The name bufotenin originates from the toad genusBufo, which includes several species ofpsychoactive toads, most notablyIncilius alvarius (formerlyBufo alvarius), thatsecretebufotoxins from theirparotoid glands.[12] However,Bufo and related species likeIncilius alvarius contain only trace amounts of bufotenin, with their major active component instead being5-MeO-DMT. In addition to DMT and serotonin, bufotenin is similar inchemical structure to other psychedelics such as 5-MeO-DMT andpsilocin (4-HO-DMT). These compounds also occur in some of the same fungus, plant, and animal species as bufotenin.
For many decades and even into the present, bufotenin has been considered by many experts, such asDavid E. Nichols, to be either inactive or only weakly active as a psychedelic in humans and to produce robusttoxic effects.[15][2][13][3]Alexander Shulgin was also uncertain whether bufotenin was an active psychedelic.[16][18][5] However,Jonathan Ott found in 2001 viaself-experimentation that bufotenin is in fact a potent psychedelic and does not necessarily produce serious adverse effects.[3][5][2][1]Hamilton Morris has further supported these findings with his own self-experimentation, although bufotenin was reported to be stronglynauseating for himself and many others.[10][5] According to Morris, the psychedelic effects of bufotenin are like a cross between those of DMT and 5-MeO-DMT.[10][5] Morris has stated that bufotenin may in fact be the psychedelic with the longest history of human entheogenic use.[10][5] Bufotenin has also been encountered as arecreational drug in forensic samples, for instance inNew York City.[19]
In 1955, Fabing and Hawkins administered bufoteninintravenously at doses of up to 16mg to prison inmates atOhio State Penitentiary.[4] A toxic effect causing purpling of the face was seen in these tests.
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."[4]
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.[4]
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.[4]
Fabing and Hawkins commented that bufotenin's psychedelic effects were "reminiscent of [LSD] andmescaline but develop and disappear more quickly, indicating rapid central action and rapid degradation of the drug".[4]
Turner and Merlis (1959)[22] experimented withintravenous administration of bufotenin (as the water-soluble creatinine sulfate salt) to schizophrenics at a New York state hospital. They reported that when one subject received 10mg during a 50-second interval, "theperipheral nervous system effects were extreme: at 17 seconds,flushing of the face, at 22 seconds, maximal inhalation, followed by maximalhyperventilation for about 2 minutes, during which the patient was unresponsive to stimuli; her face was plum-colored." Finally, Turner and Merlis reported:
on one occasion, which essentially terminated our study, a patient who received 40 mg intramuscularly, suddenly developed an extremelyrapid heart rate; no pulse could be obtained; no blood pressure measured. There seemed to have been an onset ofauricular fibrillation . . . extremecyanosis developed. Massage over the heart was vigorously executed and the pulse returned to normal . . . shortly thereafter the patient, still cyanotic, sat up saying: "Take that away. I don't like them."
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 ofCohoba intoxication."[21]
A 1985 study by McLeod and Sitaram in humans reported that bufotenin administeredintranasally at a dose of 1–16mg had no effect, other than intense local irritation. When givenintravenously at low doses (2–4mg), bufoteninoxalate caused anxiety but no other effects; however, a dose of 8mg resulted in profound emotional and perceptual changes, involving extremeanxiety, a sense of imminent death, and visual disturbance associated with color reversal and distortion, and intense flushing of the cheeks and forehead.[24]
Alexander Shulgin reviewed the literature on bufotenin in his bookTiHKAL.[16] However, he and his collaborators did not appear to try it themselves.[16]
In 2001, ethnobotanistJonathan Ott published the results of a study in which heself-administeredfree base bufotenin viainsufflation (5–100mg),sublingually (50mg),rectally (30mg),orally (100mg) and viavaporization (2–8mg).[2][1] Ott reported "visionary effects" of intranasal bufotenin and that the "visionary threshold dose" by this route was 40mg, with smaller doses eliciting perceptibly psychoactive effects.[1] He reported that "intranasal bufotenine is throughout quite physically relaxing; in no case was there facial rubescence, nor any discomfort nor disesteeming side effects".[2][1]
