Bufotenin

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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 mushrooms, plants, and toads. It is also found naturally in the human body in small amounts.<ref name="BarkerMcIlhennyStrassman2012">Template:Cite journal</ref><ref name="NeumannDheinKirchhefer2024" /><ref name="KärkkäinenForsströmTornaeus2005">Template:Cite journal</ref> Bufotenin, for instance derived from the trees Anadenanthera colubrina and Anadenanthera peregrina, has a long history of entheogenic use as a snuff in South America.<ref name="Ott2001a" /><ref name="MorrisOtt2023" /><ref name="Morris2022" /><ref name="TittarelliMannocchiPantano2015">Template:Cite journal</ref>

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 bufotoxins from their parotoid glands.<ref>Bufo Alvarius. AmphibiaWeb. Accessed on May 6, 2007.</ref> 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-HT_1A, 5-HT_2A, 5-HT_2C, and 5-HT₃ receptors, among others.<ref name="McBride2000" /><ref name="PlazasFaraone2023" /><ref name="NeumannDheinKirchhefer2024" /><ref name="BloughLandavazoDecker2014" /> It also acts as a potent and specific serotonin releasing agent.<ref name="BloughLandavazoDecker2014" /> The compound is more hydrophilic than other related tryptamines and consequently is more peripherally selective.<ref name="McBride2000" /><ref name="GumpperNichols2024" /> In relation to this, bufotenin has been associated with prominent peripheral serotonergic side effects, such as cardiovascular changes.<ref name="McBride2000" /><ref name="NeumannDheinKirchhefer2024" /><ref name="TiHKAL" /> The cardiovascular effects of bufotenin can be powerful and potentially dangerous.<ref name="Waser1967">Template:Cite book</ref>

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 toxic effects.<ref name="GumpperNichols2024">Template:Cite journal</ref><ref name="Ott2001b">Template:Cite book</ref><ref name="McBride2000" /><ref name="ShenJiangWinter2010" /> Alexander Shulgin was also uncertain whether bufotenin was an active psychedelic.<ref name="TiHKAL">Template:Cite book</ref><ref name="Shulgin2003">Template:Cite book</ref><ref name="MorrisOtt2023" /> 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.<ref name="ShenJiangWinter2010" /><ref name="MorrisOtt2023" /><ref name="Ott2001b" /><ref name="Ott2001a" /> Hamilton Morris has further supported these findings with his own self-experimentation, although bufotenin was reported to be strongly nauseating for himself and many others.<ref name="Morris2022">Template:Cite web</ref><ref name="MorrisOtt2023">Template:Cite podcast</ref> According to Morris, the psychedelic effects of bufotenin are like a cross between those of DMT and 5-MeO-DMT.<ref name="Morris2022" /><ref name="MorrisOtt2023" /> Morris has stated that bufotenin may in fact be the psychedelic with the longest history of human entheogenic use.<ref name="Morris2022" /><ref name="MorrisOtt2023" /> Bufotenin has also been encountered as a recreational drug in forensic samples, for instance in New York City.<ref name="Chamakura1994" />

Use and effects

Fabing & Hawkins (1955)

In 1955, Fabing and Hawkins administered bufotenin intravenously at doses of up to 16Template:Nbspmg to prison inmates at Ohio State Penitentiary.<ref name="FabingHawkins1956">Template:Cite journal</ref> A toxic effect causing purpling of the face was seen in these tests.

A subject given 1Template:Nbspmg 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."<ref name="FabingHawkins1956" />

Another subject given 2Template:Nbspmg 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.<ref name="FabingHawkins1956" />

Another subject given 4Template:Nbspmg 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.<ref name="FabingHawkins1956" />

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".<ref name="FabingHawkins1956" />

Isbell (1956)

In 1956, Harris Isbell at the Public Health Service Hospital in Lexington, Kentucky, experimented with bufotenin as a snuff made from Anadenanthera peregrina.<ref name="HolmstedtLindgren1967" /> He reported "no subjective or objective effects were observed after spraying with as much as 40 mg bufotenine"; however, subjects who received 10–12Template:Nbspmg by intramuscular injection reported "elements of visual hallucinations consisting of a play of colors, lights, and patterns."<ref name="ChiltonBigwoodJensen1979" /><ref name="TurnerMerlis1959" /><ref name="HolmstedtLindgren1967">Template:Cite book</ref>

Turner & Merlis (1959)

