereby increasing its cytosolic level. Further, IP3 already diffuses through the cytosol and binds to the corresponding IP-3 receptors, especially with calcium channels in the endoplasmic reticulum, increasing the level of cytosolic calcium. 5-HT2 receptors have different expression profiles with their distribution in cortex, locus coeruleus, basal ganglia, hippocampus, platelets and vascular smooth muscle. Hallucinogenic effects of mescaline are realized by intervention in serotonergic mechanisms of neurons due to its agonistic properties; though it doesn't have affinity to 5-HT1А, its action it manifests mainly at the level of 5-НТ2, while the affinity to 5-НТ2А and 2В receptors is relatively low compared to /2С form, which he is a full agonist for. Low doses of mescaline decrease 5-hydroxyindoleaceticacid (5-HIAA) level, which is the main metabolite of serotonin, high doses of this substance increase 5-HIAA level. According to this effect, mescaline increases release and/or reuptake of serotonin. Cross tolerance between mescaline and other serotonergic substances (e.g. LSD or psilocybin) is experimentally proved both in humans and in animals; it is developed after a couple of days of use, but the sensitivity is restored very quickly, within a few days. Mescaline effect is approximately 1000-3000 times weaker than that of LSD and 30 times weaker than that of psilocybin. Though mescaline is similar to other hallucinogenic drugs in terms of its mechanism of action, its effect is the least powerful among other substances of the group. However, its effect can last up to twelve hours. Mescaline, possibly, is not selective towards release of inositol-1,4,5-triphosphate and arachidonic acid. There are no studies regarding other ways of signal transmission, such as β-arrestin involvement. Catecholamines participate in neurotransmission and neurotoxicity, most of their biochemical properties are due to the presence of catechol, which undergoes oxidation to o-quinone and semiquinone. Thus, catechol it undergoes an oxylation-reduction cycle with its quinone analogue. Reports about mescaline transforming into catechol confirm ET participation in the process, as it is with catecholamine analogues. The similarity is also due to the presence of an aminoethyl side chain, which in some cases is substituted.

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Clinical effects, methods of use and doses.
Mescaline experience is influenced by many factors, including dosage, way of thinking, setting and way of administration. Considering this fact, every individual trip will be unique for each person, time and place, so it is impossible to predict exactly what will happen. Mescaline effect is usually perceived during 45-90 minutes after administration, reaches its peak in two to four hours and lasts up to eight hours. During this time user will see imagery of flowers and patterns such as mosaics, arabesques and spirals on closed eyes. These visual effects often transform into some distinct objects, such as architecture, animals and people. At the same time, regular objects in the user’s environment may seem fascinating, beautiful and surprisingly mystical – having the qualities that determine mescaline experience. The physical environment, including the user’s body, distorts in size and shape, sometimes it may feel like “losing” a limb or, for example, that solid objects (rocks and walls) have suddenly become soft and pliable to the touch. Other sensory organs become involved sometimes up to synesthesia: looks can be “heard”, thoughts can be “smelt”, sounds can be “tasted”. Mescaline often provokes temporary depersonalization and ego dissolving; the world seems to be “whole”. This experience can induce clear and interconnected thoughts, self-realization, empathy and cognitive euphoria; every thought may be deep and significant. Depersonalization is temporary, so it doesn't cause anxiety in most users. It is important to note that the effects of isolated mescaline are different from the cactus because the latter contains other alkaloids, which alter the true mescaline trip. Mescaline induces a psychedelic state similar to those produced by LSD and psilocybin, 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 that turn very complex. The English writer Aldous Huxley 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. 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 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 can occurr 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 painting.
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The apogee of this effect is true physical euphoria, similar to effects of psilocin. Tactile enhancement occurs on administration of medium and high doses of mescaline, they're proportionately intense compared to accompanying visual and cognitive effects. Usually, this effect of mescaline manifests in different pleasant sensations in the whole body.
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One of the desirable effects of mescaline is psychostimulation, which is not pronounced as psychostimulation induced by amphetamine-like substances. Spontaneous bodily sensations due to the use of this substance are characterized as is a constant and intense feeling of sudden realization and ability to feel the world with every nerve ending, almost all types of sensitivity are enhanced. The level of control over one's body improves, libido increases, the level of perception of objective reality improves, a person finds a creative approach to any activity that they are performing during mescaline trip, comes up with new ideas. Cognitive euphoria, which occurs even at low doses of mescaline, is characterized by positive psychoemotional state; a person feels mental tranquility and well-being, moderate delight and happiness. On increasing the dose, this type of euphoria is overlapped by physical euphoria. As other entactogens, mescaline increases present empathogenicity, feeling of belonging appears, sociability increases, sympathy effects predominate when there are certain factors. Mescaline is a “social” psychedelic, which means that it is very likely to make the user feel confident in a conversation, for comparison, - mushrooms are introverted psychedelics, which encourage the user to withdraw from socialite to be alone. Focus enhancement, immersion enhancement, increased music appreciation, ego death, motivation enhancement, personal bias suppression are the classic effects due to hallucinogenic psychoactive substances, including mescaline. Hallucinogenic effects of mescaline including hearing distortion, which manifests itself in improving the quality of interpretation of the sound wave, enhancing the sharpness and clarity of sound, auditory distortion (for example, audible monotonous low-frequency noise, or distortion of any sounds in the form of echo signals). At high doses of mescaline appearance of non-existent