Bufotenin

Bufotenin (also known as bufotenine), is a tryptamine related to the neurotransmitter serotonin. It is an alkaloid found in the skin of some species of toads; in mushrooms, higher plants, and mammals; and possibly in the brain, plasma, and urine of schizophrenics.

The name bufotenin originates from the Bufo genus of toads, which includes several species of psychoactive toads (such as Bufo alvarius and Bufo marinus) that secrete bufotoxins from their parotoid glands. Bufotenin is very similar in chemical structure to the hallucinogen psilocin; the only structural difference is that the hydroxyl (-OH) group is located one carbon over on the indole ring. However, pharmacologically, it is more closely related to 5-MeO-DMT and DMT, chemicals that often occur in plant and animal species in which bufotenin is found. Whether bufotenine is also hallucingenic has been the subject of debate among researchers.

Nomenclature
Bufotenin (bufotenine) is also known by the chemical names 5-hydroxy-dimethyltryptamine (5-OH-DMT), N,N-dimethyl-5-hydroxytryptamine, dimethyl serotonin, and mappine.

History
Bufotenine was first isolated, from toad skin, and named by the Austrian chemist Handovsky at the University of Prague during World War I. The structure of bufotenine was first confirmed in 1934 by Heinrich Wieland’s laboratory in Munich, and the first reported synthesis of bufotenine was by Toshio Hoshino in 1936.

Toads
Bufotenin is a chemical constituent in the venom and eggs of several species of toads belonging to the Bufo genus, including Bufo alvarius and Bufo marinus. Extracts of toad venom, 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.

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 bufotenine, Bufo venoms also contain digoxin-like cardiac glycosides, and ingestion of the venom can be fatal. Ingestion of Bufo toad venom and eggs by humans has resulted in several reported cases of poisoning,  some of which resulted in death.

Contemporary reports indicate that bufotenine-containing toad venom has been used as a street drug; that is, as an aphrodisiac, ingested orally in the form of ch’an su, and as a hallucinogen, by smoking or orally ingesting Bufo toad venom or dried Bufo skins. The use of chan'su and love stone (a related toad venom 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 venom has been referred to in popular culture and in the scientific literature as toad licking and has drawn media attention. Albert Most, founder of the Church of the Toad of Light and a proponent of recreational use of Bufo alvarius venom, published a booklet titled Bufo avlarius: The Psychedelic Toad of the Sonoran Desert in 1983 which explained how to extract and smoke the secretions.

Bufotenin is also present in the skin secretion of three arboreal amphibian species of the Osteocephalus genus (Osteocephalus taurinus, Osteocephalus oophagus, and Osteocephalus langsdorffii) from the Amazon and Atlantic rain forests.

Anadenanthera Seeds
Bufotenin is the primary active constituent of the seeds of Anadenanthera colubrina and Anadenanthera peregrina trees. Anadenanthera seeds have been in use as hallucinogens for over 4000 years. The use of these seeds have been historically linked to shamans in South America and in the Caribbean Islands. Archeological evidence shows smoking as the original route of administration of Anadenanthera seeds. The seeds are smoked alone or often mixed with tobacco. Cigars sometimes used by shamans containing ground Anadenanthera seeds mixed with tobacco are estimated to contain up to 196 mg of bufotenin. Snuff and enema usage appears later in history. Snuff preparations eventually became the most widely accepted route of administration.

The snuffs known as Vilca and Yopo (also known as Cohoba) are made from the seeds of the Anadenanthera colubrina and Anadenanthera peregrina trees, respectively. Cohoba was used by the tribe with whom Christopher Columbus made first contact, the Taino of Cuba and Hispaniola. Anadenanthera snuff is usually processed by toasting the seeds, removing the seed husks, and then grinding them to a fine powder. To improve the snuff's potency, most shamans usually add a natural form of calcium hydroxide (or calcium oxide) and a little water to the snuff. The mix is kneaded for several minutes and allowed to sit overnight. It is then dried and ground to a powder once more. Phenolic compounds such as bufotenine react with calcium hydroxide to form phenoxides. This processing with calcium hydroxide converts bufotenin (5-HO-DMT) into its phenoxide form: calcium bufotenoxide (Ca + 5-O-DMT, also known as calcium bufotenate), a compound with increased hallucinogenic properties. A typical dose of snuff contains over 100 mg of bufotenin.