Turner and Merlis (1959)<ref name="TurnerMerlis1959">Template:Cite journal</ref> experimented with intravenous 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 10Template:Nbspmg during a 50-second interval, "the peripheral nervous system effects were extreme: at 17 seconds, flushing of the face, at 22 seconds, maximal inhalation, followed by maximal hyperventilation 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 extremely rapid heart rate; no pulse could be obtained; no blood pressure measured. There seemed to have been an onset of auricular fibrillation . . . extreme cyanosis 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."{{#if:|

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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."<ref name="ChiltonBigwoodJensen1979" />

Hofmann (1963)

Albert Hofmann tried bufotenin orally at doses of up to 50Template:Nbspmg but experienced no psychoactive effects.<ref name="Hofmann1963">Template:Cite journal</ref><ref name="Ott2001a" />

McLeod and Sitaram (1985)

A 1985 study by McLeod and Sitaram in humans reported that bufotenin administered intranasally at a dose of 1–16Template:Nbspmg had no effect, other than intense local irritation. When given intravenously at low doses (2–4Template:Nbspmg), bufotenin oxalate caused anxiety but no other effects; however, a dose of 8Template:Nbspmg resulted in profound emotional and perceptual changes, involving extreme anxiety, a sense of imminent death, and visual disturbance associated with color reversal and distortion, and intense flushing of the cheeks and forehead.<ref name="McLeodSitaram1985">Template:Cite journal</ref>

Shulgin (1997)

Alexander Shulgin reviewed the literature on bufotenin in his book TiHKAL.<ref name="TiHKAL" /> However, he and his collaborators did not appear to try it themselves.<ref name="TiHKAL" />

Ott (2001)

In 2001, ethnobotanist Jonathan Ott published the results of a study in which he self-administered free base bufotenin via insufflation (5–100Template:Nbspmg), sublingually (50Template:Nbspmg), rectally (30Template:Nbspmg), orally (100Template:Nbspmg) and via vaporization (2–8Template:Nbspmg).<ref name="Ott2001b" /><ref name="Ott2001a">Template:Cite journal</ref> Ott reported "visionary effects" of intranasal bufotenin and that the "visionary threshold dose" by this route was 40Template:Nbspmg, with smaller doses eliciting perceptibly psychoactive effects.<ref name="Ott2001a" /> He reported that "intranasal bufotenine is throughout quite physically relaxing; in no case was there facial rubescence, nor any discomfort nor disesteeming side effects".<ref name="Ott2001b" /><ref name="Ott2001a" />

At 100Template:Nbspmg, effects began within 5Template:Nbspminutes, peaked at 35 to 40Template:Nbspminutes, and lasted up to 90Template:Nbspminutes.<ref name="Ott2001b" /><ref name="Ott2001a" /> Higher doses produced effects that were described as psychedelic, such as "swirling, colored patterns typical of tryptamines, tending toward the arabesque".<ref name="Ott2001b" /><ref name="Ott2001a" /> Free base bufotenin taken sublingually was found to be identical to intranasal use.<ref name="Ott2001b" /><ref name="Ott2001a" /> The potency, duration, and psychedelic action was the same.<ref name="Ott2001b" /><ref name="Ott2001a" /> Ott found vaporized free base bufotenin active from 2 to 8Template:Nbspmg with 8Template:Nbspmg producing "ring-like, swirling, colored patterns with eyes closed".<ref name="Ott2001b" /><ref name="Ott2001a" /> He noted that the visual effects of insufflated bufotenin were verified by one colleague, and those of vaporized bufotenin by several volunteers.<ref name="Ott2001b" /><ref name="Ott2001a" />

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.<ref name="Ott2001b" /><ref name="Ott2001a" />

Morris (2020s)

Hamilton Morris, a psychoactive drug journalist, the creator of Hamilton's Pharmacopeia, and a pharmacologist, has experimented with bufotenin and found that it was an active psychedelic.<ref name="Morris2022" /><ref name="MorrisOtt2023" /> 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.<ref name="Morris2022" /><ref name="MorrisOtt2023" /> Morris has also stated that bufotenin is very nauseating and this has made it unpleasant for himself and other people.<ref name="Morris2022" /><ref name="MorrisOtt2023" /> By insufflation, he has said that its duration is about 1Template:Nbsphour and is longer than that of DMT or 5-MeO-DMT.<ref name="Morris2022" /><ref name="MorrisOtt2023" />

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.<ref name="RossiHallakBousoSaiz2022">Template:Cite journal</ref><ref name="GlennonDukat2023" /><ref name="Morris2023">Template:Cite podcast</ref>

