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Bufotenin, also known as dimethylserotonin or as 5-hydroxy- N, N-dimethyltryptamine ( 5-HO-DMT), is a serotonergic psychedelic of the tryptamine family. It is a derivative of the psychedelic dimethyltryptamine (DMT) and of the neurotransmitter serotonin (5-hydroxytryptamine; 5-HT). The compound is an alkaloid found in some species of , plants, and toads. It is also found natural product in the human body in small amounts. Bufotenin, for instance derived from the trees Anadenanthera colubrina and Anadenanthera peregrina, has a long history of use as a snuff in South America.
The name bufotenin originates from the toad genus Bufo, which includes several species of psychoactive toads, most notably Incilius alvarius (formerly Bufo alvarius), that secrete from their . Bufo Alvarius. AmphibiaWeb. Accessed on May 6, 2007. However, Bufo and related species like Incilius alvarius contain only trace amounts of bufotenin, with their major active component instead being 5-MeO-DMT. In addition to DMT and serotonin, bufotenin is similar in chemical structure to other psychedelics such as 5-MeO-DMT and psilocin (4-HO-DMT). These compounds also occur in some of the same fungus, plant, and animal species as bufotenin.
Bufotenin acts as a potent and non-selective serotonin receptor agonist, including of the serotonin 5-HT1A, 5-HT2A, 5-HT2C, and 5-HT3 receptors, among others. It also acts as a potent and specific serotonin releasing agent. The compound is more hydrophilic than other related tryptamines and consequently is more peripherally selective. In relation to this, bufotenin has been associated with prominent peripheral serotonergic , such as cardiovascular changes. The cardiovascular effects of bufotenin can be powerful and potentially dangerous.
For many decades and even into the present, bufotenin has been considered by many experts, such as David E. Nichols, to be either inactive or only weakly active as a psychedelic in humans and to produce robust toxicity effects.
Alexander Shulgin was also uncertain whether bufotenin was an active psychedelic. However, Jonathan Ott found in 2001 via self-experimentation that bufotenin is in fact a potent psychedelic and does not necessarily produce serious adverse effects. Hamilton Morris has further supported these findings with his own self-experimentation, although bufotenin was reported to be strongly nausea for himself and many others. According to Morris, the psychedelic effects of bufotenin are like a cross between those of DMT and 5-MeO-DMT. Morris has stated that bufotenin may in fact be the psychedelic with the longest history of human entheogenic use. Bufotenin has also been encountered as a recreational drug in forensic samples, for instance in New York City.
A subject given 1mg reported "a tight feeling in the chest" and prickling "as if he had been jabbed by needles." This was accompanied by a "fleeting sensation of pain in both thighs and a mild nausea."
Another subject given 2mg reported "tightness in his throat." He had tightness in the stomach, tingling in pretibial areas, and developed a purplish hue in the face indicating blood circulation problems. He vomited after 3 minutes.
Another subject given 4mg complained of "chest oppression" and that "a load is pressing down from above and my body feels heavy." The subject also reported "numbness of the entire body" and "a pleasant Martini feeling-my body is taking charge of my mind." The subject reported he saw red spots passing before his eyes and red-purple spots on the floor, and the floor seemed very close to his face. Within 2 minutes these visual effects were gone, and replaced by a yellow haze, as if he were looking through a lens filter.
Fabing and Hawkins commented that bufotenin's psychedelic effects were "reminiscent of [LSD] and mescaline but develop and disappear more quickly, indicating rapid central action and rapid degradation of the drug".
After pushing doses to the morally admissible limit without producing visuals, Turner and Merlis conservatively concluded: "We must reject bufotenine . . . as capable of producing the acute phase of Cohoba intoxication."
At 100mg, effects began within 5minutes, peaked at 35 to 40minutes, and lasted up to 90minutes. Higher doses produced effects that were described as psychedelic, such as "swirling, colored patterns typical of tryptamines, tending toward the arabesque". Free base bufotenin taken sublingually was found to be identical to intranasal use. The potency, duration, and psychedelic action was the same. Ott found vaporized free base bufotenin active from 2 to 8mg with 8mg producing "ring-like, swirling, colored patterns with eyes closed". He noted that the visual effects of insufflated bufotenin were verified by one colleague, and those of vaporized bufotenin by several volunteers.
Ott concluded that free base bufotenin taken intranasally and sublingually produced effects similar to those of Yopo without the toxic peripheral symptoms, such as facial flushing, observed in other studies in which the drug was administered intravenously.