At 100mg, effects began within 5minutes, peaked at 35 to 40minutes, and lasted up to 90minutes.[2][1] Higher doses produced effects that were described as psychedelic, such as "swirling, colored patterns typical of tryptamines, tending toward the arabesque".[2][1] Free base bufotenin taken sublingually was found to be identical to intranasal use.[2][1] The potency, duration, and psychedelic action was the same.[2][1] Ott found vaporized free base bufotenin active from 2 to 8mg with 8mg producing "ring-like, swirling, colored patterns with eyes closed".[2][1] He noted that the visual effects of insufflated bufotenin were verified by one colleague, and those of vaporized bufotenin by several volunteers.[2][1]
Ott concluded that free base bufotenin taken intranasally and sublingually produced effects similar to those ofYopo without the toxic peripheral symptoms, such as facial flushing, observed in other studies in which the drug was administeredintravenously.[2][1]
Hamilton Morris, apsychoactive drugjournalist, the creator ofHamilton's Pharmacopeia, and apharmacologist, has experimented with bufotenin and found that it was an active psychedelic.[10][5] He has claimed that its effects are like a cross between those of DMT and 5-MeO-DMT, being less visual than DMT but more visual than 5-MeO-DMT.[10][5] Morris has also stated that bufotenin is verynauseating and this has made it unpleasant for himself and other people.[10][5] Byinsufflation, he has said that itsduration is about 1hour and is longer than that of DMT or 5-MeO-DMT.[10][5]
Morris and others have suggested use of theserotonin5-HT3 receptorantagonistondansetron (Zofran) to prevent nausea and vomiting with especially nauseating or serotonin 5-HT3 receptor agonistic serotonergic psychedelics like bufotenin.[25][26][27]
The acute toxicity (LD50) of bufotenin in rodents has been estimated at 200 to 300mg/kg. Death occurs by respiratory arrest.[28] In April 2017, a South Korean man died after consuming bufotenin-containingtoads that had been mistaken for edibleAsian bullfrogs,[29] while in Dec. 2019, five Taiwanese men became ill and one man died after eating bufotenin-containingCentral Formosa toads that they mistook for frogs.[30]
Bufotenin is thought to have reduced capacity to cross theblood–brain barrier due to its relatively highhydrophilicity and hence to show significantperipheral selectivity.[13] As a result, bufotenin has a greater ratio ofperipheral activity to central effect.[13] Bufotenin produces thehead-twitch response, a behavioral proxy of psychedelic effects, in rodents.[48][49][50] However, it requires doses about 10-fold higher than those of psilocybin to produce behavioral responses in rats.[6] Conversely, unlike other psychedelics, bufotenin fails to substitute forLSD,psilocybin, or5-MeO-DMT in rodentdrug discrimination tests.[51][52][53][54] Relatedly, findings on the effects of bufotenin in animals have been described as "equivocal".[55] Studies have been similarly mixed on thepsychedelic effects of bufotenin in humans, with some finding a relative lack of psychedelic effects and pronounced toxic effects, while others have found psychedelic effects without major adverse effects.[13][3][1][16] In any case, bufotenin has often been reported to produce pronounced peripheralserotonergic effects.[13][8] These have includedcardiovascular,gastrointestinal, and other effects, among them increasedrespiratory rate, chest heaviness, purpling of the head and neck skin (intenseskin flushing),nausea,vomiting, andretching.[13][8] It is possible that in addition to its limited central permeation, the peripheral effects of bufotenin have served to mask its central and hallucinogenic effects.[13] The adverse effects of bufotenin may be more pronounced withintravenous injection compared to other routes such asinsufflation.[5]
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 like5-MeO-DMT.[13] In addition, 5-MeO-DMT, theO-methylated analogue of bufotenin, which has greaterlipophilicity, is readily able to cross the blood–brain barrier and produce psychedelic effects.[13] Bufoteninprodrugesters, with greater lipophilicity than bufotenin itself, likeO-acetylbufotenin andO-pivalylbufotenin, have also shown robust psychedelic-like effects in animals.[13][56][57]
Psilocin (4-HO-DMT) is apositional isomer of bufotenin and might be expected to have similarly limited lipophilicity and blood–brain permeability.[61][13] However, psilocin appears to form atricyclicpseudo-ring system wherein itshydroxyl group andamine interact throughhydrogen bonding.[15][13][6] This in turn results in psilocin being much lesspolar, more lipophilic, and more able to cross the blood–brain barrier and exert central actions than it would be otherwise.[15][13][6] In contrast, bufotenin is not able to achieve this pseudo-ring system.[15][13][6] Accordingly, bufotenin is less lipophilic than psilocin in terms ofpartition coefficient.[15][13] In any case, bufotenin does still appear to show significant central permeability and, like psilocybin, can produce robust hallucinogenic effects in humans.[13][6][3][1]