Side effects

Side effects of bufotenin include nausea and vomiting, among others.<ref name="Ott2001b" /><ref name="Ott2001a" /><ref name="MorrisOtt2023" /><ref name="Morris2022" /> It can also produce powerful and potentially dangerous and frightening cardiovascular side effects at doses that allow for hallucinogenic effects.<ref name="Waser1967" />

Overdose

The acute toxicity (Template:LD50) of bufotenin in rodents has been estimated at 200 to 300Template:Nbspmg/kg. Death occurs by respiratory arrest.<ref name="RepkeTorres2006" /> In April 2017, a South Korean man died after consuming bufotenin-containing toads that had been mistaken for edible Asian bullfrogs,<ref name="BBC2017">Template:Cite news</ref> while in Dec. 2019, five Taiwanese men became ill and one man died after eating bufotenin-containing Central Formosa toads that they mistook for frogs.<ref>Template:Cite web</ref>

Pharmacology

Pharmacodynamics

Template:Nowrap

Target	Affinity (Ki, nM)
5-HT1A	2.5–1,023 (Ki) 13–366 (Template:Abbrlink) 95% (Template:Abbrlink)
5-HT1B	41–912
5-HT1D	3.7–29
5-HT1E	Template:Abbr
5-HT1F	31.6
5-HT2A	15–>10,000 (Ki) 3.49–232 (Template:Abbr) 83–100% (Template:Abbr)
5-HT2B	630
5-HT2C	16–145
5-HT3	34–210
5-HT4	Template:Abbr (Ki) 191–1,590 (Template:Abbr) 71% (Template:Abbr)
5-HT5A	1,000–2,900
5-HT5B	1,585
5-HT6	4.5–112
5-HT7	7.9–95
Template:Abbrlink	1,200 (Template:Abbrlink) 30.5 (Template:Abbr)
Template:Abbrlink	>10,000 (Template:Abbr)
Template:Abbrlink	>10,000 (Template:Abbr)
Notes: The smaller the value, the more avidly the drug binds to the site. Proteins are animal or human. Refs: <ref name="PDSPKiDatabase">Template:Cite web</ref><ref name="BindingDB">Template:Cite web</ref><ref name="Glennon1987">Template:Cite journal</ref><ref name="PlazasFaraone2023" /><ref name="CramervanDrimmelenLong1990" /><ref name="BloughLandavazoDecker2014" /><ref name="ChenLiYu2023a" /><ref name="ChenLiYu2023b" /><ref name="Nelson1991" /> <ref name="ColasChoiLaunay1997">Template:Cite journal</ref><ref name="DumuisAnsanayWaeber1997">Template:Cite book</ref><ref name="EganGrindeDupre2000">Template:Cite journal</ref><ref name="MedhurstKaumann1993">Template:Cite journal</ref>

Bufotenin is an analogue of the monoamine neurotransmitter serotonin.<ref name="McBride2000">Template:Cite journal</ref><ref name="PlazasFaraone2023" /> Similarly to serotonin and related compounds like dimethyltryptamine (DMT), bufotenin is an agonist of the serotonin 5-HT_1A, 5-HT_2A, 5-HT_2C, 5-HT₃, and 5-HT₄ receptors.<ref name="McBride2000" /><ref name="PlazasFaraone2023" /><ref name="BloughLandavazoDecker2014" /><ref name="CramervanDrimmelenLong1990">Template:Cite journal</ref><ref name="GlennonPeroutkaDukat1991">Template:Cite book</ref><ref name="OliviervanWijngaardenSoudijn1997">Template:Cite book</ref><ref name="Glennon1987" /> It is also known to bind with high affinity to other serotonin receptors, including the serotonin 5-HT_1B, 5-HT_1D, 5-HT_1F, 5-HT₆, and 5-HT₇ receptors.<ref name="CramervanDrimmelenLong1990" /><ref name="NeumannDheinKirchhefer2024">Template:Cite journal</ref><ref name="PlazasFaraone2023">Template:Cite journal</ref><ref name="OliviervanWijngaardenSoudijn1997" /><ref name="Glennon1987" /> Bufotenin has about 5- to 10-fold higher affinity for the serotonin 5-HT_2A receptor than 5-MeO-DMT, about the same activational potency as 5-MeO-DMT at the receptor in vitro (Template:Abbrlink = 3.49Template:NbspnM and 3.87Template:NbspnM, respectively), and about 3-fold higher in-vivo potency than 5-MeO-DMT when they are in the brain.<ref name="ShenJiangWinter2010" /><ref name="BloughLandavazoDecker2014" /> In contrast to many other psychedelic tryptamines, bufotenin shows high affinity for the serotonin 5-HT₃ receptors, similar to or higher than that of serotonin,<ref name="Dukat2004">Template:Cite journal</ref><ref name="CramervanDrimmelenLong1990" /><ref name="GlennonPeroutkaDukat1991" /> and this receptor is strongly associated with production of nausea and vomiting.<ref name="JohnstonLuRudd2014">Template:Cite journal</ref><ref name="GlennonDukat2023">Template:Cite journal</ref> In addition to its serotonin receptor agonism, bufotenin is a potent serotonin releasing agent (SRA) with an Template:Abbr value of 30.5Template:NbspnM, whereas it is inactive as a releaser of dopamine or norepinephrine (Template:Abbr > 10,000Template:NbspnM).<ref name="BloughLandavazoDecker2014">Template:Cite journal</ref>