sounds or transformation of the existing ones, appearance of voices, music, cracking or scratching. As for hallucinatory states, mescaline induces a rather high level of visual geometry, including the appearance of autonomous objects (rarely), changes in geometry of the surroundings. Visual distortions begin to appear even at low doses of mescaline, there are fluidity, "breathing" or transformation of images, objects, people's faces, change of colors, a symmetrical repetition of the visible textures (for example, if you concentrate on the carpet, it can "come to life"), various faint traces of moving objects appear (similar to how it happens in a photograph with a long exposure). Geometric imagery is characterized by fast-moving, colourful and complicated geometric patterns, which appear on closed eyes, they have different colours, smooth movement and mostly glossy colors, as a rule, this geometry is considered to be level 8A. Internal mescaline hallucinations are realized after administration of a high dose in the form of partially distinguishable images, blurred and faded in the field of view. Full immersion into an extensive scene and appearance of some autonomous creature are rare, most often it is an improvement of mental visualization with surface immersion into user’s own imagination. There is a short-term detachment from the immediate environment, reality is smeared and partially replaced by an indefinite fantasy, and the details of this visualization are spontaneous and controlled by the contents of the current stream of thoughts. It starts from zoom changes, which transform into morphing or sliding with interactive fixation (something similar to watching a video of one’s life with different inclusions from their consciousness and thoughts) within 10-15 minutes. Compressed geometry appears, and, finally, “at the exit” gradual immersion into one’s thoughts occurs with periodic geometric inclusions, the user fully understands that they are in a mescaline trip and objectively assesses the situation (except for the cases of bad trips and anxiety). Side effects include, first of all, nausea, sweating, disturbed speech at high doses, constipation, impaired potency, dysuria, headache, dysfunctional disorders of the gastrointestinal tract, increased salivation, muscle spasms, appetite suppression, increased heart rate and periodic convulsions (very rarely after mescaline use). Most people using mescaline or mescaline-containing plants consider its effects transforming the personality, and many users begin to appreciate their life and its role in the universe. Sometimes, even a simple thought about a separate identity may seem “inappropriate”. Others feel deep gratitude and unconditional compassion for everyone and everything that surrounds them at the moment or sometime after the trip. Early studies of mescaline showed that this experience gives people energy to live and improved well-being. According to a ritual use of Peyote by Indians, mescaline can also help people to solve complicated problems. In one study consisting of giving mescaline to 27 men and asking them to solve a problem they encountered at work, after one dose each participant either solved the problem or came up with a method of solving it.

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The most common are capsules, containing mescaline, but, as a rule, they contain only synthetic mescaline or mescaline in high concentrations because too much cactus is required to get psychoactive effects. The “Toss & Wash” method consists of oral administration of raw mescaline cactus; however, it has a very bitter taste, so to get the desired effect a lot of it should be consumed. Smoking is a rare method, which is barely used nowadays; dried peyote or San Pedro cactus is ground and mixed with tobacco, then administered by inhalation, unfortunately, most of the mescaline is destroyed during combustion. Ingesting mescaline by making tea is used as an alternative to the first method. So, a couple of cactus pieces are added to a pot with water, then it is boiled during 10-20 minutes, after that, it is consumed, however, high temperatures destroy mescaline as well, which can make its effects weak. Sometimes other herbs are added as well, which help with gastrointestinal side effects (ginger and peppermint). Usually, 3-6 buttons of cactus (or 10-20 g of dried peyote) are equivalent to 200-400 mescaline hydrochloride, nevertheless, concentration of these substances significantly depends on the species, geoclimatic conditions, development, age and harvested part and many other factors. Mescaline dosage varies, though insignificantly, depending on method of extraction of this compound. For example, 100 mg of mescaline hydrochloride is equivalent to 111 mg mescaline sulfate or 85 mg of mescaline free base. All of these are threshold concentrations acting as a starting point for calculating a dose. The most common range for mescaline hydrochloride is 200-300 mg, which is considered a medium dose. Doses from 300 to 500 mg are considered high, doses more than 500 mg are extremely high and are not recommended for inexperienced users. Many users have included microdosing into their week schedule, and they report increased creativity levels, anxiety, stress, depression reduction. Some enthusiasts also claim that microdosing of mescaline helped them to improve their spiritual awareness and feeling. Aside from positive cognitive effects of mescaline, it also has moderate anti-inflammatory effects. Study as of 2008 by Bangning Yu showed that mescaline has extremely powerful anti-inflammatory effect, while in 2018 Thomas W. Flanagan published data on psychedelics helping inflammatory cascade regulation, which may have an important therapeutic potential for treatment of such diseases as asthma, atherosclerosis, inflammatory diseases of the gastrointestinal tract and so on. Doses from 10 to 50 mg of mescaline hydrochloride are used in microdosing. Tolerance to mescaline develops almost instantly after ingestion. After that, 3 days are required to lower the tolerance and 7 days are required for it to go back to the initial level (in the absence of repeated use). Mescaline demonstrates cross-tolerance with all other psychedelics; this means that after ingestion of mescaline, all psychedelics will have decreased effects. It is strongly not recommended to use mescaline together with αMT. Caution is advised when using mescaline together with the following psychoactive substances (due to a high risk of side effects and deterioration of the condition): DOx, NBOMes, 2C-x, 2C-T-x, 5-MeO-xxT, cannabis, amphetamines, cocaine, MAOls, tramadol. There is a risk of increase (or decrease) of effects due to synergy between mescaline and the following substances (exclusively in low or medium doses): MDMA, N2O, PCP, caffeine, opioids, DXM, MXE, ketamine, DMT, LSD, mushrooms, alcohol, GHB/GBL, benzodiazepines, SSRls.