Morris and others have suggested use of the serotonin 5-HT3 receptor antagonist ondansetron (Zofran) to prevent nausea and vomiting with especially nauseating or serotonin 5-HT3 receptor agonistic serotonergic psychedelics like bufotenin.
Bufotenin is an analogue of the monoamine neurotransmitter serotonin. Similarly to serotonin and related compounds like dimethyltryptamine (DMT), bufotenin is an agonist of the serotonin 5-HT1A, 5-HT2A, 5-HT2C, 5-HT3, and 5-HT4 receptors.
A special property of 5-MeO-DMT is that it has much higher affinity for and activational potency at the serotonin 5-HT1A receptor compared to other psychedelic tryptamines such as DMT and this is thought to confer it with unique and distinct hallucinogenic effects. Similarly, bufotenin has also shown greatly increased affinity for the serotonin 5-HT1A receptor. Whereas the serotonin 5-HT1A receptor affinities (Ki or ) of tryptamine and DMT were 125nM and 170nM, respectively, the affinities of serotonin (5-HO-T), 5-methoxytryptamine (5-MeO-T), bufotenin (5-HO-DMT), and 5-MeO-DMT were 3nM, 9nM, 4.9nM, and 6.5nM, respectively. Comparing bufotenin to DMT, it had 35-fold higher affinity for the serotonin 5-HT1A receptor in comparison. Findings were very similar in another study not only in terms of affinities but also activational potencies. Bufotenin had a similar at the serotonin 5-HT1A receptor as serotonin, 5-MeO-T, and 5-MeO-DMT (13nM, 3nM, 14nM, and 21nM, respectively), and a far greater value than tryptamine or DMT (899nM and 1,293nM, respectively).
Bufotenin is thought to have reduced capacity to cross the blood–brain barrier due to its relatively high hydrophilicity and hence to show significant peripheral selectivity. As a result, bufotenin has a greater ratio of peripheral activity to central effect. Bufotenin produces the head-twitch response, a behavioral proxy of psychedelic effects, in rodents.
However, it requires doses about 10-fold higher than those of psilocybin to produce behavioral responses in rats. Conversely, unlike other psychedelics, bufotenin fails to substitute for LSD, psilocybin, or 5-MeO-DMT in rodent drug discrimination tests.In contrast to peripheral administration, intracerebroventricular injection of bufotenin in animals readily produces robust psychedelic-like behavioral effects similar to those of other serotonergic psychedelics like 5-MeO-DMT. In addition, 5-MeO-DMT, the O-methyl group analogue of bufotenin, which has greater lipophilicity, is readily able to cross the blood–brain barrier and produce psychedelic effects. Bufotenin prodrug , with greater lipophilicity than bufotenin itself, like O-acetylbufotenin and O-pivalylbufotenin, have also shown robust psychedelic-like effects in animals.
In rats, subcutaneously administered bufotenin (1–100μg/kg) distributes mainly to the lungs, heart, and blood, and to a much lesser extent, the brain (hypothalamus, brain stem, striatum, and cerebral cortex), and liver. Only very small amounts of bufotenin reach the brain in rats following intravenous administration, which is attributed to its poor lipophilicity and consequent peripheral selectivity.
The brain-to-blood ratio of 5-MeO-DMT ( O-methylbufotenin) was 15times higher than that of bufotenin in the study. Bufotenin reaches peak circulating concentrations at one hour and is nearly eliminated within 8hours. In humans, intravenous administration of bufotenin results in excretion of (70%) of injected drug in the form of 5-HIAA, an endogenous metabolite of serotonin, while roughly 4% is eliminated unmetabolized in the urine. Orally administered bufotenin undergoes extensive first-pass metabolism by the enzyme monoamine oxidase.Psilocin (4-HO-DMT) is a positional isomer of bufotenin and might be expected to have similarly limited lipophilicity and blood–brain permeability. However, psilocin appears to form a tricyclic pseudo-ring system wherein its hydroxyl group and amine interact through hydrogen bond. This in turn results in psilocin being much less polar, more lipophilic, and more able to cross the blood–brain barrier and exert central actions than it would be otherwise. In contrast, bufotenin is not able to achieve this pseudo-ring system. Accordingly, bufotenin is less lipophilic than psilocin in terms of partition coefficient. In any case, bufotenin does still appear to show significant central permeability and, like psilocybin, can produce robust hallucinogenic effects in humans.
The predicted log P of bufotenin ranges from 0.89 to 2.04. For comparison, the predicted log P of DMT is 2.06 to 2.5, of serotonin is 0.2 to 0.56, of 5-MeO-DMT is 1.5 to 2.38. and of psilocin is -0.14 to 2.1.