A special property of 5-MeO-DMT is that it has much higher affinity for and activational potency at the serotonin 5-HT_1A receptor compared to other psychedelic tryptamines such as DMT and this is thought to confer it with unique and distinct hallucinogenic effects.<ref name="DourronNicholsSimonsson2023">Template:Cite journal</ref><ref name="ReckwegUthaugSzabo2022">Template:Cite journal</ref><ref name="ShenJiangWinter2010">Template:Cite journal</ref> Similarly, bufotenin has also shown greatly increased affinity for the serotonin 5-HT_1A receptor.<ref name="Nelson1991">Template:Cite journal</ref> Whereas the serotonin 5-HT_1A receptor affinities (K_i or Template:Abbr) of tryptamine and DMT were 125Template:NbspnM and 170Template:NbspnM, respectively, the affinities of serotonin (5-HO-T), 5-methoxytryptamine (5-MeO-T), bufotenin (5-HO-DMT), and 5-MeO-DMT were 3Template:NbspnM, 9Template:NbspnM, 4.9Template:NbspnM, and 6.5Template:NbspnM, respectively.<ref name="Nelson1991" /> Comparing bufotenin to DMT, it had 35-fold higher affinity for the serotonin 5-HT_1A receptor in comparison.<ref name="Nelson1991" /> Findings were very similar in another study not only in terms of affinities but also activational potencies.<ref name="ChenLiYu2023a">Template:Cite journal</ref><ref name="ChenLiYu2023b">Template:Cite journal</ref> Bufotenin had a similar Template:Abbr at the serotonin 5-HT_1A receptor as serotonin, 5-MeO-T, and 5-MeO-DMT (13Template:NbspnM, 3Template:NbspnM, 14Template:NbspnM, and 21Template:NbspnM, respectively), and a far greater value than tryptamine or DMT (899Template:NbspnM and 1,293Template:NbspnM, respectively).<ref name="ChenLiYu2023a" /><ref name="ChenLiYu2023b" />

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.<ref name="McBride2000" /> As a result, bufotenin has a greater ratio of peripheral activity to central effect.<ref name="McBride2000" /> Bufotenin produces the head-twitch response, a behavioral proxy of psychedelic effects, in rodents.<ref name="WieczorekWitkowskaJasicka-Misiak2015">Template:Cite book</ref><ref name="CornePickering1967">Template:Cite journal</ref><ref name="ZhangYangYang2025">Template:Cite journal</ref> However, it requires doses about 10-fold higher than those of psilocybin to produce behavioral responses in rats.<ref name="PlazasFaraone2023" /> Conversely, unlike other psychedelics, bufotenin fails to substitute for LSD, psilocybin, or 5-MeO-DMT in rodent drug discrimination tests.<ref name="Baker2018">Template:Cite book</ref><ref name="HelsleyFiorellaRabin1998">Template:Cite journal</ref><ref name="WinterRiceAmorosi2007">Template:Cite journal</ref><ref name="SpencerGlaserTraber1987">Template:Cite journal</ref> Relatedly, findings on the effects of bufotenin in animals have been described as "equivocal".<ref name="BrimblecombePinder1975" /> Studies have been similarly mixed on the psychedelic 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.<ref name="McBride2000" /><ref name="ShenJiangWinter2010">Template:Cite journal</ref><ref name="Ott2001a" /><ref name="TiHKAL" /> In any case, bufotenin has often been reported to produce pronounced peripheral serotonergic effects.<ref name="McBride2000" /><ref name="NeumannDheinKirchhefer2024" /> These have included cardiovascular, gastrointestinal, and other effects, among them increased respiratory rate, chest heaviness, purpling of the head and neck skin (intense skin flushing), nausea, vomiting, and retching.<ref name="McBride2000" /><ref name="NeumannDheinKirchhefer2024" /> 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.<ref name="McBride2000" /> The adverse effects of bufotenin may be more pronounced with intravenous injection compared to other routes such as insufflation.<ref name="MorrisOtt2023" />