Mushrooms
Bufotenine is also found in several species of Amanita mushrooms, including Amanita muscaria, Amanita citrina and Amanita porphyria.

Other Sources
Bufotenin has been identified as a component in the latex of the takini (Brosimum acutifolium) tree, which is used as a hallucinogen by South American shamans, and in the seeds of Mucuna pruriens DC

Uptake and Elimination
In rats, subcutaneously administered bufotenin (1–100 μg/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. It reaches peak concentrations at 1 hour and is nearly completely eliminated within 8 hours. In humans, bufotenine is rapidly absorbed following intravenous administration and is excreted in the urine predominantly (70%) in the form of 5-HIAA, an endogenous metabolite of serotonin, while roughly 4% is eliminated unmetabolized in the urine. Orally administered bufotenine undergoes extensive first-pass metabolism by the enzyme monoamine oxidase.

Lethal Dose
The acute toxicity of bufotenin in rodents has been calculated to have an LD50 of between 200 and 300 mg/kg, which by comparison, is comparable to the LD50 for intravenous morphine (200-300 mg/kg) in mice. Death occurs by respiratory arrest.

Fabing & Hawkins (1955)
In 1955, Fabing and Hawkins administered bufotenin intravenously at doses of up to 16 mg to prison inmates at Ohio State Penitentiary. A troubling toxic blood circulation effect causing a purpling of the face was seen in these tests.

A subject given 1 mg 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 2 mg 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 4 mg 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 hallucinogenic effects were "reminiscent of LSD and mescaline but develop and dispappear more quickly, indicating rapid central action and rapid degradation of the drug".

Isbell (1956)
In 1956, Dr. Harris S. Isbell at the Public Health Service Hospital in Lexington, Kentucky experimented with bufotenine as a snuff. He reported “no subjective or objective effects were observed after spraying with as much as 40 mg bufotenine”; however subjects who received 10-12 mg injected intramuscularly reported “elements of visual hallucinations consisting of a play of colors, lights, and patterns”.

Turner & Merlis (1959)
Turner and Merlis (1959) experimented with intravenous administration of bufotenine (as the water soluble creatinine sulfate salt) to schizophrenics at a New York state hospital. They reported that when one subject received 10 mg 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 that:
 * “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’.”

After pushing doses to the morally admissible limit without producing hallucinations, Turner and Merlis conservatively concluded: “We must reject bufotenine…as capable of producing the acute phase of Cohoba intoxication”.

McLeod and Sitaram (1985)
A 1985 study by McLeod and Sitaram in humans reported that bufotenine administered intranasally at a dose of 1-16 mg had no effect, other than intense local irritation. When given intravenously at low doses (2-4 mg), bufotenine oxalate caused anxiety but no other effects; however, a dose of 8 mg 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.

Ott (2001)
In 2001, Jonathan Ott, an amateur ethnobotanist, published the results of a study in which he self-administered free base bufotenin intranasally (5-100 mg), sublingually (50 mg), intrarectally (30 mg), orally (100 mg) and via vaporization (2-8 mg). Ott reported “visionary effects" of intranasal bufotenine and that the "visionary threshold dose" by this route was 40 mg, with smaller doses eliciting perceptibly psychoactive effects. He reported that "intranasal bufotenine is throughout quite physically relaxing; in no case was there facial rubescence, nor any discomfort nor disesteeming side effects".

At 100 mg, effects began within 5 minutes, peaked at 35-40 minutes, and lasted up to 90 minutes. Higher doses produced effects that were described as hallucinogenic, 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 hallucinogenic action was the same. Ott found vaporized free base bufotenin active from 2-8 mg with 8 mg producing "ring-like, swirling, colored patterns with eyes closed".

Ott noted 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 the drug was administered intravenously.

Association With Schizophrenia and Other Mental Disorders
A study conducted in the late 1960s reported the detection of bufotenin in the urine of schizophrenic subjects; however, subsequent research has failed to confirm these findings.

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.

Legal Status
Bufotenine is regulated as a Schedule I drug (ID number 7403) by the U.S. Drug Enforcement Agency. It is classified as a Schedule I controlled substance according to the Criminal Code Regulations of the government of Australia.