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Mescaline use implies very low risk for the user, even though there are certain side effects. There are no lethal outcomes directly associated with mescaline use. Theoretical median lethal dose for mescaline is about 880 mg/kg, which is considered extremely high, 300 times exceeding standard psychoactive dose. 12-year review of the California Database of Poison Control Centre revealed only 31 cases of mescaline toxicity for quite long period of time and no lethal cases. Certainly, there are other risks of mescaline use, which are mostly associated with mental disorders such as paranoia or anxiety disorder. Nevertheless, a number of studies have been published stating that psychedelics including mescaline have a very low risk of inducing mental disorders even after a “bad experience”. Mescaline doesn't cause addiction like most classic psychedelics. Surveys show that average recreational user of psychoactive cacti or mescaline uses it 2-3 times in their life, which is very far from “drug abuse”. Moreover, studies show that mescaline has anti-dependent properties; it is one of the best candidates, which has been currently tried as a component in treatment of addiction due to psychoactive substances. So, it is distinguished from other psychedelics such as ayahuasca, psilocybin and LSD due to its potential to be a solution to the problem of addiction in a commonly spread epidemic of drug use. Studies on ceremonial use of Peyote among Native Americans have revealed that mescaline doesn't have long-term consequences, while risk of developing HPPD is the least compared to all other hallucinogens. Since mescaline is associated with abnormal fetal development, it is prohibited for use by pregnant or nursing women. It is recommended to avoid sharp objects and objects which you can stumble upon while using mescaline. It is reasonable to provide easy access to water, a toilet or a bucket, just in case. A responsible sitter is also a great idea, at least for beginners. Mescaline should be ingested on an empty stomach to minimize nausea and increase absorption, 3-4 days prior it is recommended to start a course of omeprazole in therapeutic doses. Mescaline can increase learning ability. So, in experiments on fish which were administered low doses of mescaline, scientists have found that mescaline helped the fish to learn how to avoid shock. As with many others psychedelic substances, the potential of mescaline as a therapeutic substance was studied from 1950 to 1960, especially, in combination with LSD. First results revealed that mescaline can be used for successful treatment of addiction and depression. Study of mescaline therapeutic potential are still limited, however, renewed interest to this drug shows that it can be successfully used in the treatment of mental disorders. It has been found in experiments that mescaline can increase blood flow and activity in prefrontal cortex, which is an area responsible for planning, problem-solving, emotional regulation and behavior. Low activity of this area is associated with depression and anxiety, which encouraged scientists to assume that mescaline can relieve the symptoms of these disorders. As a result of studies, it has been revealed that antidepressive effect of mescaline correlates with the willingness of the subjects to participate in the experience, to face their inner self and act in accordance with the findings. According to researchers from the University of Alabama, mescaline can contribute to the reducing of suicidal thoughts. Using the data from National survey of drug use and health, scientists found out that people who used a psychedelic substance at least once in their life demonstrate lower level of suicidal thoughts. The study as of 2013 showed that lifelong use of mescaline or Peyote in small doses is associated with lower level of agoraphobia, anxiety disorder, which makes subjects perceive the environment as threatening. And, as it has been mentioned above, addiction is another promising application of mescaline therapeutic potential. Thus, researchers from Harvard medical school came to the conclusion that mescaline causes a statistically significant decrease in alcoholism and drug abuse, and it can be used in treatment of addiction both in terms of monotherapy and in multicomponent treatment.​

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Mescaline (3,4,5-trimethoxyphenethylamine) is a substance of plant origin. It belongs to phenylethylamine group and entheogenic class of psychoactive substances. It has mostly psychedelic effects like LSD and, to some extent, psilocybin, however, one of mescaline distinctive effects is higher level of sociability. This substance is found in cacti genera Lophophora and Echinopsis (known before as trichocereus). The most common species of the above-mentioned cacti are Peyote, San Pedro, and Peruvian Torch. These species of plants have slow goth rate, they are most commonly found in southern parts of the USA, Mexico, Central and South America. Also, some acacia species can contain certain amounts of mescaline, for example, Acacia Berlandieri and Fernasiana, however, aside from mescaline they contain significantly higher concentrations of other psychoactive substances, Chronology of mescaline use goes back at least 5000 years, there is archaeological data evident of that. Initially, either fast-growing cacti San Pedro, which tower over mountainous desert shrubs in the Andes, or slow-growing creeping Peyote were consumed. Europeans first encountered Peyote at the beginning of sixteenth century when Spain defeated Mexico. Missionaries’ attempts to ban the use of cacti turned out to be successful. In fact, it resulted in various Peyote-using rituals spreading among Native Americans (e.g. Osage Nation) after they had to move to reservations. Up to twentieth century there was only small number of people who knew about mescaline and neither belonged to nor shared the culture of the American indigenous peoples. Their reports about this substance effects provoked huge interest in medicine and spirituality. In traditional rites, the phase of hallucinations is described as “constantly shifting/drifting”. In 1887, a doctor from Texas John Raleigh Briggs (1851–1907) first described in a medical magazine his own symptoms during use of this substance, which were pronounced and intense including, among other symptoms, increased heart rate and difficulty breathing after eating a small part of “Peyote button”- dried top of the cactus. Pharmaceutical company Parke-Davis in Detroit, which was researching botanical sources of potential medicine of South America and other countries, took note of this information because they were searching for cocaine alternative. In 1983 representatives of this company offered Peyote tincture as a psychostimulant. After that, by trial and error studies of mescaline began with no ethical and safety considerations at that point.