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.<ref name="McBride2000" /> In addition, 5-MeO-DMT, the O-methylated analogue of bufotenin, which has greater lipophilicity, is readily able to cross the blood–brain barrier and produce psychedelic effects.<ref name="McBride2000" /> Bufotenin prodrug esters, with greater lipophilicity than bufotenin itself, like O-acetylbufotenin and O-pivalylbufotenin, have also shown robust psychedelic-like effects in animals.<ref name="McBride2000" /><ref name="GlennonGessnerGodse1979">Template:Cite journal</ref><ref name="GessnerDankova1975">Template:Cite journal</ref>

Pharmacokinetics

Bufotenin has been reported to undergo a strong first-pass effect<ref name="NeumannDheinKirchhefer2024" /> and to not be orally active.<ref name="McBride2000" /> This is in contrast to its positional isomer psilocin, which is thought to form a pseudo-ring system that limits its susceptibility to metabolism by monoamine oxidase (MAO).<ref name="McBride2000" /> However, bufotenin actually does show oral activity if sufficiently high doses are taken.<ref name="NeumannDheinKirchhefer2024" /> About 10-fold higher doses of bufotenin seem to be required orally compared to parenterally for effects.<ref name="NeumannDheinKirchhefer2024" />

In rats, subcutaneously administered bufotenin (1–100Template:Nbspμg/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.<ref name="ShenJiangWinter2010" /><ref name="FullerSnoddyPerry1995" /> 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.<ref name="BrimblecombePinder1975">Template:Cite book</ref><ref name="Vogel1969">Template:Cite journal</ref><ref name="SandersBush1967">Template:Cite journal</ref> The brain-to-blood ratio of 5-MeO-DMT (O-methylbufotenin) was 15Template:Nbsptimes higher than that of bufotenin in the study.<ref name="SandersBush1967" /> Bufotenin reaches peak circulating concentrations at one hour and is nearly eliminated within 8Template:Nbsphours.<ref name="FullerSnoddyPerry1995">Template:Cite journal</ref> 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.

Theoretical intramolecular hydrogen bond and pseudo-ring system occurring with psilocin (4-HO-DMT) but not with bufotenin (5-HO-DMT).<ref name="GumpperNichols2024" /><ref name="McBride2000" />

Psilocin (4-HO-DMT) is a positional isomer of bufotenin and might be expected to have similarly limited lipophilicity and blood–brain permeability.<ref>Template:Cite journal</ref><ref name="McBride2000" /> However, psilocin appears to form a tricyclic pseudo-ring system wherein its hydroxyl group and amine interact through hydrogen bonding.<ref name="GumpperNichols2024" /><ref name="McBride2000" /><ref name="PlazasFaraone2023" /> 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.<ref name="GumpperNichols2024" /><ref name="McBride2000" /><ref name="PlazasFaraone2023" /> In contrast, bufotenin is not able to achieve this pseudo-ring system.<ref name="GumpperNichols2024" /><ref name="McBride2000" /><ref name="PlazasFaraone2023" /> Accordingly, bufotenin is less lipophilic than psilocin in terms of partition coefficient.<ref name="GumpperNichols2024" /><ref name="McBride2000" /> In any case, bufotenin does still appear to show significant central permeability and, like psilocybin, can produce robust hallucinogenic effects in humans.<ref name="McBride2000" /><ref name="PlazasFaraone2023" /><ref name="ShenJiangWinter2010" /><ref name="Ott2001a" />

Chemistry

Bufotenin, also known as 5-hydroxy-N,N-dimethyltryptamine (5-HO-DMT), is a substituted tryptamine and a derivative of dimethyltryptamine (DMT; N,N-dimethyltryptamine) and serotonin (5-hydroxytryptamine; 5-HT).<ref name="TiHKAL" /> It is also closely related to psilocin (4-HO-DMT) and 5-MeO-DMT.<ref name="TiHKAL" />