The predictedlog P of bufotenin ranges from 0.89 to 2.04.[62][63][64] For comparison, the predicted log P of DMT is 2.06 to 2.5,[65][66][67] of serotonin is 0.2 to 0.56,[68][69][70] of 5-MeO-DMT is 1.5 to 2.38.[71][72][73] and of psilocin is -0.14 to 2.1.[74][75][76]
Bufotenin is found in the skin and eggs of several species of toads belonging to the genusBufo, but is most concentrated in theColorado River toad (formerlyBufo alvarius, nowIncilius alvarius), the only toad species with enough bufotenin for a psychoactive effect. Extracts oftoad toxin, containing bufotenin and otherbioactive compounds, have been used in some traditional medicines such asch'an su (probably derived fromBufo gargarizans), which has been used medicinally for centuries in China.[77] It is also found in thecane toad (Rhinella marina).[35]
The toad was "recurrently depicted inMesoamerican art",[78] which some authors have interpreted as indicating that the effects of ingestingBufo secretions have been known in Mesoamerica for many years; however, others doubt that this art provides sufficient "ethnohistorical evidence" to support the claim.[77]
In addition to bufotenin,Bufo secretions also containdigoxin-likecardiac glycosides, and ingestion of these toxins can be fatal. Ingestion ofBufo toad poison and eggs by humans has resulted in several reported cases of poisoning,[79][80][81] 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.[81][82][83]
Reports in the mid-1990s indicated that bufotenin-containing toad secretions had appeared as astreet drug, supposedly but in factnot anaphrodisiac,[84] ingested orally in the form ofch'an su,[81] or as a psychedelic, by smoking or orally ingestingBufo toad secretions or driedBufo skins. The use ofchan'su andlove stone (a related toad skin preparation used as an aphrodisiac in theWest Indies) has resulted in several cases of poisoning and at least one death.[81][85] 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.[86][87][88] Albert Most, founder of the defunctChurch of the Toad of Light and a proponent of spiritual use ofBufo alvarius toxin, published a booklet in 1984 titledBufo Alvarius: The Psychedelic Toad of the Sonoran Desert[89][90] which explained how to extract and smoke the secretions.
Yopo seeds from the perennialAnadenanthera peregrina tree have a long history of entheogenic use and induce a short but distinct psychedelic experience.
Bufotenin is a constituent of theseeds ofAnadenanthera colubrina andAnadenanthera peregrina trees. Anadenanthera seeds have been used as an ingredient in psychedelicsnuff preparations by indigenous cultures of the Caribbean, Central and South America since pre-Columbian times.[28][92][93] The oldest archaeological evidence of use ofAnadenanthera beans is over 4,000 years old.[92]
A study conducted in the late 1960s reported the detection of bufotenin in the urine of schizophrenic subjects;[98] however, subsequent research failed to confirm these findings until 2010.[99][100][101][102][103]
Studies have detected endogenous bufotenin in urine specimens from individuals with other psychiatric disorders,[104] such as infant autistic patients.[105] 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.[106]
A 2010 study utilized amass 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.[103]
A 2025 systematic review of eight studies found that urinary bufotenine was detected more often and at higher concentrations in many patients with psychiatric diagnoses than in controls, but significant methodological heterogeneity and overlap between groups mean the evidence is currently insufficient to support bufotenine as a reliable biomarker for mental illness[107]
Bufotenin, or bufotenine, is also known by the names 5-hydroxy-N,N-dimethyltryptamine (5-HO-DMT),N,N-dimethyl-5-hydroxytryptamine, dimethylserotonin, and mappine, among others.[117]
Bufotenin is classified as a Schedule I controlled substance according to the Criminal Code Regulations of the Government of the Commonwealth of Australia.[118] It is also listed as a Schedule 9 substance under thePoisons Standard (October 2015).[119] 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."[120]
Under the Misuse of Drugs Act 1981 6.0 grams (0.21 oz) is determined to be enough for court of trial and 2.0 grams (0.071 oz) is considered intent to sell and supply.[121]
^abcdefghijklmnHamilton Morris (1 September 2021)."PODCAST 28: A talk with Jonathan Ott".The Hamilton Morris Podcast (Podcast). Patreon. Event occurs at 49:20–50:36. Retrieved20 January 2025.[Morris:] I've used [bufotenine] a couple times, once at 50 milligrams of the freebase snorted. [...] I found it to be extremely nauseating. I found it to be qualitatively intermediate between 5-MeO-DMT and DMT in that it was more visual than my experiences with 5-MeO-DMT but less visual than my typical experiences with DMT. It had a longer duration than 5-MeO-DMT and maybe even a longer duration than DMT as well. It was about an hour. Although I don't have all that much experience snorting DMT freebase.