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In 1895, two reports describing unpredictability of this substance came out from the organization, which is now called George Washington University in Washington. In one of them a young chemist chewed a ” Peyote button”, then described the following symptoms: nausea, followed by pleasant visions, which he had control over to some extent, then depression and insomnia occurred which lasted 8 hours. In 1897, German chemist Arthur Carl Wilhelm Heffter first managed to isolate and identify mescaline from Peyote. In 1913, pharmacologists Alwyn Knauer and William Maloney carried out rather big study at that time on 23 participants; they hoped that mescaline could reveal the mystery of schizophrenia and most of the other psychotic events. However, the experiments didn't reveal any pattern that could help solve their problem. In 1919 Ernst Späth first synthesized mescaline. At that time mescaline was one of the first psychedelics used by western intellectuals, such as Aldous Huxley, (who was offered mescaline by his psychiatrist Humphry Osmond) who described its effects in his essay "The Doors of Perception" in 1954. Huxley gave a very sincere feedback, calling mescaline “a window to the world as it really is, not the way people perceive it”. According to his words, mescaline use is a priceless experience for everybody, especially for intellectuals. But the epic milestones of history do not end there. In 1955, Osmond gave 400 mg to a member of British Parliament Christopher Mayhew in BBC documentary film, but the footage of this episode was excluded from the show. Now this historic moment is available for watching here. Mayhew called this experience “the most interesting thing that he has ever done”. At that moment, governments of many countries were interested in mescaline, but their interest was exclusively political. It was known from history that mescaline was used as truth serum by the nazi in concentration camps during the World War II. CIA had this information and funded the CHATTER project, continuing the trials of mescaline as truth serum etc. In 1953, this project was officially discontinued after 6 years from its start. Also, mescaline is an important part of Alexander Shulgin’s life, who used it as a starting point of synthesis of dozens of new psychedelic phenylethylamine compounds, which belong to the families 2С-х and DOx, working under the auspices of Dow Chemical Company in the 1960s. Mescaline is a part of the so - called "magical half-dozen", which includes the most important phenylethylamine compounds. Peyote became more famous in 1960s due to anthropologists officially documenting the sacred hunt for Peyote with Indians Huichol. American anthropologist and writer Carlos Castaneda became one of the important popularizers of mescaline after he published his own Peyote trip in the book "The Teachings of Don Juan: A Yaqui Way of Knowledge", which became a bestseller. The other name, associated with mescaline at that time, was Hunter Stockton Thompson, who described his experience with mescaline in the well-known book "Fear and Loathing in Las Vegas: A Savage Journey to the Heart of the American Dream". It is interesting to note, that if you track Google queries on mescaline and Peyote, the most publications on the subject will peak in 1940-1950s, then there will be a sharp spike in 1960-1970s just after Carlos Castaneda’s book. Then, in thje 1990s the number of publications will rise again, presumably, due to Peyote listing as endangered species by Mexican government and the 1994 amendment to American Indian Religious Freedom Act. Meanwhile, since 2004 search queries on Peyote has shown an increase related to mescaline, this can be explained by a presence of Peyote in a game Grand Theft Auto V. There is a myth that mescal beans contain mescaline. However, this is not true. Though “mescal beans” Sophora secundiflora have certain psychoactive properties, they do not contain mescaline at all. The term "mescal" was initially misinterpreted and applied to Peyote, more specifically to its tops, “buttons”; actually this word comes from "mexcalli", which in the Aztec language Nahuatl means «agave». In recent history, according to Global Drug Survey as of 2014, mescaline and Peyote have been in top 20 the most popular psychoactive drugs exclusively in Mexico. Nowadays popularity of mescaline is very little, nevertheless, relevance and significance of the substance from the moment of its discovery still remains.

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Mescaline has been documented in many species aside from Lophophora williamsii (the actual peyote) and T. pachanoi (wachuma, San Pedro, San Pedro hembra). Nevertheless, this alkaloid is seldom abundant and, because of its low psychedelic potency (oral doses of about 300 mg of the free base are required for a full-blown hallucinogenic experience), L. williamsii and T. pachanoi are the only widely consumed botanical sources. T. peruvianus (Peruvian torch, San Pedro macho) and T. bridgesii (Bolivian torch), both also called wachuma, are used, though less frequently. An exhaustive list of mescaline-containing cacti and their chemistry was compiled by Trout. Regarding the nomenclature of these cacti, the genus Lophophora was only segregated from Anhalonium by Coulter in 1894, explaining why peyote was called Anhalonium williamsii or A. lewinii in the early literature. The homeopathic pharmacopoeia still retains the older name. Today, there are only two generally recognized Lophophora species, L. williamsii and L. diffusa (Queret́aro peyote). The latter contains little mescaline, and the tetrahydroisoquinoline pellotine is the main alkaloid. This may have been the material first analyzed by Heffter. His “pellote” paper includes two beautiful illustrations by R. Sperling of Anhalonium williamsii and Anhalonium lewinii. Studying a sample of plants founds in commerce in Japan and probably not representative of wild populations, it was suggested that there are two different forms of L. williamsii, one of them lacking mescaline, that can be distinguished from each other and from L. dif f usa morphologically, on the basis of their mescaline content and by the length of a chloroplast DNA sequence.19 Trichocereus is a South American genus comprising about 45 species. It has been proposed that Trichocereus be included in the related Echinopsis, but this change is not supported by DNA analysis.20,21 As a consequence, T. pachanoi sometimes appears in the literature as E. pachanoi, T. peruvianus as E. peruviana and, more confusingly, T. bridgesii as E. lageniformis. Moreover, T. pachanoi and T. peruvianus have recently been combined into a single species as T. macrogonus var. pachanoi and T. macrogonus var. peruvianus. In this review, we retained the traditional name Trichocereus. As early as 1898, Heffter remarked that the upper chlorophyll containing part of what he called Anhalonium williamsii is very bitter, while the roots are hardly bitter at all. An analysis carried out on cacti received “fresh from Saltillo” showed that the green tops contained 6−7 times higher concentrations of total alkaloids than the rest of the plant. Klein et al. reported that 10 individual peyote plants from a southern Texan population contained (calculated on dry weight) 1.82−5.5% mescaline in the crown and 1−2 orders of magnitude less in the nonchlorophyllous stem and root, lending modern support to Heffter’s work and the traditional use of the tops. Nevertheless, a recent paper reported the analysis of the crown and the root of a single L. williamsii plant, which gave similar total alkaloid contents in both parts but with radically different compositions. Practically all the mescaline (15.7% of the alkaloids) was found in the crown with the simple isoquinolines anhalidine, pellotine, lophophorine, and anhalonine making up most of the rest (14.6,19.8,13.3 and 6.0%, respectively), and very little of these in the “root”, where the phenethylamine hordenine was by far the major alkaloidal component. Natural sources of mescaline include: lophophora williamsii (mescaline 3-6%) lophophora diffusa (hordenine 0.5% of total alkaloid, N-methyltyramine 0.1% of total alkaloid, mescaline - trace); echinopsis pachanoi(mescaline 0.006-0.12%); echinopsis peruviana (mescaline 0.0005%-0.12%); echinopsis lageniformis (mescaline 0.025%,3,4-Dimethoxyphenylethylamine 1%, 3-Methoxytyramine 1%, tyramine 1%); echinopsis macrogona (mescaline - 0.01-0.05%);echinopsis tacaquirensis (mescaline - 0.005-0.025%); echinopsis terscheckii (mescaline - 0,005-0,025%); echinopsis valida (mescaline - 0.025%); opuntia basilaris (mecaline - 0.01%); cylindropuntia spinosior (mescaline - 0.00004%).