Properties

The predicted log P of bufotenin ranges from 0.89 to 2.04.<ref name="PubChem">Template:Cite web</ref><ref name="DrugBank">Template:Cite web</ref><ref name="ChemSpider">Template:Cite web</ref> For comparison, the predicted log P of DMT is 2.06 to 2.5,<ref name="PubChem-DMT">Template:Cite web</ref><ref name="DrugBank-DMT">Template:Cite web</ref><ref name="ChemSpider-DMT">Template:Cite web</ref> of serotonin is 0.2 to 0.56,<ref name="PubChem-5-HT">Template:Cite web</ref><ref name="DrugBank-5-HT">Template:Cite web</ref><ref name="ChemSpider-5-HT">Template:Cite web</ref> of 5-MeO-DMT is 1.5 to 2.38.<ref name="PubChem-5-MeO-DMT">Template:Cite web</ref><ref name="ChemSpider-5-MeO-DMT">Template:Cite web</ref><ref name="DrugBank-5-MeO-DMT">Template:Cite web</ref> and of psilocin is -0.14 to 2.1.<ref name="PubChem-Psilocin">Template:Cite web</ref><ref name="ChemSpider-Psilocin">Template:Cite web</ref><ref name="DrugBank-Psilocin">Template:Cite web</ref>

Synthesis

The chemical synthesis of bufotenin has been described.<ref name="TiHKAL" />

Analogues and derivatives

Some analogues and derivatives of bufotenin (5-HO-DMT), aside from serotonin and DMT, include psilocin (4-HO-DMT) (a positional isomer), 6-HO-DMT (another positional isomer), 5-MeO-DMT (O-methylbufotenin), O-acetylbufotenine (5-AcO-DMT), O-pivalylbufotenine (5-t-BuCO-DMT), bufotenidine (N-methylbufotenin), bufoviridine (bufotenin O-sulfate), 5-HO-DET, 5-HO-DPT, 5-HO-DiPT, and α-methylserotonin (AMS; 5-HO-AMT), among others.<ref name="TiHKAL" />

Natural occurrence

Toads

Bufotenin is found in the skin and eggs of several species of toads belonging to the genus Bufo, but is most concentrated in the Colorado River toad (formerly Bufo alvarius, now Incilius alvarius), the only toad species with enough bufotenin for a psychoactive effect. Extracts of toad toxin, containing bufotenin and other bioactive compounds, have been used in some traditional medicines such as ch'an su (probably derived from Bufo gargarizans), which has been used medicinally for centuries in China.<ref name=davis/> It is also found in the cane toad (Rhinella marina).<ref name="ChenLiYu2023a" />

The toad was "recurrently depicted in Mesoamerican art",<ref>Template:Cite journal</ref> 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.<ref name=davis>Template:Cite journal</ref>

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,<ref name=hitt>Template:Cite journal</ref><ref name=ragonesi>Template:Cite journal</ref><ref name=brubacher>Template:Cite journal</ref> 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.<ref name=brubacher/><ref name=godwa>Template:Cite journal</ref><ref>Template:Cite book</ref>

Reports in the mid-1990s indicated that bufotenin-containing toad secretions had appeared as a street drug, supposedly but in fact not an aphrodisiac,<ref>Rodrigues, R.J. Aphrodisiacs through the Ages: The Discrepancy Between Lovers' Aspirations and Their Desires. ehealthstrategies.com </ref> ingested orally in the form of ch'an su,<ref name=brubacher/> 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.<ref name=brubacher/><ref name=cdc>Template:Cite journal</ref> 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.<ref name="Lyttle1993">Template:Cite journal</ref><ref>The Dog Who Loved to Suck on Toads. NPR. Accessed on May 6, 2007.</ref><ref>Psychoactive toad: Cultural references</ref> 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 Bufo Alvarius: The Psychedelic Toad of the Sonoran Desert<ref name="most">Template:Cite web</ref><ref name="m076">Template:Cite web</ref> 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.<ref name=costa>Template:Cite journal</ref>

Anadenanthera seeds

Yopo seeds from the perennial Anadenanthera peregrina tree have a long history of entheogenic use and induce a short but distinct psychedelic experience.