^abcBarker SA, McIlhenny EH, Strassman R (2012). "A critical review of reports of endogenous psychedelic N, N-dimethyltryptamines in humans: 1955-2010".Drug Test Anal.4 (7–8):617–635.doi:10.1002/dta.422.PMID22371425.
^abKärkkäinen J, Forsström T, Tornaeus J, Wähälä K, Kiuru P, Honkanen A, et al. (2005). "Potentially hallucinogenic 5-hydroxytryptamine receptor ligands bufotenine and dimethyltryptamine in blood and tissues".Scand J Clin Lab Invest.65 (3):189–199.doi:10.1080/00365510510013604.PMID16095048.
^abcdefghijHamilton Morris (1 December 2022)."A New One-Hour Talk On 5-MeO-DMT".The Hamilton Morris Podcast. Patreon. Event occurs at 6:27–8:40, 10:15–11:13. Retrieved21 January 2025.[Morris:] Bufotenine is a drug that I have tried. I've tried isolated pure bufotenine and it is a psychedelic that is both pharmacologically and experientially and chemically intermediate between DMT and 5-MeO-DMT. So it has a longer duration than actually both 5-MeO-DMT and DMT. It's yet less visual than DMT but more visual than 5-MeO-DMT, so it's kind of like in-between the two. It's also very nauseating, which is the main reason that people seem not to enjoy it very much. But it is a classical psychedelic drug that produces visionary effects. And Jonathan Ott actually liked the effect of it quite a bit.
^abcdefgGumpper RH, Nichols DE (October 2024). "Chemistry/structural biology of psychedelic drugs and their receptor(s)".Br J Pharmacol bph.17361.doi:10.1111/bph.17361.PMID39354889.The weaker pKa of psilocin relative to bufotenine means that psilocin is less highly ionized at pH 7.4—that is, 8.5% free base versus 0.53% for bufotenine at pH 7.4. Ionized amines must be unionized and desolvated to cross the blood–brain barrier; the intramolecular H bond in psilocin compensates for that as reflected by the higher lipophilicity of psilocin relative to bufotenine. [...] This would explain why bufotenine is still an agonist at the 5-HT2A receptor but due to its poor physiochemical properties is not psychoactive in humans.
^abcdefghiShulgin AT, Shulgin A (1997).TiHKAL: The Continuation (1st ed.). Berkeley, CA: Transform Press.ISBN9780963009692.OCLC38503252.And so it is with bufotenine. Is it an active psychedelic? Absolutely yes, absolutely no, and maybe yes and maybe no. [...] Some clinicians demand that the compound is unquestionably a psychotomimetic and it must be catalogued right up there along with LSD and psilocybin. Others, equally sincere, present human trials that suggest only peripheral toxicity and conclude that there is no central action to be seen. And there are many who state that there are no effects for it at all, either inside or outside the CNS. The psychopharmacological status of bufotenine, like that of Uri Geller, may be essentially unanswerable. [...] A second report carries, at least for me, much more impact. A study of the use of the seeds of a South American legume, Anadenanthera colubrina var. Cebil by the Argentine Shamans in Chaco Central, shows then to be dramatically psychedelic. And yet, extremely sophisticated spectroscopic analysis has shown them to contain bufotenine and only bufotenine as their alkaloid component. At the bottom line, I do not really know of bufotenine is a psychedelic drug. Maybe yes and maybe no.