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Back in his early years, Heffter began to study mescaline by synthesis of various salts, including neutral sulfate dihydrate. Surprisingly, he reported a free base, which had an appearance of a solid substance softening at the temperature exceeding 100 °C, with a melting point about 150 °C. Unfortunately, the substance wasn't analyzed and presumably was a carbonate, because mescaline, as it is known, easily absorbs CO2 and water. Mescaline itself as a pure substance has an appearance of white crystalline or powdery substance. A more complicated method of extraction produces more concentrated and pure substance, such as mescaline sulfate or hydrochloride. The substance has a chemical structure of substituted phenylethylamine, which contains a phenyl ring, bound to the amino-NH2 group via an ethyl chain. Also mescaline has three metoxy- functional groups, attached to carbon atoms at R3-R5 of the phenyl ring. The full name of mescaline is 2-(3,4,5-trimethoxyphenyl)-ethanamine. Boiling point is 180 °С at 12 mmHg., melting point 35.5 °С, moderately soluble in water (with calculated parameters 8.41X10+4 mg/L at 25 °C), in ethanol (poorly soluble in lignin), chloroform and benzene, but almost insoluble in the ether and petroleum ether; log Kow = 0.78; Henry's Law constant = 1.68X10-10 atm-cu m/mol at 25 °C; рКа=9.56; needles: melting point 181 °C; soluble in water, alcohol.

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Pharmacokinetics and pharmacodynamics.
Biosynthesis process of mescaline starts from tyrosine, which is produced from phenylethylamine by phenylalanine hydroxylase. In Lophophora williamsii dopamine transforms into mescaline through a pathway, which includes m-O-methylation and aromatic hydroxylation. Tyrosine and phenylalanine act as metabolic precursors in mescaline biosynthesis. Tyrosine either undergoes decarboxylation by tyrosine decarboxylase producing tyramine or, first, is hydroxylated by tyrosine hydroxylase into L-DOPA and then decarboxylated into DOPA. They create dopamine, which is methylated by COMT, and the resulting intermediate product is again oxidized by hydroxylase, then by monophenol hydroxylase at 5 carbon atoms, then it is again methylated by COMT. The resulting product, methylated in two meta-positions with respect to the alkyl substituent, undergoes final methylation at 4 carbon atoms mediated by guaiacol-O-methyltransferase by a SAM-dependent mechanism, which yields mescaline. Mescaline is rapidly absorbed in gastrointestinal tract, a significant amount of the dose is distributed in kidneys and liver, it binds to the respectable liver proteins, keeping the concentration in blood and increasing half-life. This "delays" the onset of psychoactive effect. Mescaline has poor ability to pass the blood-brain barrier, high doses are needed for that to happen. Usually, the onset of effects is within 30 minutes since use, the peak of psychedelic effect is after two hours with a gradual decline for ten hours. Peak of effects doesn't always coincide with peak concentrations of mescaline in the brain, which allows us to assume that mescaline undergoes bioactivation for it to reach maximum efficacy. In studies with prior administration of chloropromasine 30 minutes before administration of trance-dosage of mescaline, a significant retention of hallucinogen in the brain and other studied tissues occurred due to blockade of mescaline elimination from different tissues. Half life period of mescaline after oral administration is about six hours in humans, about 80% is excreted unchanged in urine during the first hour. About 13% of the dose is excreted in a form of 3,4,5-trimethoxypheny-lacetic acid, elimination rate of this metabolite increases with time. 87% TMP-A is eliminated within the first 24 hours and reaches 96% at 48 hours. Mescaline can be detected in urine within 3 days, in hair samples – within 90 days. In blood tests, mescaline can be detected approximately within 24 hours since use, in saliva – within 10 days. According to the data of numerous studies, insignificant amount of other metabolites can be detected in urine as well, for example: N-acetyl-3,4-dimethoxy-5-hydroxyphenylethylamine, 3,4,5-trimethoxybenzoic acid, 3,4-dimethoxy-5-hydroxyphenethylamine and 3,4-dihydroxy-5- methoxyphenacetylglutamine. Mescaline undergoes metabolism mostly through the oxidative deamination pathway yielding an intermediate unstable aldehyde - 3,4,5-trimethoxyphenylacetaldehyde, which, in turn, is rapidly oxidized into inactive TMP-A or reducted into inactive 3,4,5-trimethoxyphenylethanol. The fact that there is inconsistency in peak of mescaline effects and its brain concentrations is evident of mescaline metabolites contributing to its hallucinogenic effects. The enzyme responsible for deamination of mescaline into aldehyde derivative remains unknown to this day. This process can be mediated by both monoamine oxidase and diamine oxidase. However, it has been proved that this metabolic pathway is inhibited by TPN, nicotinamide, iproniazide and semicrbazide. TMP-A is metabolized into 3,4-dihydroxy-5- methoxyphenylacetic acid or 3,4,5-trimethoxybenzoic acid. The first metabolite of mescaline is formed as a result of demethylation of TMP-A, then it combines with glutamine by glutamine N-acyltransferase and is excreted in urine in the form of 3,4-dihydroxy-5-methoxyphenacetylglutamine. This reaction is similar to amphetamine degradation yielding benzoic acid, which combines with glycine and is eliminated from the body. The highest concentration of 3,4,5-TMPA is detected in the brain compared to the other tissues (liver, heart and kidneys), this explains the position of the enzyme catalyzing the formation of TMP-A, which is located in the nuclear and microsomal fractions of this organ. MAO and DAO inhibitors do not affect the formation of this metabolite. N-acetylation of mescaline is the most important metabolic pathway in the brain, which