Bufotenin is a constituent of the seeds of Anadenanthera colubrina and Anadenanthera peregrina trees. Anadenanthera seeds have been used as an ingredient in psychedelic snuff preparations by indigenous cultures of the Caribbean, Central and South America since pre-Columbian times.<ref name="RepkeTorres2006">Template:Cite book</ref><ref name=":0">Template:Cite journal</ref><ref>Template:Cite journal</ref> The oldest archaeological evidence of use of Anadenanthera beans is over 4,000 years old.<ref name=":0" />

Other sources

Bufotenin has been identified as a component in the latex of the takini (Brosimum acutifolium) tree, which is used as a psychedelic by South American shamans,<ref name=gaillard>Template:Cite journal</ref> and in the seeds of Mucuna pruriens.<ref name="Chamakura1994" /> Bufotenin has also been identified in Amanita muscaria, Amanita citrina, A. porphyria, and A. tomentella.<ref name="Rumack">Template:Cite book</ref><ref>Template:Cite journal</ref>

Occurrence in humans

Bufotenin occurs in trace amounts in the human body.<ref name="BarkerMcIlhennyStrassman2012" /><ref name="NeumannDheinKirchhefer2024" /><ref name="KärkkäinenForsströmTornaeus2005" /><ref name="JiménezBouso2022" /> It can be biosynthesized from serotonin by indolethylamine N-methyltransferase (INMT) enzymes.<ref name="BarkerMcIlhennyStrassman2012" /><ref name="JiménezBouso2022">Template:Cite journal</ref>

Association with psychiatric conditions

A study conducted in the late 1960s reported the detection of bufotenin in the urine of schizophrenic subjects;<ref name="nature_2204">Template:Cite journal</ref> however, subsequent research failed to confirm these findings until 2010.<ref name="pm5860629">Template:Cite journal</ref><ref name=pomilio>Template:Cite journal</ref><ref name=ciprian>Template:Cite journal</ref><ref name=carpenter>Template:Cite journal</ref><ref name="pm20150873" />

Studies have detected endogenous bufotenin in urine specimens from individuals with other psychiatric disorders,<ref name="pm8747157">Template:Cite journal</ref> such as infant autistic patients.<ref name="pm7749594">Template:Cite journal</ref> 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.<ref name="pm6147728">Template:Cite journal</ref>

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.<ref name="pm20150873">Template:Cite journal</ref>

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 <ref>Clarke AJ. Elevated Endogenous Psychedelic Bufotenine in the Urine of Patients Diagnosed With a Mental Illness: A Systematic Review. Cureus. 2025 May 20;17(5):e84510. doi: https://doi.org/10.7759/cureus.84510. PMID: 40546466; PMCID: PMC12179411.</ref>

History

Bufotenine was first isolated from secretions of the toad Bufo vulgaris by French scientists Césaire Phisalix and Gabriel Bertrand in 1893.<ref name="Shulgin1981">Template:Cite journal</ref><ref name="LyttleGoldsteinGartz1996">Template:Cite journal</ref><ref name="BochnerGoyffon2007">Bochner, R., & Goyffon, M. (2007). L’œuvre scientifique de Césaire Phisalix (1852-1906), découvreur du sérum antivenimeux. Bull Soc Herp Fr, 123, 15-46. https://www.icict.fiocruz.br/sites/www.icict.fiocruz.br/files/L%20oeuvre%20scientifique%20de%20Cesaire%20Phisalix%20(1852--1906)%20decouvreur%20du%20serum%20antivenimeux.pdf</ref><ref name="PhisalixBertrand1893">Phisalix C, Bertrand G (1893) Toxicité comparée du sang et du venin de crapaud commun, considérée au point de vue de la sécrétion interne des glandes cutanées de cet animal. C R Soc Biol 45:477–479. https://scholar.google.com/scholar?cluster=14905926340091797397</ref> It was also subsequently isolated from many other natural sources, including plants, fungi, and other toads over time.<ref name="Shulgin1981" /><ref name="Chamakura1994" /> The compound was first isolated to purity by Austrian chemist Hans Handovsky in 1920.<ref name="LyttleGoldsteinGartz1996" /><ref name="ChiltonBigwoodJensen1979">Template:Cite journal</ref> The chemical structure of bufotenine was confirmed by German chemist Heinrich Wieland and colleagues in 1934.<ref name="WielandKonzMittasch1934">Template:Cite journal</ref> The first reported synthesis of bufotenine was by Japanese researchers Toshio Hoshino and Kenya Shimodaira in 1935.<ref name="HoshinoShimodaira1935">Template:Cite journal</ref>