^abHolmstedt B, Daly JW, Del Pozo EC, Horning EC, Isbel H, Szara S (1967)."Discussion on the Psychoactive Action of Various Tryptamine Derivatives".Ethnopharmacologic Search for Psychoactive Drugs. Raven Press. pp. 374–382 (377).ISBN978-0-89004-047-8.[DR. ISBELL:] It has been said that bufotenine is not a psychotomimetic drug. I don't think we should say that. The difficulty is that bufotenine is a drug that has extremely powerful and dangerous cardiovascular effects, and for that reason it is not possible to push the dose in man. Also, it would be difficult to differentiate whether psychotic reactions were due to central effects or to cardiovascular actions. Cardiovascular actions include hypertension and development of an arrhythmia which actually amounts to a ventricular standstill. The auricle does not beat, the beat drops out, and the ventricle takes over, and it is very frightening. Simultaneously with the hypertension and ventricular escapes, one sees spectacular cynanosis in the upper part of the body, similar to that which has been described in the carcinoid flush, which is presumably due to serotonin. So bufotenine is a difficult drug to work in man for this reason, and it would not be too surprising if it did not have some kind of a central action if it were possible to extract it out.
^Shulgin AT (2003)."Basic Pharmacology and Effects". In Laing RR (ed.).Hallucinogens: A Forensic Drug Handbook. Forensic Drug Handbook Series. Elsevier Science. pp. 67–137.ISBN978-0-12-433951-4. Retrieved1 February 2025.For a number of reasons, some pharmacological and some political, the compound 5-hydroxy-N,N-dimethyltryptamine, bufotenine, deserves special comment. From the pharmacological point of view, the compound is clearly active, but the nature of this activity is difficult to classify. The early studies that report effects in humans followed intravenous administration, and the responses noted (anxiety, panic, visual distortion, intense flushing) have been ascribed to extreme cardiovascular action and possible increases in interocular pressure. No effects have been observed following intranasal or oral administration. Recent studies with snuffs from roasted red seeds of the South American trees of the Anadenanthera species have proved highly active and yet careful analysis have shown that the only alkaloid present was bufotenine. Yet there are several reports in the medical literature of human studies where the compound is reported to be without activity.
^abHolmstedt B, Lindgren JE (1967)."Chemical Constituents and Pharmacology of South American Snuffs". In Efron DH, Holmstedt B, Kline NS (eds.).Ethnopharmacologic Search for Psychoactive Drugs, Proceedings of a Symposium held in San Francisco, California, January 28-30, 1967. Raven Press. pp. 339–373.ISBN978-0-89004-047-8.OCLC14498182.In a letter, Dr. Harris Isbell describes his experiment with the same compounds in the following way: "We studied several forms of the material: Untreated snuff, roasted snuff, limed and roasted snuff, fermented snuff, fermented and limed snuff, fermented, limed and roasted snuff. Our subjects inhaled the snuff through straws. We obtained no reports that there were any subjective effects after inhalation of this material in amounts ranging up to 1 gram, and we further were unable to obtain any evidence of objective effects on pupillary size, tendon reflexes, body temperature, respiration, blood pressure etc., after doses ranging up to 1 gram orally. Inhalation of pure bufotenine in aerosol suspension, or oral ingestion of bufotenine in doses running up to 100 mg (total dose) also were without effect." The above quoted experiments were all performed with snuff made from the sample of Piptadenia peregrina in which Horning et al. had found 5-OH-DMT (bufotenine) to be the main component, and this fully explains the negative results.
^abcdChilton WS, Bigwood J, Jensen RE (1979). "Psilocin, bufotenine and serotonin: historical and biosynthetic observations".Journal of Psychedelic Drugs.11 (1–2):61–69.doi:10.1080/02791072.1979.10472093.PMID392119.
^Hofmann A (August 1963)."Psychotomimetic Substances".The Indian Journal of Pharmacy.25 (8):245–256. Archived fromthe original on 7 April 2025.Bufotenin, which was first discovered in the skin glands of toads34, has a similar activity to dimethyltryptamne35 when administered by intravenous injection. Other investigators found no hallucinogenic activity after i.v. injections up to 20 mg.35 In personal experiments by the writer doses up to 50 mg. bufotenin taken perorally did not produce any psychic effects17. [...] It could be that the special application of these substances in the form of a snuff powder modifies in some way their psychic activity. [...] 17. Hofmann, A. Unpublished results.
^Rossi GN, Hallak JE, Bouso Saiz JC, Dos Santos RG (June 2022). "Safety issues of psilocybin and LSD as potential rapid acting antidepressants and potential challenges".Expert Opinion on Drug Safety.21 (6):761–776.doi:10.1080/14740338.2022.2066650.PMID35426754.
^abGlennon RA, Dukat M (2 May 2023). "Quipazine: Classical hallucinogen? Novel psychedelic?".Australian Journal of Chemistry.76 (5):288–298.doi:10.1071/CH22256.ISSN0004-9425.