results in the formation of such metabolites as N-acetylmescaline, N-acetyl-3,5-dimethoxy-4-hydroxy-phenylethylamine and N-acetyl-3,4-dimethoxy-5-hydroxy-phenylethylamine. The above-mentioned derivatives comprise about 30% of the total number of metabolites excreted in urine, and N-acetylation is the main pathway of detoxication of mescaline in the central nervous system. Secondary metabolic pathways include its demethylation by O-demethylase to 3,5-dimethoxy-4-hydroxyphenethylamine and 3,4-dimethoxy-5-hydroxy-phenethylamine, yielding formaldehyde. The above-mentioned reaction doesn't depend on CYP2D6 metabolism. Minor metabolite 3,4-dihydroxy-5-methoxyphene-thylamine is methylated into 3,5-dimethoxy-4-hydroxyphene-thylamine by catecholamine O-methyl transferase. As other biogenic amines, mescaline has the ability to be bioactivated by dopamine-β-hydroxylase, which, in the end, leads to formation of β-hydroxymescaline. However, to this date, this metabolite hasn't been identified in humans.
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5-HT2A/2B and /2С receptor subfamilies, characterized by significant homology: 46-50% in the total amino acid sequence and more than 70% in transmembrane domains, regulate excitatory neurotransmission through the G-protein family (predominantly Gaq or Gq/11), which activate phospholipase C, leading to hydrolysis of phosphatidylinositol 4,5-bisphosphate into soluble inositol-1,4,5-triphosphate, thereby increasing its cytosolic level. Further, IP3 already diffuses through the cytosol and binds to the corresponding IP-3 receptors, especially with calcium channels in the endoplasmic reticulum, increasing the level of cytosolic calcium. 5-HT2 receptors have different expression profiles with their distribution in cortex, locus coeruleus, basal ganglia, hippocampus, platelets and vascular smooth muscle. Hallucinogenic effects of mescaline are realized by intervention in serotonergic mechanisms of neurons due to its agonistic properties; though it doesn't have affinity to 5-HT1А, its action it manifests mainly at the level of 5-НТ2, while the affinity to 5-НТ2А and 2В receptors is relatively low compared to /2С form, which he is a full agonist for. Low doses of mescaline decrease 5-hydroxyindoleaceticacid (5-HIAA) level, which is the main metabolite of serotonin, high doses of this substance increase 5-HIAA level. According to this effect, mescaline increases release and/or reuptake of serotonin. Cross tolerance between mescaline and other serotonergic substances (e.g. LSD or psilocybin) is experimentally proved both in humans and in animals; it is developed after a couple of days of use, but the sensitivity is restored very quickly, within a few days. Mescaline effect is approximately 1000-3000 times weaker than that of LSD and 30 times weaker than that of psilocybin. Though mescaline is similar to other hallucinogenic drugs in terms of its mechanism of action, its effect is the least powerful among other substances of the group. However, its effect can last up to twelve hours. Mescaline, possibly, is not selective towards release of inositol-1,4,5-triphosphate and arachidonic acid. There are no studies regarding other ways of signal transmission, such as β-arrestin involvement. Catecholamines participate in neurotransmission and neurotoxicity, most of their biochemical properties are due to the presence of catechol, which undergoes oxidation to o-quinone and semiquinone. Thus, catechol it undergoes an oxylation-reduction cycle with its quinone analogue. Reports about mescaline transforming into catechol confirm ET participation in the process, as it is with catecholamine analogues. The similarity is also due to the presence of an aminoethyl side chain, which in some cases is substituted.

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Clinical effects, methods of use and doses.
Mescaline experience is influenced by many factors, including dosage, way of thinking, setting and way of administration. Considering this fact, every individual trip will be unique for each person, time and place, so it is impossible to predict exactly what will happen. Mescaline effect is usually perceived during 45-90 minutes after administration, reaches its peak in two to four hours and lasts up to eight hours. During this time user will see imagery of flowers and patterns such as mosaics, arabesques and spirals on closed eyes. These visual effects often transform into some distinct objects, such as architecture, animals and people. At the same time, regular objects in the user’s environment may seem fascinating, beautiful and surprisingly mystical – having the qualities that determine mescaline experience. The physical environment, including the user’s body, distorts in size and shape, sometimes it may feel like “losing” a limb or, for example, that solid objects (rocks and walls) have suddenly become soft and pliable to the touch. Other sensory organs become involved sometimes up to synesthesia: looks can be “heard”, thoughts can be “smelt”, sounds can be “tasted”. Mescaline often provokes temporary depersonalization and ego dissolving; the world seems to be “whole”. This experience can induce clear and interconnected thoughts, self-realization, empathy and cognitive euphoria; every thought may be deep and significant. Depersonalization is temporary, so it doesn't cause anxiety in most users. It is important to note that the effects of isolated mescaline are different from the cactus because the latter contains other alkaloids, which alter the true mescaline trip. Mescaline induces a psychedelic state similar to those produced by LSD and psilocybin, 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 that turn very complex. The English writer Aldous Huxley 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. 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 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 can occurr 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 painting.