Bufotenin was established as a major component of hallucinogenic snuffs made from Anadenanthera peregrina such as cohoba and yopo in 1954.<ref name="Shulgin1981" /><ref name="Chamakura1994" /><ref name="Stromberg1954">Template:Cite journal</ref><ref name="FishHorning1956">Template:Cite journal</ref> It was also isolated from Anadenanthera colubrina in 1955.<ref name="Chamakura1994" /><ref name="FishJohnsonHorning1955">Template:Cite journal</ref><ref name="FishHorning1956" /> Clinical studies assessed the effects of bufotenin and were published starting in 1956.<ref name="LyttleGoldsteinGartz1996" /><ref name="McBride2000" /><ref name="ShenJiangWinter2010" /><ref name="FabingHawkins1956" /><ref name="TurnerMerlis1959" /> However, the findings of these studies were conflicting, and bufotenin developed a long-standing reputation of being non-hallucinogenic as well as toxic.<ref name="LyttleGoldsteinGartz1996" /><ref name="McBride2000" /><ref name="ShenJiangWinter2010" /> In any case, bufotenin nonetheless became a Schedule I controlled substance in the United States in 1967.<ref name="Lyttle1993" /><ref name="LyttleGoldsteinGartz1996" /><ref name="ChiltonBigwoodJensen1979"/>

American ethnobotanist Jonathan Ott and colleagues subsequently showed in 2001 that bufotenin is in fact a psychedelic and does not necessarily produce major adverse effects, although marked nausea and vomiting are prominent.<ref name="ShenJiangWinter2010" /><ref name="Ott2001b" /><ref name="Ott2001a" /> Bufotenin was first encountered as a novel recreational drug in 1992.<ref name="Chamakura1994" /> Journalist Hamilton Morris corroborated Ott and colleagues' findings on the hallucinogenicity of bufotenin in the early 2020s.<ref name="Morris2022" /><ref name="MorrisOtt2023" />

Society and culture

Names

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.<ref name="dea">Template:Cite web</ref>

Recreational use

Bufotenin has been encountered as a recreational drug in forensic samples, for instance in New York City.<ref name="Chamakura1994">Template:Cite journal</ref>

Legal status

Australia

Bufotenin is classified as a Schedule I controlled substance according to the Criminal Code Regulations of the Government of the Commonwealth of Australia.<ref name=ccr>Template:Citation</ref> It is also listed as a Schedule 9 substance under the Poisons Standard (October 2015).<ref name="Poisons Standard">Poisons Standard October 2015 https://www.comlaw.gov.au/Details/F2015L01534</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."<ref>Poisons Act 1964 Template:Webarchive. slp.wa.gov.au</ref>

Under the Misuse of Drugs Act 1981 Template:Convert is determined to be enough for court of trial and Template:Convert is considered intent to sell and supply.<ref>Misuse of Drugs Act 1981 (2015) Template:Webarchive. slp.wa.gov.au</ref>

Sweden

Sweden's public health agency suggested classifying Bufotenin as a hazardous substance, on May 15, 2019.<ref>Template:Cite web</ref>

United Kingdom

In the United Kingdom, bufotenin is a Class A drug under the 1971 Misuse of Drugs Act.

United States

Bufotenin (DEA Drug Code 7403) is regulated as a Schedule I drug by the Drug Enforcement Administration at the federal level in the United States and is therefore illegal to buy, possess, and sell.<ref name="PART 1308 — SCHEDULES OF CONTROLLED SUBSTANCES - 1308.11 Schedule I">§1308.11 Schedule I. Template:Webarchive deadiversion.usdoj.gov</ref>

Research

Bufotenin is being investigated as a potential pharmaceutical drug by the Usona Institute.<ref name="Synapse">Template:Cite web</ref> As of May 2025, it is in the discovery or preclinical research stage of development.<ref name="Synapse" />

Bufotenin has shown antiviral activity against the rabies virus and has been found to increase survival rates against rabies in rodents.<ref name="CoelhodaSilvaBeraldo-Neto2021">Template:Cite journal</ref><ref name="VigerelliScianiPereira2020">Template:Cite journal</ref>

See also

• Substituted tryptamine
• List of entheogens

External links

• Bufotenin - Isomer Design
• Bufotenin - PsychonautWiki
• Bufotenin - Erowid
• The Big & Dandy Bufotenine (5-HO-DMT) Thread - Bluelight
• Bufotenin - TiHKAL - Erowid
• Bufotenin - TiHKAL - Isomer Design
• Bufotenin - Trout's Notes
• Psychoactive Toad Venom (Bufo Alvarius) - Tripsitter
• Yopo (Anadenanthera peregrina): Psychedelic Snuff From the Amazon - Tripsitter

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