^abcGlennon RA (January 1987). "Central serotonin receptors as targets for drug research".J Med Chem.30 (1):1–12.doi:10.1021/jm00384a001.PMID3543362.Table II. Affinities of Selected Phenalkylamines for 5-HT1 and 5-HT2 Binding Sites
^abcdCramer W, van Drimmelen M, Long S, Tulp M (1990). "Bufotenin: actions of 5-HT3 receptors".European Journal of Pharmacology.183 (6):2148–2149.doi:10.1016/0014-2999(90)93672-D.
^Egan C, Grinde E, Dupre A, Roth BL, Hake M, Teitler M, et al. (February 2000). "Agonist high and low affinity state ratios predict drug intrinsic activity and a revised ternary complex mechanism at serotonin 5-HT(2A) and 5-HT(2C) receptors".Synapse.35 (2):144–150.doi:10.1002/(SICI)1098-2396(200002)35:2<144::AID-SYN7>3.0.CO;2-K.PMID10611640.
^abGlennon RA, Peroutka SJ, Dukat M (1991). "Binding Characteristics of a Quaternary Amine Analog of Serotonin: 5-HTQ".Serotonin: Molecular Biology, Receptors and Functional Effects. Basel: Birkhäuser Basel. pp. 186–191.doi:10.1007/978-3-0348-7259-1_17.ISBN978-3-0348-7261-4.
^abVan Wijngaarden I, Soudijn W (1997)."5-HT2A, 5-HT2B and 5-HT2C receptor ligands.". In Olivier B, Van Wijngaarden I, Soudijn W (eds.).Serotonin Receptors and their Ligands. Pharmacochemistry Library. Elsevier Science. p. 161.ISBN978-0-08-054111-2. Retrieved22 January 2025.
^Dukat M (1 June 2004). "5-HT3 Serotonin Receptor Agonists: A Pharmacophoric Journey".Current Medicinal Chemistry - Central Nervous System Agents.4 (2):77–94.doi:10.2174/1568015043356995.ISSN1568-0150.
^Johnston KD, Lu Z, Rudd JA (January 2014). "Looking beyond 5-HT(3) receptors: a review of the wider role of serotonin in the pharmacology of nausea and vomiting".European Journal of Pharmacology.722:13–25.doi:10.1016/j.ejphar.2013.10.014.PMID24189639.
^Dourron HM, Nichols CD, Simonsson O, Bradley M, Carhart-Harris R, Hendricks PS (December 2023). "5-MeO-DMT: An atypical psychedelic with unique pharmacology, phenomenology & risk?".Psychopharmacology (Berl).242 (7):1457–1479.doi:10.1007/s00213-023-06517-1.PMID38072874.
^Corne SJ, Pickering RW (1967). "A possible correlation between drug-induced hallucinations in man and a behavioural response in mice".Psychopharmacologia.11 (1):65–78.doi:10.1007/BF00401509.PMID5302272.
^Zhang M, Yang Y, Yang Z, Wen X, Zhang C, Xiao P, et al. (January 2025). "Structural insights into tryptamine psychedelics: The role of hydroxyl indole ring site in 5-HT2A receptor activation and psychedelic-like activity".Eur J Med Chem.281 117049.doi:10.1016/j.ejmech.2024.117049.PMID39541872.
^Baker LE (2018). "Hallucinogens in Drug Discrimination".Behavioral Neurobiology of Psychedelic Drugs. Curr Top Behav Neurosci. Vol. 36. pp. 201–219.doi:10.1007/7854_2017_476.ISBN978-3-662-55878-2.PMID28484970.An example of stimulus generalization (i.e., drug substitution) is depicted in Fig. 1, reprinted from a study reported by Winter et al. (2007). This figure illustrates dose-response curves obtained with LSD, psilocin, DMT, and bufotenine in rats trained to discriminate 0.5 mg/kg psilocybin. LSD and psilocin produced full substitution for psilocybin, whereas DMT produced only 73% psilocybin-appropriate responding and bufotenine produced less than 20% psilocybin-appropriate responding at the doses tested.
^Helsley S, Fiorella D, Rabin RA, Winter JC (May 1998). "A comparison of N,N-dimethyltryptamine, harmaline, and selected congeners in rats trained with LSD as a discriminative stimulus".Prog Neuropsychopharmacol Biol Psychiatry.22 (4):649–663.doi:10.1016/s0278-5846(98)00031-1.PMID9682278.