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The apogee of this effect is true physical euphoria, similar to effects of psilocin. Tactile enhancement occurs on administration of medium and high doses of mescaline, they're proportionately intense compared to accompanying visual and cognitive effects. Usually, this effect of mescaline manifests in different pleasant sensations in the whole body.
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One of the desirable effects of mescaline is psychostimulation, which is not pronounced as psychostimulation induced by amphetamine-like substances. Spontaneous bodily sensations due to the use of this substance are characterized as is a constant and intense feeling of sudden realization and ability to feel the world with every nerve ending, almost all types of sensitivity are enhanced. The level of control over one's body improves, libido increases, the level of perception of objective reality improves, a person finds a creative approach to any activity that they are performing during mescaline trip, comes up with new ideas. Cognitive euphoria, which occurs even at low doses of mescaline, is characterized by positive psychoemotional state; a person feels mental tranquility and well-being, moderate delight and happiness. On increasing the dose, this type of euphoria is overlapped by physical euphoria. As other entactogens, mescaline increases present empathogenicity, feeling of belonging appears, sociability increases, sympathy effects predominate when there are certain factors. Mescaline is a “social” psychedelic, which means that it is very likely to make the user feel confident in a conversation, for comparison, - mushrooms are introverted psychedelics, which encourage the user to withdraw from socialite to be alone. Focus enhancement, immersion enhancement, increased music appreciation, ego death, motivation enhancement, personal bias suppression are the classic effects due to hallucinogenic psychoactive substances, including mescaline. Hallucinogenic effects of mescaline including hearing distortion, which manifests itself in improving the quality of interpretation of the sound wave, enhancing the sharpness and clarity of sound, auditory distortion (for example, audible monotonous low-frequency noise, or distortion of any sounds in the form of echo signals). At high doses of mescaline appearance of non-existent sounds or transformation of the existing ones, appearance of voices, music, cracking or scratching. As for hallucinatory states, mescaline induces a rather high level of visual geometry, including the appearance of autonomous objects (rarely), changes in geometry of the surroundings. Visual distortions begin to appear even at low doses of mescaline, there are fluidity, "breathing" or transformation of images, objects, people's faces, change of colors, a symmetrical repetition of the visible textures (for example, if you concentrate on the carpet, it can "come to life"), various faint traces of moving objects appear (similar to how it happens in a photograph with a long exposure). Geometric imagery is characterized by fast-moving, colourful and complicated geometric patterns, which appear on closed eyes, they have different colours, smooth movement and mostly glossy colors, as a rule, this geometry is considered to be level 8A. Internal mescaline hallucinations are realized after administration of a high dose in the form of partially distinguishable images, blurred and faded in the field of view. Full immersion into an extensive scene and appearance of some autonomous creature are rare, most often it is an improvement of mental visualization with surface immersion into user’s own imagination. There is a short-term detachment from the immediate environment, reality is smeared and partially replaced by an indefinite fantasy, and the details of this visualization are spontaneous and controlled by the contents of the current stream of thoughts. It starts from zoom changes, which transform into morphing or sliding with interactive fixation (something similar to watching a video of one’s life with different inclusions from their consciousness and thoughts) within 10-15 minutes. Compressed geometry appears, and, finally, “at the exit” gradual immersion into one’s thoughts occurs with periodic geometric inclusions, the user fully understands that they are in a mescaline trip and objectively assesses the situation (except for the cases of bad trips and anxiety). Side effects include, first of all, nausea, sweating, disturbed speech at high doses, constipation, impaired potency, dysuria, headache, dysfunctional disorders of the gastrointestinal tract, increased salivation, muscle spasms, appetite suppression, increased heart rate and periodic convulsions (very rarely after mescaline use). Most people using mescaline or mescaline-containing plants consider its effects transforming the personality, and many users begin to appreciate their life and its role in the universe. Sometimes, even a simple thought about a separate identity may seem “inappropriate”. Others feel deep gratitude and unconditional compassion for everyone and everything that surrounds them at the moment or sometime after the trip. Early studies of mescaline showed that this experience gives people energy to live and improved well-being. According to a ritual use of Peyote by Indians, mescaline can also help people to solve complicated problems. In one study consisting of giving mescaline to 27 men and asking them to solve a problem they encountered at work, after one dose each participant either solved the problem or came up with a method of solving it.

