Laboratory and animal studies on the chemistry of bufotenin. Quantitative determination on bufotenin in human urine.
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Chromatography, Paper↗
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Tissue distribution, metabolism and effects of bufotenine administered to rats.
Bufotenine (N, N-dimethyl-5-hydroxytryptamine) is a serotonin analog reported to be hallucinogenic. Bufotenine concentrations were measured by liquid chromatography with electrochemical detection after the s.c. injection of bufotenine (1, 30 or 100 mg/kg) into rats. At 1 hr, bufotenine was high in lung, heart and blood and lower in brain and liver. No N-monomethyl-5-hydroxytryptamine was detected, but 5-hydroxyindoleacetic acid (5HIAA) was increased due to bufotenine metabolism. Bufotenine disappeared nearly completely by 8 hr. Bufotenine concentrations were slightly higher in hypothalamus and brain stem than in striatum or cortex; serotonin was slightly decreased, and 5HIAA was increased in these brain regions. Pargyline reduced concentrations of 5HIAA in blood and tissues after bufotenine injection; LY51641 but not deprenyl mimicked pargyline, suggesting type A not type B monoamine oxidase metabolizes bufotenine. Bufotenine injection increased serum corticosterone concentration, an effect not blocked by metergoline at a dose that blocked a similar increase elicited by quipazine. Although only 2% of the serotonin was found in platelet-poor plasma, more than 99% of the bufotenine was found in platelet-poor plasma, indicating that bufotenine is not stored in platelets. These experiments indicate that bufotenine is rapidly eliminated, in part by type A monoamine oxidase, after its injection into rats and that bufotenine penetrates the blood-brain barrier poorly.
Animals↗
Urinary excretion of bufotenin (N,N-dimethyl-5-hydroxytryptamine) is increased in suspicious violent offenders: a confirmatory study.
We previously reported that violent offenders with paranoid symptoms or whose violent actions had been directed against family members had higher urinary levels of bufotenin than other violent offenders. In the present study, patients were evaluated with the Karolinska Scales of Personality (KSP), and urinary levels of bufotenin were determined by mass spectrometry. In drug-free patients suspiciousness was positively correlated, and socialization was negatively correlated, with urinary bufotenin excretion. These two personality variables were strongly interdependent. In drug users, bufotenin excretion was correlated positively with social desirability and negatively with irritability, but not with suspiciousness. Bufotenin excretion was not found to be associated with violence toward family members in the present study. The results are in keeping with the earlier finding that violent offenders with paranoid personality traits have higher urinary levels of bufotenin than other violent offenders.
Adult↗
Determination of serotonin and bufotenin as their dansyl derivatives.
A method is described which permits the determination of serotonin and bufotenin in the same tissue sample. It comprises the following steps: (a) tissue extraction with acetone-0.1 M hydrochloric acid (19:1); (b) reaction of the tissue extract with dansyl (Dns) chloride; (c) pre-separation of O-Dns-bufotenin from O,N-bis-Dns-serotonin and other Dns-amides on a small silica gel column (this step is dispensable if only serotonin or bufotonin is being determined); (d) TLC separation of O-Dns-bufotenin and O,N-bis-Dns-serotonin from other Dns derivatives; (e) quantitative evaluation of the separated compounds by fluorimetry for O-Dns-bufotenin and by fluorimetry or mass spectrometry for the serotonin derivative. The photometer response is linear within the range 0.1-300 nmole. With the mass spectrometric method, 2 pmole of O,N-bis-Dns-serotonin could be determined with a standard deivation of +/-9%. The recovery of the amines from tissue was better than 85%. Reserpine treatment of toads caused a concomitant decrease in serotonin and bufotenin in the brain, but not in the skin of the animals. Repletion of bufotenin in the brain occurs at a higher rate than the repletion of the serotonin pool.
Animals↗
Bufotenine: toward an understanding of possible psychoactive mechanisms.