The toad was "recurrently depicted in Mesoamerican art", which some authors have interpreted as indicating that the effects of ingesting Bufo secretions have been known in Mesoamerica for many years; however, others doubt that this art provides sufficient "ethnohistorical evidence" to support the claim.
In addition to bufotenin, Bufo secretions also contain digoxin-like cardiac glycosides, and ingestion of these toxins can be fatal. Ingestion of Bufo toad poison and eggs by humans has resulted in several reported cases of poisoning, some of which resulted in death. A court case in Spain, involving a physician who dosed people with smoked Mexican Toad poison, one of his customers died after inhaling three doses, instead of the usual of only one, had images of intoxicated with this smoke suffering obvious hypocalcemic hand muscular spasms.
Reports in the mid-1990s indicated that bufotenin-containing toad secretions had appeared as a street drug, supposedly but in fact not an aphrodisiac,Rodrigues, R.J. Aphrodisiacs through the Ages: The Discrepancy Between Lovers' Aspirations and Their Desires. ehealthstrategies.com ingested orally in the form of ch'an su, or as a psychedelic, by smoking or orally ingesting Bufo toad secretions or dried Bufo skins. The use of chan'su and love stone (a related toad skin preparation used as an aphrodisiac in the West Indies) has resulted in several cases of poisoning and at least one death. The practice of orally ingesting toad poison has been referred to in popular culture and in the scientific literature as toad licking and has drawn media attention. The Dog Who Loved to Suck on Toads. NPR. Accessed on May 6, 2007. Albert Most, founder of the defunct Church of the Toad of Light and a proponent of spiritual use of Bufo alvarius toxin, published a booklet in 1984 titled which explained how to extract and smoke the secretions.
Bufotenin is also present in the skin secretion of three arboreal hylid frogs of the genus Osteocephalus ( Osteocephalus taurinus, Osteocephalus oophagus, and Osteocephalus langsdorfii) from the Amazon and Atlantic rain forests.
Studies have detected endogenous bufotenin in urine specimens from individuals with other psychiatric disorders, such as infant autistic patients. Another study indicated that paranoid violent offenders or those who committed violent behaviour towards family members have higher bufotenin levels in their urine than other violent offenders.
A 2010 study utilized a mass spectrometry approach to detect levels of bufotenin in the urine of individuals with severe autism spectrum disorder (ASD), schizophrenia, and asymptomatic subjects. Their results indicate significantly higher levels of bufotenin in the urine of the ASD and schizophrenic groups when compared to asymptomatic individuals.
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/ref> It was also subsequently isolated from many other natural product, including , fungi, and other toads over time. The compound was first isolated to chemical purity by Austrian people chemist Hans Handovsky in 1920. The chemical structure of bufotenine was confirmed by German people chemist Heinrich Wieland and colleagues in 1934. The first reported synthesis of bufotenine was by Japanese people researchers Toshio Hoshino and Kenya Shimodaira in 1935.
Bufotenin was established as a major component of hallucinogenic snuffs made from Anadenanthera peregrina such as cohoba and yopo in 1954. It was also isolated from Anadenanthera colubrina in 1955. Clinical study assessed the effects of bufotenin and were published starting in 1956. However, the findings of these studies were conflicting, and bufotenin developed a long-standing reputation of being non- as well as toxicity. In any case, bufotenin nonetheless became a Schedule I controlled substance in the United States in 1967.
American people ethnobotanist Jonathan Ott and colleagues subsequently showed in 2001 that bufotenin is in fact a psychedelic and does not necessarily produce major , although marked nausea and vomiting are prominent. Bufotenin was first encountered as a novel recreational drug in 1992. Journalist Hamilton Morris corroborated Ott and colleagues' findings on the hallucinogenicity of bufotenin in the early 2020s.
/ref> A schedule 9 drug is outlined in the Poisons Act 1964 as "Substances which may be abused or misused, the manufacture, possession, sale or use of which should be prohibited by law except when required for medical or scientific research, or for analytical, teaching or training purposes with approval of the CEO." Poisons Act 1964 . slp.wa.gov.au
Under the Misuse of Drugs Act 1981 is determined to be enough for court of trial and is considered intent to sell and supply. Misuse of Drugs Act 1981 (2015) . slp.wa.gov.au
Bufotenin has shown antiviral activity against the rabies virus and has been found to increase survival rates against rabies in rodents.
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