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The most common are capsules, containing mescaline, but, as a rule, they contain only synthetic mescaline or mescaline in high concentrations because too much cactus is required to get psychoactive effects. The “Toss & Wash” method consists of oral administration of raw mescaline cactus; however, it has a very bitter taste, so to get the desired effect a lot of it should be consumed. Smoking is a rare method, which is barely used nowadays; dried peyote or San Pedro cactus is ground and mixed with tobacco, then administered by inhalation, unfortunately, most of the mescaline is destroyed during combustion. Ingesting mescaline by making tea is used as an alternative to the first method. So, a couple of cactus pieces are added to a pot with water, then it is boiled during 10-20 minutes, after that, it is consumed, however, high temperatures destroy mescaline as well, which can make its effects weak. Sometimes other herbs are added as well, which help with gastrointestinal side effects (ginger and peppermint). Usually, 3-6 buttons of cactus (or 10-20 g of dried peyote) are equivalent to 200-400 mescaline hydrochloride, nevertheless, concentration of these substances significantly depends on the species, geoclimatic conditions, development, age and harvested part and many other factors. Mescaline dosage varies, though insignificantly, depending on method of extraction of this compound. For example, 100 mg of mescaline hydrochloride is equivalent to 111 mg mescaline sulfate or 85 mg of mescaline free base. All of these are threshold concentrations acting as a starting point for calculating a dose. The most common range for mescaline hydrochloride is 200-300 mg, which is considered a medium dose. Doses from 300 to 500 mg are considered high, doses more than 500 mg are extremely high and are not recommended for inexperienced users. Many users have included microdosing into their week schedule, and they report increased creativity levels, anxiety, stress, depression reduction. Some enthusiasts also claim that microdosing of mescaline helped them to improve their spiritual awareness and feeling. Aside from positive cognitive effects of mescaline, it also has moderate anti-inflammatory effects. Study as of 2008 by Bangning Yu showed that mescaline has extremely powerful anti-inflammatory effect, while in 2018 Thomas W. Flanagan published data on psychedelics helping inflammatory cascade regulation, which may have an important therapeutic potential for treatment of such diseases as asthma, atherosclerosis, inflammatory diseases of the gastrointestinal tract and so on. Doses from 10 to 50 mg of mescaline hydrochloride are used in microdosing. Tolerance to mescaline develops almost instantly after ingestion. After that, 3 days are required to lower the tolerance and 7 days are required for it to go back to the initial level (in the absence of repeated use). Mescaline demonstrates cross-tolerance with all other psychedelics; this means that after ingestion of mescaline, all psychedelics will have decreased effects. It is strongly not recommended to use mescaline together with αMT. Caution is advised when using mescaline together with the following psychoactive substances (due to a high risk of side effects and deterioration of the condition): DOx, NBOMes, 2C-x, 2C-T-x, 5-MeO-xxT, cannabis, amphetamines, cocaine, MAOls, tramadol. There is a risk of increase (or decrease) of effects due to synergy between mescaline and the following substances (exclusively in low or medium doses): MDMA, N2O, PCP, caffeine, opioids, DXM, MXE, ketamine, DMT, LSD, mushrooms, alcohol, GHB/GBL, benzodiazepines, SSRls.

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Mescaline use implies very low risk for the user, even though there are certain side effects. There are no lethal outcomes directly associated with mescaline use. Theoretical median lethal dose for mescaline is about 880 mg/kg, which is considered extremely high, 300 times exceeding standard psychoactive dose. 12-year review of the California Database of Poison Control Centre revealed only 31 cases of mescaline toxicity for quite long period of time and no lethal cases. Certainly, there are other risks of mescaline use, which are mostly associated with mental disorders such as paranoia or anxiety disorder. Nevertheless, a number of studies have been published stating that psychedelics including mescaline have a very low risk of inducing mental disorders even after a “bad experience”. Mescaline doesn't cause addiction like most classic psychedelics. Surveys show that average recreational user of psychoactive cacti or mescaline uses it 2-3 times in their life, which is very far from “drug abuse”. Moreover, studies show that mescaline has anti-dependent properties; it is one of the best candidates, which has been currently tried as a component in treatment of addiction due to psychoactive substances. So, it is distinguished from other psychedelics such as ayahuasca, psilocybin and LSD due to its potential to be a solution to the problem of addiction in a commonly spread epidemic of drug use. Studies on ceremonial use of Peyote among Native Americans have revealed that mescaline doesn't have long-term consequences, while risk of developing HPPD is the least compared to all other hallucinogens. Since mescaline is associated with abnormal fetal development, it is prohibited for use by pregnant or nursing women. It is recommended to avoid sharp objects and objects which you can stumble upon while using mescaline. It is reasonable to provide easy access to water, a toilet or a bucket, just in case. A responsible sitter is also a great idea, at least for beginners. Mescaline should be ingested on an empty stomach to minimize nausea and increase absorption, 3-4 days prior it is recommended to start a course of omeprazole in therapeutic doses. Mescaline can increase learning ability. So, in experiments on fish which were administered low doses of mescaline, scientists have found that mescaline helped the fish to learn how to avoid shock. As with many others psychedelic substances, the potential of mescaline as a therapeutic substance was studied from 1950 to 1960, especially, in combination with LSD. First results revealed that mescaline can be used for successful treatment of addiction and depression. Study of mescaline therapeutic potential are still limited, however, renewed interest to this drug shows that it can be successfully used in the treatment of mental disorders. It has been found in experiments that mescaline can increase blood flow and activity in prefrontal cortex, which is an area responsible for planning, problem-solving, emotional regulation and behavior. Low activity of this area is associated with depression and anxiety, which encouraged scientists to assume that mescaline can relieve the symptoms of these disorders. As a result of studies, it has been revealed that antidepressive effect of mescaline correlates with the willingness of the subjects to participate in the experience, to face their inner self and act in accordance with the findings. According to researchers from the University of Alabama, mescaline can contribute to the reducing of suicidal thoughts. Using the data from National survey of drug use and health, scientists found out that people who used a psychedelic substance at least once in their life demonstrate lower level of suicidal thoughts. The study as of 2013 showed that lifelong use of mescaline or Peyote in small doses is associated with lower level of agoraphobia, anxiety disorder, which makes subjects perceive the environment as threatening. And, as it has been mentioned above, addiction is another promising application of mescaline therapeutic potential. Thus, researchers from Harvard medical school came to the conclusion that mescaline causes a statistically significant decrease in alcoholism and drug abuse, and it can be used in treatment of addiction both in terms of monotherapy and in multicomponent treatment.​

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Thank you for this, it's so hard to find detailed deep dives in psychoactive drugs on the internet.
 
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