A review of the neuropharmacology of the alleged hallucinogen bufotenine is presented, including recent experimental results showing activity similar to LSD and other known hallucinogens (psilocin and 5-MeO-DMT) at the purported hallucinogenic serotonin (5-HT) receptors, 5-HT2A and 5-HT2C. In addition, current reports of computer modeling of the receptors and ligand binding sites give evidence of bufotenine's ability to bind and activate these receptors. While binding and activation of the purported hallucinogenic receptors are not the full extent of the hallucinogenic signature, this evidence shows support for the rationale that the reported lack of the drug's classic hallucinogenic response in human experiments is due to poor ability to cross the blood brain barrier (BBB), not lack of activation of the appropriate brain receptors. Further evidence is reviewed that in some physiological states, some drugs with characteristics similar to bufotenine which do not normally cross the BBB, cross it and enter the brain. While direct human experimental evidence of bufotenine's hallucinogenic activity seems lacking, the above combined factors are considered, and possible explanations of bufotenine's reported psychoactivity are suggested. Additionally, updated experimental models testing the possible nature of bufotenine's hallucinogenic potential are proposed.
Blood-Brain Barrier↗
Bufotenine reconsidered as a diagnostic indicator of psychiatric disorders.
We have analyzed products of the serotonin-degradative pathway, in which both N-methylserotonin and bufotenine are formed in urine specimens of products with psychiatric disorders by three-dimensional HPLC with electrochemical detection. Bufotenine was detected in urine from all autistic patients with mental retardation and epilepsy (n = 18) and many autistic patients (32/47) with mental retardation. Bufotenine was detected in the urine of 15 of 18 patients with depression. Thirteen of 15 schizophrenic patients were also positive for bufotenine. N-methylserotonin was also detected in some cases of each disorder. Only two of 200 urine specimens from healthy controls were positive for bufotenine. Thus, the presence and levels of bufotenine might be useful and important markers of some psychiatric disorders.
Adult↗
The influence of bufotenin on the feeding behavior and cerebral serotonin content in rats.
By researches carried out in male adult rats (Wistar), the influence of the intraperitoneally injected bufotenin (5 mg/kg b.w. active substance in saline solution) was followed on: I--feeding behavior; II--the serotonin concentration in hypothalamus, rhinencephalon, mesencephalon and sensorimotor cerebral cortex. The obtained results show that bufotenin influences the feeding behavior by reducing the motor functions. Its action depends on the physiological state of the animal: by increasing the alimentary motivation the rats can escape the bufotenin influence, showing a normal behavior; bufotenin does not influence the sensorials, the natural dispositions and the excitability level of the feeding and satiety hypothalamic centers. Bufotenin increases serotonin concentration only in the mesencephalic region, but not in the other studied regions. The results are interpreted as a primary bufotenin action on the serotoninic vasoconstrictive receptors at the mesencephalic level, thus disturbing the serotonin-releasing processes and possibly other chemical neurotransmitters.
Animals↗
Dual mechanism of the stimulant action of N,N-dimethyl-5-hydroxy-tryptamine (bufotenine) on cardiac sympathetic nerves.
The indirect sympathomimetic effects of N,N-dimethyl-5-hydroxytryptamine (bufotenine) have been analysed on the rabbit heart perfused in vitro by the Langendorff technique. Comparisons have been made with the effects of 5-hydroxytryptamine (5-HT), which activates tryptamine receptors, and dimethylphenylpiperazinium (DMPP), which stimulates nicotine receptors. Bufotenine, 5-HT and DMPP stimulated the rate and force of cardiac contraction but whereas all were powerful stimulants of cardiac rate, bufotenine and DMPP were much stronger stimulants of atrial and particularly ventricular tension than 5-HT. Responses to 5-HT were markedly reduced by perfusion of hearts with an excess of 5-HT, and those to DMPP, during perfusion with hexamethonium. A combination of 5-HT with hexamethonium was necessary to abolish the effects of bufotenine. The data suggest a dual mechanism of stimulant action of bufotenine on the cardiac sympathetic nerves of the rabbit heart involving activation of receptors sensitive to 5-HT and nicotine receptors.
Animals↗
Potentially hallucinogenic 5-hydroxytryptamine receptor ligands bufotenine and dimethyltryptamine in blood and tissues.