^Winter JC, Rice KC, Amorosi DJ, Rabin RA (October 2007)."Psilocybin-induced stimulus control in the rat".Pharmacol Biochem Behav.87 (4):472–480.doi:10.1016/j.pbb.2007.06.003.PMC2000343.PMID17688928.The failure of bufotenine to mimic psilocybin is in keeping with previous reports in rats in which bufotenine did not substitute for 5-MeO-DMT (Spencer et al., 1987), for LSD (Helsley et al., 1998), or for TVX Q 7821, a 5-HT1A receptor agonist (Spencer and Traber, 1987). The hallucinogenicity of bufotenine has been a matter of controversy for some time (Shulgin and Shulgin, 1997, pages 473–478; Torres and Repke, 2006). Nonetheless, the absence of activity with respect to stimulus activity in the rat as exemplified in Fig. 3 is plausibly explained on the basis of low lipid solubility and an associated inability to cross the blood–brain barrier. While psilocin has a chloroform/water coefficient of 5.52, that of bufotenine is only 0.06 (Gessner et al., 1968). In keeping with a primarily peripheral mechanism in the rat for bufotenine is the observation that the hypothermic effects of bufotenine are antagonized by xylamidine, a peripherally acting 5-HT antagonist (Winter, 1972).
^Spencer DG, Glaser T, Traber J (1987). "Serotonin receptor subtype mediation of the interoceptive discriminative stimuli induced by 5-methoxy-N,N-dimethyltryptamine".Psychopharmacology (Berl).93 (2):158–166.doi:10.1007/BF00179927.PMID3122248.
^abBrimblecombe RW, Pinder RM (1975). "Indolealkylamines and Related Compounds".Hallucinogenic Agents. Bristol: Wright-Scientechnica. pp. 98–144.ISBN978-0-85608-011-1.OCLC2176880.OL4850660M.[...] only very small amounts of bufotenin are found in rat brain following intravenous administration (Vogel, 1969), a finding in keeping with the low lipid solubility of the drug as measured by a chloroform-water coefficient of only 0·06 at physiological pH (Gessner, Godse, Krull, and McMullan, 1968). [...] Animal studies with bufotenin are equally equivocal to those in man. [...]
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^Gumpper RH, Nichols DE (October 2024). "Chemistry/structural biology of psychedelic drugs and their receptor(s)".Br J Pharmacol bph.17361.doi:10.1111/bph.17361.PMID39354889.In contrast to DMT, psilocybin is orally active. [...] A structurally related molecule, [5-HO-DMT], known as bufotenine, is inactive after oral administration. How does the simple transposition of the hydroxy from the 4 to the 5 position alter the physicochemical properties of the DMT core? We asked that question more than four decades ago. In a study by Migliaccio et al. (1981), the 360 MHz proton NMR, the amine pKa values and the octanol–water Log P values were determined experimentally and compared for both psilocin and bufotenine (Figure 3a). The side chain protons in the NMR for bufotenine were shown to be rapidly rotating with no preference for gauche or trans conformations, whereas the side chain for psilocin was less mobile and was determined to favour a gauche (80%) versus trans (20%) conformation. Because psilocin is a weaker base but is also more lipid soluble, it was proposed that psilocin formed an intramolecular hydrogen bond, as illustrated in Figure 3a. In the energy-minimized structure of this conformation, the length of the hydrogen bond is 1.88 Å. The weaker pKa of psilocin relative to bufotenine means that psilocin is less highly ionized at pH 7.4—that is, 8.5% free base versus 0.53% for bufotenine at pH 7.4. Ionized amines must be unionized and desolvated to cross the blood–brain barrier; the intramolecular H bond in psilocin compensates for that as reflected by the higher lipophilicity of psilocin relative to bufotenine. Finally, the mechanism of deamination by MAO involves either a single electron transfer or a nucleophilic mechanism (Gaweska & Fitzpatrick, 2011; Zapata-Torres et al., 2015), either of which is more enzymically difficult when the amine electrons are hydrogen-bonded by the 4-hydroxy group (Figure 3a). Very recently, Lenz et al. (2022) have confirmed and extended the finding of the potential intramolecular hydrogen bond partially being responsible for slow MAO deamination as well as psilocin's enhanced ability to cross the blood–brain barrier. [...] This would explain why bufotenine is still an agonist at the 5-HT2A receptor but due to its poor physiochemical properties is not psychoactive in humans.
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