Bufotenine and N,N-dimethyltryptamine (DMT) are hallucinogenic dimethylated indolethylamines (DMIAs) formed from serotonin and tryptamine by the enzyme indolethylamine N-methyltransferase (INMT) ubiquitously present in non-neural tissues. In mammals, endogenous bufotenine and DMT have been identified only in human urine. The DMIAs bind effectively to 5HT receptors and their administration causes a variety of autonomic effects, which may reflect their actual physiological function. Endogenous levels of bufotenine and DMT in blood and a number of animal and human tissues were determined using highly sensitive and specific quantitative mass spectrometric techniques. A new finding was the detection of large amounts of bufotenine in stools, which may be an indication of its role in intestinal function. It is suggested that fecal and urinary bufotenine originate from epithelial cells of the intestine and the kidney, respectively, although the possibility of their synthesis by intestinal bacteria cannot be excluded. Only small amounts of the DMIAs were found in somatic or neural tissues and none in blood. This can be explained by rapid catabolism of the DMIAs by mitochondrial monoamino-oxidase or by the fact that the dimethylated products of serotonin and tryptamine are not formed in significant amounts in most mammalian tissues despite the widespread presence of INMT in tissues.
Animals↗
The presence of free and conjugated bufotenin in normal human urine.
The N,N-dimethylated derivative of serotonin, bufotenin , is excreted into normal human urine as a free amine. Conjugation of bufotenin is, however, possible because of the phenolic hydroxyl group on the molecule. In the present study the urinary excretion of free and conjugated bufotenin of ten healthy, drug free subjects was examined. Acid as well as enzymatic hydrolysis was used to liberate the amine from its conjugate. Quantification was achieved by isotope dilution mass fragmentography. Of total urinary bufotenin a relatively constant amount, 59.9 - 69.0%, was excreted in conjugated form. The conjugate was tentatively identified as a glucuronide.
Bufotenin↗
Comparison of solution conformational preferences for the hallucinogens bufotenin and psilocin using 360-MHz proton NMR spectroscopy.
The 360-MHz 1H NMR spectra of bufotenin and psilocin were obtained, both as the free bases in CDCl3 and as protonated salts in D2O. Coupling constants for the side-chain methylenes were derived using the LAOCN3 program. These time-averaged coupling constants indicate that the trans and gauche rotamers of both compounds have about equal energy in D2O. There is a slight excess of the trans rotamer of bufotenin in CDCl3. For psilocin, in contrast, the gauche form is highly favored in CDCl3. The magnitude of this stabilization was estimated at about 1 kcal/mol using rotamer populations and free energy of transfer from published partitioning studies. It is suggested that this could result from a very weak hydrogen bond. On the other hand, the difference in partitioning between bufotenin and psilocin, which seems to be a major determinant of biological activity, is largely due to a difference in the basicity of the two compounds. The pKa values for the amino group of psilocin and bufotenin were determined to be 8.47 and 9.67, respectively.
Bufotenin↗
Bufo toads and bufotenine: fact and fiction surrounding an alleged psychedelic.
This paper investigates the supposedly psychedelic Bufo toad and the allegedly psychedelic drug bufotenine, which is contained in the skin and glands of this toad. The bufo toad has held a place in human mythologies and medicines worldwide since archaic times. Used by ancient peoples for a variety of purposes, its most spectacular effects, according to lore, involve magical and shamanic or occult uses for casting spells and for divination. In the Middle Ages, the Bufo toad was celebrated as a panacea and persecuted as a powerful poison. More recently, in the 1960s the Bufo toad was resurrected as a countercultural icon, with people purportedly licking or smoking the secretions to get high. Bufotenine has been at the center of a scientific debate since its discovery in 1893. This paper examines the extensive literature surrounding the Bufo toad and bufotenine, and untangles many of the myths and the misinformation that continue to vex both science and popular reporting. Finally, to promote further investigation, a comprehensive bibliography is provided that charts the history of the Bufo toad and bufotenine.
Animals↗
Carbon 11 labeling of the psychoactive drug o-methyl-bufotenine and its distribution in the animal organism.
A methylated derivative of serotonin, O-methyl-bufotenine has been labeled with 11C on the two methyl groups of the amine function. In order to avoid the cyclization which occurs during the Eschweiler-Clarke synthesis, we adopted a milder methylation procedure, based on Borch's method using [11C]formaldehyde and sodium cyanoborohydride. Several tens of millicuries of injectable product could be obtained in 50 min in a perfectly pure state and having a specific radioactivity of 50 to 100 mCi/mumol. The distribution study of O-methyl-bufotenine in the mouse and rabbit showed an accumulation of significant quantities of the compound in the brain, kidneys, lungs and liver. The study of the rapid kinetics of this hallucinogenic molecule is compatible with labeling by 11C, having a period of 20 min. The use of O-methyl-[11C]bufotenine to detect serotonin receptors in vivo in mental diseases, is considered.
Animals↗
Occurrence of bufotenin in the Osteocephalus genus (Anura: Hylidae).
Bufotenin (5-hydroxy-N,N-dimetyltryptamine) is a tryptamine alkaloid widely spread among anuran families as a component of their chemical defense system, acting as a potent hallucinogenic factor, showing similar activity to LSD upon interaction with the 5HT2 human receptor. This work demonstrates the presence of bufotenin in the skin secretion of three arboreal amphibian species of the Osteocephalus genus (Osteocephalus taurinus, Osteocephalus oophagus and Osteocephalus langsdorffii) from the Amazon and the Atlantic rain forests using RP-HPLC, ESI-MS/MS, UV, IR and multidimensional NMR techniques. To our knowledge, this is the first description of bufotenin in the Osteocephalus genus, so far.
Animals↗
Bufotenine esters.
Bufotenine (5-hydroxy-N,N-dimethyltryptamine) has been reported to be behaviorally inactive or only very weakly active in man and animals; this may be a consequence of its low partition coefficient and resultant inability to penetrate the blood--brain barrier. The acetyl, propionyl, butyryl, isobutyryl, and pivalyl esters of bufotenine were prepared for future pharmacological evaluation. Unexpectedly, it was found that these esters all possess a relatively high affinity for the serotonin receptors of the isolated rat stomach fundus preparation. A semiquantitative chromatographic measurement of ester hydrolysis suggests that extensive hydrolysis of the esters to bufotenine does not occur under the conditions of the affinity assay.
Animals↗
Pharmañopo-psychonautics: human intranasal, sublingual, intrarectal, pulmonary and oral pharmacology of bufotenine.
Summarized are psychonautic bioassays (human self-experiments) of pharmañopo--crystalline bufotenine (5-HO-DMT; 5-hydroxy-N,N-dimethyltryptamine; dimethylserotonine), at times combined with harmaline or harmine-via intranasal, sublingual, intrarectal, pulmonary (inhaled vapor) and oral routes. This is done by way of pharmacological modeling of diverse South American shamanic inebriants, principally the snuffs ñopolyopo and cebílhaáj, prepared from seeds of Anadenanthera peregrina var. peregrina and A. colubrina var. Cebil, respectively. Psychoptic (visionary) activity of bufotenine has been established and the 1967 Holmstedt-Lindgren hypothesis of the paricá effect-intranasal potentiation of tryptamines by concomitant administration of monoamine-oxidase-inhibiting (MAOI) beta-carbolines from stems of Banisteriopsis caapi admixed with the snuffs-has been confirmed by 25 psychonautic bioassays. Salient phytochemical and psychonautic literature is reviewed, and isolation of bufotenine from Anadenanthera seeds detailed (with one table and eight references).
Administration, Inhalation↗
Nialamide, an MAO inhibitor, increases urinary excretion of endogenously produced bufotenin in man.
Nialamide, an MAO inhibitor, was given per os (PO) to a normal man who volunteered in two separate trials (total intake 300 mg and 1000 mg, respectively), and his bufotenin excretion was followed by consecutive urine samples. In both experiments the excretion rose well above the values measured from the same test subject when not taking nialamide (median 0.089 nmol/mmol creatinine, range 0.002-1.78). At its highest, the excretion was 16.5 nmol/mmol creatinine, and the maximum urinary output was 495 nmoles (56 micrograms) in 24 hr. The levels of bufotenin in plasma required for the excretion of the latter amounts are not far from those that produce psychic symptoms in man.
Administration, Oral↗
Identification of 5-hydroxy-tryptamine (bufotenine) in takini (Brosimumacutifolium Huber subsp. acutifolium C.C. Berg, Moraceae), a shamanic potion used in the Guiana Plateau.
This paper is the first thorough analysis of takini, a hallucinogen used by the shamans of several peoples in Suriname, French Guiana, and the region east of the Para in Brazil. The drug is contained in the latex of the Brosimum acutifolium tree, and until now, its psychotropic properties appeared inconsistent with the more general medicinal uses of the tree in the surrounding region. Our chemical and botanical studies reveal that the active ingredient of takini is bufotenine; and that this compound is only contained in the subspecies Brosimum acutifolium Huber subsp. acutifolium C.C. Berg that is found in the same area of the eastern Guianas.
Bufotenin↗